Association of DRD4 promoter-associated methylation with mild cognitive impairment in Han and Uygur populations

Association of DRD4 promoter-associated methylation with mild cognitive impairment in Han and Uygur populations | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Association of DRD4 promoter-associated methylation with mild cognitive impairment in Han and Uygur populations Chunshuang Xu, Guili Liu, Huihui Ji, Qi Yao, Wei Cui, Shujun Xu, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6939122/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 26 Nov, 2025 Read the published version in European Journal of Medical Research → Version 1 posted 10 You are reading this latest preprint version Abstract Purpose Mild cognitive impairment (MCI), the symptomatic pre-dementia phase of Alzheimer’s disease, is characterized by objective or subjective memory impairment without affecting daily activity. Dopamine receptors play a pivotal role in the modulation of memory and cognitive functions. Our study focused on the association between DRD4 methylation and MCI in Uygur and Han populations. Patients and methods: Methylation was measured using bisulfite pyrosequencing. Results Our results indicated that MCI-related hypermethylation was detected in the Uygur (CpG 1) and Han (CpG 1–3) populations, and subgroup analyses by sex in the Uygur population indicated consistent results, while in the Han subgroup, DRD4 hypermethylation was only observed in the male group. Ethnic differences in CpG 4(CpG: Cytosine Phosphate Guanine)in male cases, CpG 1 in overall control and CpG 3 in male controls. Regional distinctions were shown between CpG 1 and CpG 4 in the male subgroup. Diverse correlations were observed. CpG 1 methylation in the Uygur male control, Uygur female case, and Han female control groups was significantly correlated with age, Glu, and HDL-C, respectively. CpG 2 in Uygur male controls and Uygur female patients showed correlations with Glu and TG levels. CpG 3 in Uygur male and Han male controls was significantly correlated with TC and HDL-C levels. CpG 4 in Uygur female controls and Han female patients correlated with Glu and age. Conclusion Our findings provide novel insights into DRD4 methylation in Uygur and Han populations. mild cognitive impairment dopamine receptor DRD4 DNA methylation peripheral blood Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Mild cognitive impairment (MCI), the symptomatic predementia phase of AD, is characterized by objective or subjective impairment of memory without affecting daily activity. 1 , 2 Approximately 12% of patients with MCI annually deteriorate into AD. 3 Various factors, including age, diet, hyperlipidemia, and abnormalities of genes contribute to the incidence of MCI. 4 , 5 Therefore, epigenetic mechanisms, deemed as the combined effects of genetic and environmental factors, arise in the exploration of disease. Moreover, recent studies have revealed the important roles of epigenetic alterations, especially DNA methylation, in the pathologies of mental diseases, 6 , 7 which could affect gene expression by adding a methyl group to cytosine from the CG context, especially in the gene promoter region. 8 Growing evidence suggests that DNA methylation modulates memory function by stabilizing the transcription and expression activities of neurons and synaptic plasticity and existing research has demonstrated that decreased global DNA methylation was shown in MCI, 9 , 10 and that BDNF and KLOTH methylation are involved in MCI. 11 – 13 Dopamine receptors are widely distributed in the brain and are involved in the pathology of mental disease. 14 – 16 Decreased expression of DA receptors, including D4R and D3R , were consistent in AD patients or AD mouse models with cognitive impairment. 17 – 19 Moreover, a previous epigenetic study showed that hypermethylation of DRD2 is associated with anorexia nervosa. 20 Others indicated that dopamine D3 receptors along with aberrant methylation modification in the gene body are associated with schizophrenia. 21 The dopamine D4 receptor, encoded by the DRD4 gene, is mainly scattered in the hippocampus, prefrontal cortex, and amygdala, 22 plays a pivotal role in modulating memory and cognitive function, and has been well-studied in heroin dependence, 23 – 25 schizophrenia, bipolar disorder, 26 and Parkinson's disease. 27 A previous study showed that polymorphisms in the DRD4 gene were associated with AD. 28 Others illustrated that DRD 4 expression could be inhibited by abnormal methylation. 29 In the present study, given the inaccessibility of brain tissue, we investigated the association between DRD4 promoter-associated methylation and MCI in blood samples from Han and Uygur populations. Materials and methods Subjects The participants were from the Xinjiang and Zhejiang regions of China, specifically 48 Uygur and Han individuals with mild cognitive impairment (MCI), along with 48 age- and sex-matched controls for each ethnic group. Personal information, including demographics, lifestyle, disease history, and physiological indices such as height, weight, blood pressure, blood glucose, and lipid profiles, were collected through a standardized epidemiological survey. Cognitive function was assessed using the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MOCA), Activities of Daily Living (ADL), and Hachinski Ischemic Scale (HIS). MCI was diagnosed by psychologists and neurologists according to the DSM-IV criteria. Participants were excluded if they had a history of mental illness, congenital mental retardation, depression, neurological disorders, head injury, specific medication use, severe infectious diseases, or toxic encephalopathy. Bisulfite pyrosequencing assay DNA extraction from preserved blood samples was performed using a nucleic acid extraction analyzer (Xiamen City, China). DNA concentration was quantified using a Nanodrop 2000. Bisulfite-converted DNA was then amplified using polymerase chain reaction (PyroMark PCR Kit; Qiagen). DRD4 methylation levels were measured using the PyroMark Q24 instrument. Statistical analyses Data were analyzed using SPSS version 16 (SPSS Inc., Chicago, IL, USA). Normality tests were performed using nonparametric tests. The two independent samples t-test was used to compare the methylation levels. Pearson’s correlation or Spearman’s correlation was used to assess whether there were correlations between the physiological–biochemical indices and methylation. Statistical significance was defined as a two-tailed p -value less than 0.05. Results DRD4 promoter-associated methylation was quantified using pyrosequencing. The target CpG sites showed different associations between ethnicities (Fig. 1 ). We compared DRD4 methylation levels between patients with MCI and controls based on ethnicity (Table 1 and Fig. 2 ). CpG 1 and CpG 1–3 in patients with MCI showed higher methylation levels than in controls in the Uygur and Han populations, respectively (Uygur: CpG 1, p = 1.96E-05; Han: CpG 1, p = 0.01, CpG 2, p = 4.88E-03, CpG 3, p = 4.64E-03). When stratified by sex, the Uygur population showed the same results as above (male: CpG 1, p = 8.84E-05; female CpG1, p = 0.02), whereas in the Han subgroup, males showed hypermethylation in MCI compared to controls (male: CpG 1, p = 0.04; CpG 2, p = 1.95E-04, CpG 3, p = 0.01; CpG 4, p = 0.02). Table 1 Case-control comparisons of DRD4 methylation levels Uygur Han class case control p case control p CpG1 13.81 ± 4.96 9.73 ± 3.87 1.96E-05 13.17 ± 4.84 12.13 ± 5.37 0.01 CpG2 10.73 ± 4.77 9.75 ± 4.64 0.31 12.02 ± 4.14 9.79 ± 4.48 4.88E-03 CpG3 14.60 ± 3.32 16.25 ± 5.46 0.08 15.00 ± 3.61 12.44 ± 4.99 4.64E-03 CpG4 13.65 ± 5.60 13.67 ± 4.57 0.98 15.46 ± 4.96 12.65 ± 4.53 0.07 male CpG1 13.88 ± 4.42 9.29 ± 2.79 8.84E-05 13.25 ± 4.58 10.75 ± 3.40 0.04 CpG2 10.00 ± 4.09 9.71 ± 4.42 0.81 12.83 ± 4.00 8.83 ± 2.73 1.95E-04 CpG3 13.92 ± 3.23 16.13 ± 4.93 0.07 15.25 ± 3.94 12.67 ± 2.81 0.01 CpG4 11.92 ± 5.27 14.29 ± 5.02 0.12 16.25 ± 5.46 13.04 ± 3.97 0.02 female CpG1 13.75 ± 5.54 10.17 ± 4.73 0.02 13.08 ± 5.18 13.50 ± 6.59 0.81 CpG2 11.46 ± 5.36 9.79 ± 4.94 0.27 11.21 ± 4.20 10.75 ± 5.63 0.75 CpG3 15.29 ± 3.34 16.38 ± 6.06 0.45 14.75 ± 3.31 12.21 ± 6.55 0.10 CpG4 15.38 ± 5.49 13.04 ± 4.09 0.10 14.67 ± 4.38 12.25 ± 5.08 0.08 In the present study, the subjects were Han and Uygur; therefore, comparisons based on ethnicity are shown in Table 2 and Fig. 3 In the overall analyses, significant differences were detected in CpG 1 and CpG 3 in the control group (CpG 1: p = 0.02, CpG 3: p = 5.65E-04). Stratified analyses based on sex showed that, for MCI patients, CpG 2 and CpG 4 harbored lower methylation levels in Uygur males than in Han males (CpG 2: p = 0.02, CpG 4: p = 7.45E-03), whereas, for controls, CpG 3 in both sexes showed higher methylation in Uygur subgroups (male: CpG 3, p = 5.01E-03, female: CpG 3, p = 0.03). However, when the analyses were adjusted for age, given the imbalance between the two ethnicities, the previous results were no longer significant except for CpG 4 in male patients and CpG 3 in male controls (CpG 4: p = 0.01, CpG 3: p = 0.03). Table 2 Ethnic comparisons of DRD4 methylation levels Case Uygur Han p adjusted p CpG1 13.81 ± 4.96 13.17 ± 4.84 0.52 0.37 CpG2 10.73 ± 4.77 12.02 ± 4.14 0.16 0.38 CpG3 14.60 ± 3.32 15.00 ± 3.61 0.58 0.85 CpG4 13.65 ± 5.60 15.46 ± 4.96 0.10 0.14 male CpG1 13.88 ± 4.42 13.25 ± 4.58 0.63 0.64 CpG2 10.00 ± 4.09 12.83 ± 4.00 0.02 0.07 CpG3 13.92 ± 3.23 15.25 ± 3.94 0.21 0.37 CpG4 11.92 ± 5.27 16.25 ± 5.46 7.45E-03 0.01 female CpG1 13.75 ± 5.54 13.08 ± 5.18 0.67 0.47 CpG2 11.46 ± 5.36 11.21 ± 4.20 0.86 0.71 CpG3 15.29 ± 3.34 14.75 ± 3.31 0.58 0.51 CpG4 15.38 ± 5.49 14.67 ± 4.38 0.62 0.28 Control CpG1 9.73 ± 3.87 12.13 ± 5.37 0.02 0.02 CpG2 9.75 ± 4.64 9.79 ± 4.48 0.96 0.95 CpG3 16.25 ± 5.46 12.44 ± 4.99 5.65E-04 0.09 CpG4 13.67 ± 4.57 12.65 ± 4.53 0.27 0.32 male CpG1 9.29 ± 2.79 10.75 ± 3.40 0.11 0.08 CpG2 9.71 ± 4.42 8.83 ± 2.73 0.41 0.75 CpG3 16.13 ± 4.93 12.67 ± 2.81 5.01E-03 0.03 CpG4 14.29 ± 5.02 13.04 ± 3.97 0.34 0.33 female CpG1 10.17 ± 4.73 13.50 ± 6.59 0.05 0.17 CpG2 9.79 ± 4.94 10.75 ± 5.63 0.53 0.88 CpG3 16.38 ± 6.06 12.21 ± 6.55 0.03 0.06 CpG4 13.04 ± 4.09 12.25 ± 5.08 0.56 0.75 Previous findings concerning Han controls from the Zhejiang region were used for comparisons with the Xinjiang Han population. As shown in Table 3 and Fig. 4 , CpG 1 and CpG 4 in the male group were significantly different between the two regions (CpG 1: p = 0.01, CpG 4: p = 0.04). Table 3 Comparisons of DRD4 methylation levels of control from Xinjiang and Zhejiang control Zhejiang Xinjiang p CpG1 13.37 ± 4.97 12.13 ± 5.37 0.21 CpG2 10.26 ± 4.01 9.79 ± 4.48 0.57 CpG3 12.69 ± 9.81 12.44 ± 4.99 0.87 CpG4 11.10 ± 5.06 12.65 ± 4.53 0.10 male CpG1 14.00 ± 4.93 10.75 ± 3.40 0.01 CpG2 10.56 ± 3.75 8.83 ± 2.73 0.05 CpG3 12.69 ± 11.10 12.67 ± 2.81 0.24 CpG4 10.62 ± 4.70 13.04 ± 3.97 0.04 female CpG1 11.71 ± 4.82 13.50 ± 6.59 0.35 CpG2 9.47 ± 4.67 10.75 ± 5.63 0.45 CpG3 12.71 ± 5.31 12.21 ± 6.55 0.80 CpG4 12.35 ± 5.88 12.25 ± 5.08 0.95 Moreover, we performed analyses related to sex differences. As shown in Table 4 , the current results demonstrated that sex was only associated with CpG 4 in Uygur patients (CpG 4: p = 0.03). Given the age imbalance between the two ethnicities in the control group, corrected analyses indicated sex differences in CpG1 (CpG 1: adjusted p = 4.46E-02). Table 4 Comparisons of DRD4 methylation levels between male and female case male female p CpG1 13.56 ± 4.46 13.42 ± 5.32 0.88 CpG2 11.42 ± 4.25 11.33 ± 4.76 0.93 CpG3 14.58 ± 3.63 15.02 ± 3.30 0.54 CpG4 14.08 ± 5.74 15.02 ± 4.93 0.39 Uygur case CpG1 13.88 ± 4.42 13.75 ± 5.54 0.93 CpG2 10.00 ± 4.09 11.46 ± 5.36 0.29 CpG3 13.92 ± 3.23 15.29 ± 3.34 0.15 CpG4 11.92 ± 5.27 15.38 ± 5.49 0.03 Han case CpG1 13.25 ± 4.58 13.08 ± 5.18 0.91 CpG2 12.83 ± 4.00 11.21 ± 4.20 0.18 CpG3 15.25 ± 3.94 14.75 ± 3.31 0.64 CpG4 16.25 ± 5.46 14.67 ± 4.38 0.27 Control * CpG1 10.02 ± 3.17 11.83 ± 5.92 0.06 CpG2 9.27 ± 3.66 10.27 ± 5.26 0.28 CpG3 14.40 ± 4.34 14.29 ± 6.58 0.93 CpG4 13.67 ± 4.52 12.65 ± 4.58 0.27 Uygur control CpG1 9.29 ± 2.79 10.17 ± 4.73 0.44 CpG2 9.71 ± 4.42 9.79 ± 4.94 0.95 CpG3 16.13 ± 4.93 16.38 ± 6.06 0.88 CpG4 14.29 ± 5.02 13.04 ± 4.09 0.35 Han control CpG1 10.75 ± 3.40 13.50 ± 6.59 0.08 CpG2 8.83 ± 2.73 10.75 ± 5.63 0.14 CpG3 12.67 ± 2.81 12.21 ± 6.55 0.75 CpG4 13.04 ± 3.97 12.25 ± 5.08 0.55 Note : Significant difference was only detected in CpG 1 site (CpG 1: p = 4.64E-02; CpG 2: p = 0.29; CpG 3: p = 0.68; CpG 4: p = 0.23) after adjusted by age given its imbalance between male controls and female controls ( p = 0.04) The correlation analyses between allelic methylation and physiobiochemical indices are shown in Supplementary Table S1 , and their visualization is shown in Figs. 5 and 6 . In the Han control group, HDL-C was significantly correlated with CpG 3 and CpG 1 methylation in males and females, respectively (CpG 3: r = 0.46, p = 0.02; CpG1: r = −0.46, p = 0.02). Moreover, age positively correlated with CpG 4 methylation level in female patients (r = 0.43, p = 0.04). These correlations were distinct in the Uyghur population. Age, Glu, and TC in male controls were significantly correlated with CpG 1, CpG 2, and CpG 3 methylation, respectively (CpG 1: r = −0.45, p = 0.03, CpG 2: r = 0.45, p = 0.03; CpG 3: r = 0.43, p = 0.04). Meanwhile, in the female group, Glu was significantly correlated with CpG 1 and CpG 4 methylation in the MCI and control groups, respectively (CpG 1: r = −0.43, p = 0.04; CpG 4: r = 0.55, p = 0.01), while TG levels were positively correlated with CpG1 and CpG 2 (CpG1: r = 0.64, p = 8.33E-04; CpG2: r = 0.52, p = 0.01). Discussion In the present study, we performed pyrosequencing analysis of DRD4 promoter methylation in patients with MCI and controls from the Uygur and Han populations. More importantly, assessment of DRD4 methylation levels under the effects of age, sex, and ethnicity has been the focus of current research. MCI-related hypermethylation was detected in the Uygur (CpG 1) and Han (CpG 1–3) population, and subgroup analyses by sex in the Uygur population indicated consistent results, while in the Han subgroup, DRD4 hypermethylation was only observed in the male group. Ethnic differences were detected in CpG 4 in male cases, CpG 1 in overall control, and CpG 3 in male controls. Regional distinctions were shown between CpG 1 and CpG 4 in the male subgroup. Diverse correlations were observed. CpG 1 methylation in the Uygur male control, Uygur female case, and Han female control groups was significantly correlated with age, Glu, and HDL-C, respectively. CpG 2 in Uygur male controls and Uygur female patients showed correlations with Glu and TG levels. CpG 3 in Uygur male and Han male controls was significantly correlated with TC and HDL-C levels. CpG 4 in Uygur female controls and Han female patients correlated with Glu and age. MCI, multi-pathogenesis psychiatric disease, could progress to various diseases such as Alzheimer’s disease, frontotemporal dementia, Lewy body disease, or vascular disease among them, AD possessed the highest conversion rate. 30 Increasing studies demonstrated that methylation was an important mechanism in memory formation and involved in the pathology of psychiatry diseases. 31 Memory associated genes such as PP1 and reelin showed different degrees of methylation, thus further influencing memory function through modulating their transcription and expression. 32 DRD4 explored in our study occupied an important role in mental disorders due to its modulation function in cognition and synaptic plasticity and pharmacological role in psychiatric disorders. 33 , 34 A study conducted by Unland et al. demonstrated that methylation of DRD4 ranging from 0.95–95.46% was detected in CNS tumors of childhood. 35 Previous findings demonstrated that hypomethylation in the DRD4 gene associated with hyperactivity disorder, 36 moreover, lately results have further revealed that epigenetic modification in particular sites is associated with the disease. 37 In our current study, results indicated that all significant sites were hypermethylated in MCI; thus we may hypothesize there is DRD4 suppression in MCI. Previous studies that focused on schizophrenia using methylation-specific PCR showed that aberrant methylation of DRD4 scarcely existed in brain sample. 38 Besides, the impact of gender on methylation was detected in the Han population; therefore, we deduced that CpG 1 may play a critical role in increasing the risk of MCI by lowering the expression of DRD4 . Further investigation of the influence of DRD4 hypermethylation on MCI is warranted. In the present study, ethnic disparities were detected only in the male subgroup. In the Uygur population, CpG 4 in the MCI group showed hypomethylation while CpG 3 in the control group was hypermethylated compared to the control group. Regional discrepancy analyses indicated significant differences in CpGs 1 and 4 in the male subgroups. Men and women differed in the incidence and progression of MCI. 39 Lastly, a study in Caucasian populations indicated that males tended to suffer from multiple diseases that elevated the risk of MCI . 40 Moreover, previous studies found that DRD4 polymorphism in the third exon had an effect on emotion-related behavior in a particular environment. 41 , 42 Religious beliefs, particularly in men with DRD4 polymorphism, showed an effect on individual behaviors. 41 Other than gender-specific differences, CpG 4 in Uygur cases and CpG 1 in overall controls showed gender differences. Methylation of CpG 1 in Uygur male controls was negatively correlated with age, in contrast with the positive correlation of CpG 4 methylation in Han female patients with age; simultaneously, this tendency was consistent with the results of our study. In addition, a previous study indicated an increased risk of MCI with age. 43 Glu, a known risk factor for MCI and AD, 44 showed a negative correlation with methylation of CpG 1 in Uygur female patients, whereas positive correlations in CpG 2 and CpG 4 methylation were observed separately in male and female from Uygur controls. This has aroused much interest in the Glu methylation interactions in MCI. Methylation of 1 and 3 showed opposite changes with increasing HDL-C in females and males from the Han control groups. The methylation of 3 increased with TC treatment in the Uygur male controls. The methylation of 1 and 3 in Uygur females increased with increasing TG levels. This study had several limitations. First, fewer sites were investigated; therefore, other target fragments in the promoter should be sequenced in future studies. Second, we excluded other confounding factors. Third, the combined actions of various indices should be explored. Conclusion In summary, hypermethylation in DRD4 was associated with MCI risk. Other confounding factors, including age, sex, and ethnicity, showed a potential risk of the disease. Correlations between DRD4 methylation and hematological indicators indicated the role of DRD4 methylation. Abbreviations MCI Mild cognitive impairment DRD4 Dopamine Receptor D4 AD Alzheimer’s Disease CpG Cytosine-phosphate-Guanine site Glu Glucose HDL-C High-Density Lipoprotein Cholesterol TG Triglyceride TC Total Cholesterol. Declarations Ethics Approval and Informed Consent Written informed consent was obtained from all participants, and the study was approved by the Ningbo University Medical Ethics Committee (No. NBU-2020-158). Acknowledgments We gratefully acknowledge the support of the First Affiliated Hospital of Xinjiang Medical University and Ningbo University Medical Ethics Committee for their approval. Special thanks go to the patients who participated in this trial for entrusting us with their health and time. Their participation is the cornerstone of our research, and we honor their contribution to medical advancement. We extend our sincere thanks to the pathophysiology graduate student team for their dedicated assistance and valuable insights throughout this research. Funding This work was supported by the Zhejiang Key Research and Development Project (2024C03101) and the National Natural Science Foundation of China (U1503223, 32171035), which was also sponsored by K. C. Wong Magna and funded by Ningbo University. Disclosure The authors report no conflicts of interest in this work. Author Contribution Author Contributions：Conceptualization: Huihui Ji. Data acquisition: Guili Liu, Qi Yao, Xiaohui Zhou. Formal analysis: Chunshuang Xu，Wei Cui, Shujun Xu,. Writing—original draft: Chunshuang Xu. Writing-review and editing: Jingbo Yu, Qinwen Wang. References Amini N, Ibn Hach M, Lapauw L, et al. Meta-analysis on the interrelationship between sarcopenia and mild cognitive impairment, Alzheimer’s disease and other forms of dementia. J Cachexia Sarcopenia Muscle 2024;15:1240–1253. Mian M, Tahiri J, Eldin R, et al. Overlooked cases of mild cognitive impairment: Implications to early Alzheimer’s disease. Ageing Res Rev 2024;98:102335. Wu Y, Wang X, Gu C, et al. Investigating predictors of progression from mild cognitive impairment to Alzheimer’s disease based on different time intervals. Age Ageing 2023;52:afad182. Hönig M, Altomare D, Caprioglio C, et al. Association Between Years of Education and Amyloid Burden in Patients With Subjective Cognitive Decline, MCI, and Alzheimer Disease. Neurology 2024;102:e208053. Niu Y-Y, Yan H-Y, Zhong J-F, et al. Association of dietary choline intake with incidence of dementia, Alzheimer disease, and mild cognitive impairment: a large population-based prospective cohort study. Am J Clin Nutr 2024;S0002-9165(24)00869–4. Smith RG, Pishva E, Kouhsar M, et al. Blood DNA methylomic signatures associated with CSF biomarkers of Alzheimer’s disease in the EMIF-AD study. Alzheimers Dement J Alzheimers Assoc 2024;20:6722–6739. Koetsier J, Cavill R, Reijnders R, et al. Blood‐based multivariate methylation risk score for cognitive impairment and dementia. Alzheimers Dement 2024;alz.14061. Hoang D-T, Shulman ED, Turakulov R, et al. Prediction of DNA methylation-based tumor types from histopathology in central nervous system tumors with deep learning. Nat Med 2024;30:1952–1961. Zhang X-X, Wei M, Wang H-R, et al. Mitochondrial dysfunction gene expression, DNA methylation, and inflammatory cytokines interaction activate Alzheimer’s disease: a multi-omics Mendelian randomization study. J Transl Med 2024;22:893. De Plano LM, Saitta A, Oddo S, et al. Epigenetic Changes in Alzheimer’s Disease: DNA Methylation and Histone Modification. Cells 2024;13:719. Zhang Y, Shen S. Epigenome-wide DNA methylation analysis of late-stage mild cognitive impairment. Front Cell Dev Biol 2024;12:1276288. Ma W, Zhou X, Ji H, et al. Population difference in the association of BDNF promoter methylation with mild cognitive impairment in the Xinjiang Uygur and Han populations. Psychiatry Res 2015;229:926–932. Luo M, Zhou X, Ji H, et al. Population Difference in the Associations of KLOTH Promoter Methylation with Mild Cognitive Impairment in Xinjiang Uygur and Han Populations. PloS One 2015;10:e0132156. Franco R, Reyes-Resina I, Navarro G. Dopamine in Health and Disease: Much More Than a Neurotransmitter. Biomedicines 2021;9:109. Poulin J-F, Gaertner Z, Moreno-Ramos OA, et al. Classification of Midbrain Dopamine Neurons Using Single-Cell Gene Expression Profiling Approaches. Trends Neurosci 2020;43:155–169. Zhao X, Huang Y, Chen K, et al. −141 C insertion/deletion polymorphism of the dopamine D 2 receptor gene is associated with schizophrenia in C hinese H an population: Evidence from an ethnic group‐specific meta‐analysis. Asia-Pac Psychiatry 2016;8:189–198. Su H, Wang X, Bai J, et al. Role of dopamine D3 receptors in methamphetamine-induced behavioural sensitization and the characterization of dopamine receptors (D1R-D5R) gene expression in the brain. Folia Neuropathol 2022;60:105–113. Kiss B, Laszlovszky I, Krámos B, et al. Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders. Biomolecules 2021;11:104. Ferré S, Belcher AM, Bonaventura J, et al. Functional and pharmacological role of the dopamine D4 receptor and its polymorphic variants. Front Endocrinol 2022;13:1014678. Käver L, Hinney A, Rajcsanyi LS, et al. Epigenetic alterations in patients with anorexia nervosa-a systematic review. Mol Psychiatry 2024;29:3900–3914. Dai D, Cheng J, Zhou K, et al. Significant association between DRD3 gene body methylation and schizophrenia. Psychiatry Res 2014;220:772–777. Kuang J, Kafetzopoulos V, Deth R, et al. Dopamine D4 Receptor Agonist Drastically Increases Delta Activity in the Thalamic Nucleus Reuniens: Potential Role in Communication between Prefrontal Cortex and Hippocampus. Int J Mol Sci 2023;24:15289. Latif S, Jahangeer M, Maknoon Razia D, et al. Dopamine in Parkinson’s disease. Clin Chim Acta Int J Clin Chem 2021;522:114–126. Kanarik M, Grimm O, Mota NR, et al. ADHD co-morbidities: A review of implication of gene environment effects with dopamine-related genes. Neurosci Biobehav Rev 2022;139:104757. Zhang R, Dang W, Zhang J, et al. Methylation quantitative locus rs3758653 in the DRD4 gene is associated with duration from first heroin exposure to addiction. Brain Res 2022;1775:147746. Bolat H, Ercan ES, Ünsel-Bolat G, et al. DRD4 genotyping may differentiate symptoms of attention-deficit/hyperactivity disorder and sluggish cognitive tempo. Rev Bras Psiquiatr Sao Paulo Braz 1999 2020;42:630–637. Paudel P, Choi JS, Prajapati R, et al. In Vitro Human Monoamine Oxidase Inhibition and Human Dopamine D4 Receptor Antagonist Effect of Natural Flavonoids for Neuroprotection. Int J Mol Sci 2023;24:15859. Ji H, Wang Y, Jiang D, et al. Elevated DRD4 promoter methylation increases the risk of Alzheimer’s disease in males. Mol Med Rep 2016;14:2732–2738. Unland R, Kerl K, Schlosser S, et al. Epigenetic repression of the dopamine receptor D4 in pediatric tumors of the central nervous system. J Neurooncol 2014;116:237–249. Amini N, Ibn Hach M, Lapauw L, et al. Meta-analysis on the interrelationship between sarcopenia and mild cognitive impairment, Alzheimer’s disease and other forms of dementia. J Cachexia Sarcopenia Muscle 2024;15:1240–1253. Hop PJ, Zwamborn RAJ, Hannon E, et al. Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS. Sci Transl Med 2022;14:eabj0264. Rudenko A, Tsai L-H. Epigenetic regulation in memory and cognitive disorders. Neuroscience 2014;264:51–63. Gilman TL, Ford MT, Jasnow AM, et al. DRD4 polymorphism associated with greater positive affect in response to negative and neutral social stimuli. Ann Hum Genet 2022;86:218–223. Taheri N, Pirboveiri R, Sayyah M, et al. Association of DRD2, DRD4 and COMT genes variants and their gene-gene interactions with antipsychotic treatment response in patients with schizophrenia. BMC Psychiatry 2023;23:781. Unland R, Kerl K, Schlosser S, et al. Epigenetic repression of the dopamine receptor D4 in pediatric tumors of the central nervous system. J Neurooncol 2014;116:237–249. Bolat H, Ercan ES, Ünsel-Bolat G, et al. DRD4 genotyping may differentiate symptoms of attention-deficit/hyperactivity disorder and sluggish cognitive tempo. Rev Bras Psiquiatr Sao Paulo Braz 1999 2020;42:630–637. Thursina C, Nurputra DK, Harahap ISK, et al. Determining the association between polymorphisms of the DAT1 and DRD4 genes with attention deficit hyperactivity disorder in children from Java Island. Neurol Int 2020;12:8292. Alelú-Paz R, González-Corpas A, Ashour N, et al. DNA methylation pattern of gene promoters of major neurotransmitter systems in older patients with schizophrenia with severe and mild cognitive impairment. Int J Geriatr Psychiatry 2015;30:558–565. Greenberg BD, Pettigrew C, Soldan A, et al. CSF Alzheimer Disease Biomarkers: Time-Varying Relationships With MCI Symptom Onset and Associations With Age, Sex, and ApoE4. Neurology 2022;99:e1640–e1650. Bai W, Chen P, Cai H, et al. Worldwide prevalence of mild cognitive impairment among community dwellers aged 50 years and older: a meta-analysis and systematic review of epidemiology studies. Age Ageing 2022;51:afac173. Jiang Y, Bachner-Melman R, Chew SH, et al. Dopamine D4 receptor gene and religious affiliation correlate with dictator game altruism in males and not females: evidence for gender-sensitive gene × culture interaction. Front Neurosci 2015;9:338. Uzefovsky F, Shalev I, Israel S, et al. The dopamine D4 receptor gene shows a gender-sensitive association with cognitive empathy: evidence from two independent samples. Emot Wash DC 2014;14:712–721. Li G, Toschi N, Devanarayan V, et al. The age-specific comorbidity burden of mild cognitive impairment: a US claims database study. Alzheimers Res Ther 2023;15:211. Zeng Z, He J, Yao T. Characteristic early changes of Glu and Cho in brain regions affected by different types of subjective cognitive decline and their clinical significance. Medicine (Baltimore) 2023;102:e36457. Additional Declarations No competing interests reported. Supplementary Files supplementarytable1.doc Cite Share Download PDF Status: Published Journal Publication published 26 Nov, 2025 Read the published version in European Journal of Medical Research → Version 1 posted Editorial decision: Revision requested 21 Jul, 2025 Reviews received at journal 10 Jul, 2025 Reviews received at journal 09 Jul, 2025 Reviewers agreed at journal 03 Jul, 2025 Reviewers agreed at journal 29 Jun, 2025 Reviewers agreed at journal 29 Jun, 2025 Reviewers invited by journal 24 Jun, 2025 Editor assigned by journal 21 Jun, 2025 Submission checks completed at journal 21 Jun, 2025 First submitted to journal 20 Jun, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6939122","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":476318643,"identity":"f315c0d4-b7ce-4925-9fd0-c1d58c1721ae","order_by":0,"name":"Chunshuang Xu","email":"","orcid":"","institution":"The First Affiliated Hospital，Ningbo University","correspondingAuthor":false,"prefix":"","firstName":"Chunshuang","middleName":"","lastName":"Xu","suffix":""},{"id":476318644,"identity":"9cdf3255-918b-4dfe-8c5b-02465635ba3d","order_by":1,"name":"Guili Liu","email":"","orcid":"","institution":"Ningbo Ninth Hospital","correspondingAuthor":false,"prefix":"","firstName":"Guili","middleName":"","lastName":"Liu","suffix":""},{"id":476318645,"identity":"61000ea6-8818-450d-bcc0-66e869fdf6a6","order_by":2,"name":"Huihui Ji","email":"","orcid":"","institution":"the Second Affiliated Hospital of Wenzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Huihui","middleName":"","lastName":"Ji","suffix":""},{"id":476318649,"identity":"77c318e0-b22c-4f9b-ad64-cccf77221727","order_by":3,"name":"Qi Yao","email":"","orcid":"","institution":"The First Affiliated Hospital，Ningbo University","correspondingAuthor":false,"prefix":"","firstName":"Qi","middleName":"","lastName":"Yao","suffix":""},{"id":476318650,"identity":"46163e03-42e5-4acb-92c3-48b9a2aa77c5","order_by":4,"name":"Wei Cui","email":"","orcid":"","institution":"Ningbo University","correspondingAuthor":false,"prefix":"","firstName":"Wei","middleName":"","lastName":"Cui","suffix":""},{"id":476318651,"identity":"02c65953-14f2-4686-8b46-664834fbe7ea","order_by":5,"name":"Shujun Xu","email":"","orcid":"","institution":"Ningbo University","correspondingAuthor":false,"prefix":"","firstName":"Shujun","middleName":"","lastName":"Xu","suffix":""},{"id":476318652,"identity":"73a9c32c-46a6-4a4f-ab7b-5b0e8f4dfa34","order_by":6,"name":"Xiaohui Zhou","email":"","orcid":"","institution":"the First Affiliated Hospital of Xinjiang Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xiaohui","middleName":"","lastName":"Zhou","suffix":""},{"id":476318653,"identity":"64f0b5ba-fff9-47c1-9cc4-3bbafa286bed","order_by":7,"name":"Jingbo Yu","email":"","orcid":"","institution":"The First Affiliated Hospital，Ningbo University","correspondingAuthor":false,"prefix":"","firstName":"Jingbo","middleName":"","lastName":"Yu","suffix":""},{"id":476318655,"identity":"47e821b7-83db-4fcd-a098-b1248f12a3f0","order_by":8,"name":"Qinwen Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA40lEQVRIiWNgGAWjYNACAxDBfIAZzDlAvBa2BFK0gAGPAXFaDI6fPfziTcGdxH7pnm+PC9sY5PhuJDB+LsCn5UxemuUcg2eJM+ec3W48s43BWPJGArP0DDxazA7kmBnzGBzO3XAjd5s0bxtD4oYbCWzMPPi0nH8D0bL/Rs4zkJZ6wlpu5Bg/BtsikcMG0pJgQEiL/Y03ZoxzDA7Xz7iRZiY945yE4cwzD5ul8WmR7M8x/vDmz2Fj/hnJz6QLymzk+Y4nH/yMTwsQsEkgKZAAYsYG/BqACeUDATNHwSgYBaNgpAMALXdN95O2lJMAAAAASUVORK5CYII=","orcid":"","institution":"The First Affiliated Hospital，Ningbo University","correspondingAuthor":true,"prefix":"","firstName":"Qinwen","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2025-06-20 12:53:42","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6939122/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6939122/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s40001-025-03416-3","type":"published","date":"2025-11-26T15:58:43+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":85824258,"identity":"453bd6d5-b8e9-41e6-a447-681daf59db87","added_by":"auto","created_at":"2025-07-02 07:00:32","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":403302,"visible":true,"origin":"","legend":"\u003cp\u003eSchematic representation of correlations among four sites in DRD4 promoters by ethnicity.\u003c/p\u003e\n\u003cp\u003e*denotes a correlation with a lack of significance.\u003c/p\u003e","description":"","filename":"figure1.tif.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6939122/v1/c28ab78d8948280151ea7e79.jpg"},{"id":85822073,"identity":"126cebfb-e370-4189-894d-647dd7bff4de","added_by":"auto","created_at":"2025-07-02 06:44:32","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":840648,"visible":true,"origin":"","legend":"\u003cp\u003eCase-control comparisons of DRD4 methylation levels by ethnicity.\u003c/p\u003e\n\u003cp\u003eMethylation of the four sites was compared between the MCI and control groups, where distinct significant differences were detected in the Uygur and Han populations, and further subgroup analyses by sex showed sex differences in the Uygur population.\u003c/p\u003e","description":"","filename":"figure2.tif.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6939122/v1/00089b3f30a4fd39250537ac.jpg"},{"id":85822996,"identity":"63e2a3aa-a958-4477-9a09-c806bc875ea5","added_by":"auto","created_at":"2025-07-02 06:52:32","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":828702,"visible":true,"origin":"","legend":"\u003cp\u003eEthnic comparisons of DRD4 methylation levels.\u003c/p\u003e\n\u003cp\u003eAge-adjusted methylation of four sites was compared between the two ethnic groups separately in the MCI and control groups, and significant differences were detected in the overall analyses of CpG 1 in the control group; further subgroup analyses by sex showed sex-specific differences in the CpG 4 site in patients and CpG 3 in controls.\u003c/p\u003e","description":"","filename":"figure3.tif.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6939122/v1/409e689ddf6f8750794b05c6.jpg"},{"id":85822082,"identity":"9836b786-de47-48ff-870a-373c1e487f3c","added_by":"auto","created_at":"2025-07-02 06:44:32","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":401929,"visible":true,"origin":"","legend":"\u003cp\u003eComparisons of DRD4 methylation levels between the Xinjiang and Zhejiang regions.\u003c/p\u003e\n\u003cp\u003eRegional differences were detected in CpG 1 and CpG 4 in males.\u003c/p\u003e","description":"","filename":"figure4.tif.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6939122/v1/ca05f083f8c708d90bebd129.jpg"},{"id":85822995,"identity":"2a153fa2-e3ad-432c-93dd-78ed7fdb581e","added_by":"auto","created_at":"2025-07-02 06:52:32","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":278459,"visible":true,"origin":"","legend":"\u003cp\u003eCorrelations of allele-specific methylation and baseline indexes in the Uygur population.\u003c/p\u003e","description":"","filename":"figure5.tif.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6939122/v1/46cf9579168c546b8ab39e07.jpg"},{"id":85823000,"identity":"2a23a126-1e92-465b-a477-874c902cf483","added_by":"auto","created_at":"2025-07-02 06:52:32","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":115504,"visible":true,"origin":"","legend":"\u003cp\u003eCorrelations of allele-specific methylation and baseline indexes in the Han population.\u003c/p\u003e","description":"","filename":"figure6.tif.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6939122/v1/84091fdaa9a10136f4975be0.jpg"},{"id":97179347,"identity":"3f804e10-c2f7-4f94-87ac-68e9e8f72b05","added_by":"auto","created_at":"2025-12-01 16:14:53","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3723098,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6939122/v1/b01ed934-7a9b-4e8f-a8f4-fbba63b7938e.pdf"},{"id":85822992,"identity":"d6344513-617a-416a-8de9-44ad83658f6f","added_by":"auto","created_at":"2025-07-02 06:52:31","extension":"doc","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":78848,"visible":true,"origin":"","legend":"","description":"","filename":"supplementarytable1.doc","url":"https://assets-eu.researchsquare.com/files/rs-6939122/v1/7959b76acd1cccfd34f2014c.doc"}],"financialInterests":"No competing interests reported.","formattedTitle":"Association of DRD4 promoter-associated methylation with mild cognitive impairment in Han and Uygur populations","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMild cognitive impairment (MCI), the symptomatic predementia phase of AD, is characterized by objective or subjective impairment of memory without affecting daily activity.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Approximately 12% of patients with MCI annually deteriorate into AD.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e Various factors, including age, diet, hyperlipidemia, and abnormalities of genes contribute to the incidence of MCI.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e Therefore, epigenetic mechanisms, deemed as the combined effects of genetic and environmental factors, arise in the exploration of disease. Moreover, recent studies have revealed the important roles of epigenetic alterations, especially DNA methylation, in the pathologies of mental diseases,\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e which could affect gene expression by adding a methyl group to cytosine from the CG context, especially in the gene promoter region.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Growing evidence suggests that DNA methylation modulates memory function by stabilizing the transcription and expression activities of neurons and synaptic plasticity and existing research has demonstrated that decreased global DNA methylation was shown in MCI,\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e and that \u003cem\u003eBDNF\u003c/em\u003e and \u003cem\u003eKLOTH\u003c/em\u003e methylation are involved in MCI.\u003csup\u003e\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eDopamine receptors are widely distributed in the brain and are involved in the pathology of mental disease.\u003csup\u003e\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e Decreased expression of DA receptors, including \u003cem\u003eD4R\u003c/em\u003e and \u003cem\u003eD3R\u003c/em\u003e, were consistent in AD patients or AD mouse models with cognitive impairment.\u003csup\u003e\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e Moreover, a previous epigenetic study showed that hypermethylation of \u003cem\u003eDRD2\u003c/em\u003e is associated with anorexia nervosa.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e Others indicated that dopamine \u003cem\u003eD3\u003c/em\u003e receptors along with aberrant methylation modification in the gene body are associated with schizophrenia.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e The dopamine D4 receptor, encoded by the \u003cem\u003eDRD4\u003c/em\u003e gene, is mainly scattered in the hippocampus, prefrontal cortex, and amygdala,\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e plays a pivotal role in modulating memory and cognitive function, and has been well-studied in heroin dependence,\u003csup\u003e\u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e schizophrenia, bipolar disorder,\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e and Parkinson's disease.\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e A previous study showed that polymorphisms in the \u003cem\u003eDRD4\u003c/em\u003e gene were associated with AD.\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e Others illustrated that \u003cem\u003eDRD\u003c/em\u003e4 expression could be inhibited by abnormal methylation.\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn the present study, given the inaccessibility of brain tissue, we investigated the association between \u003cem\u003eDRD4\u003c/em\u003e promoter-associated methylation and MCI in blood samples from Han and Uygur populations.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSubjects\u003c/h2\u003e \u003cp\u003eThe participants were from the Xinjiang and Zhejiang regions of China, specifically 48 Uygur and Han individuals with mild cognitive impairment (MCI), along with 48 age- and sex-matched controls for each ethnic group. Personal information, including demographics, lifestyle, disease history, and physiological indices such as height, weight, blood pressure, blood glucose, and lipid profiles, were collected through a standardized epidemiological survey. Cognitive function was assessed using the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MOCA), Activities of Daily Living (ADL), and Hachinski Ischemic Scale (HIS). MCI was diagnosed by psychologists and neurologists according to the DSM-IV criteria. Participants were excluded if they had a history of mental illness, congenital mental retardation, depression, neurological disorders, head injury, specific medication use, severe infectious diseases, or toxic encephalopathy.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eBisulfite pyrosequencing assay\u003c/h3\u003e\n\u003cp\u003eDNA extraction from preserved blood samples was performed using a nucleic acid extraction analyzer (Xiamen City, China). DNA concentration was quantified using a Nanodrop 2000. Bisulfite-converted DNA was then amplified using polymerase chain reaction (PyroMark PCR Kit; Qiagen). DRD4 methylation levels were measured using the PyroMark Q24 instrument.\u003c/p\u003e\n\u003ch3\u003eStatistical analyses\u003c/h3\u003e\n\u003cp\u003eData were analyzed using SPSS version 16 (SPSS Inc., Chicago, IL, USA). Normality tests were performed using nonparametric tests. The two independent samples t-test was used to compare the methylation levels. Pearson\u0026rsquo;s correlation or Spearman\u0026rsquo;s correlation was used to assess whether there were correlations between the physiological\u0026ndash;biochemical indices and methylation. Statistical significance was defined as a two-tailed \u003cem\u003ep\u003c/em\u003e-value less than 0.05.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eDRD4 promoter-associated methylation was quantified using pyrosequencing. The target CpG sites showed different associations between ethnicities (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eWe compared DRD4 methylation levels between patients with MCI and controls based on ethnicity (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). CpG 1 and CpG 1\u0026ndash;3 in patients with MCI showed higher methylation levels than in controls in the Uygur and Han populations, respectively (Uygur: CpG 1, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.96E-05; Han: CpG 1, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.01, CpG 2, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.88E-03, CpG 3, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.64E-03). When stratified by sex, the Uygur population showed the same results as above (male: CpG 1, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.84E-05; female CpG1, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.02), whereas in the Han subgroup, males showed hypermethylation in MCI compared to controls (male: CpG 1, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.04; CpG 2, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.95E-04, CpG 3, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.01; CpG 4, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.02).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCase-control comparisons of \u003cem\u003eDRD4\u003c/em\u003e methylation levels\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUygur\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHan\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eclass\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ecase\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003econtrol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ecase\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003econtrol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13.81\u0026thinsp;\u0026plusmn;\u0026thinsp;4.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.73\u0026thinsp;\u0026plusmn;\u0026thinsp;3.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e1.96E-05\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13.17\u0026thinsp;\u0026plusmn;\u0026thinsp;4.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12.13\u0026thinsp;\u0026plusmn;\u0026thinsp;5.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.01\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.73\u0026thinsp;\u0026plusmn;\u0026thinsp;4.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.75\u0026thinsp;\u0026plusmn;\u0026thinsp;4.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12.02\u0026thinsp;\u0026plusmn;\u0026thinsp;4.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9.79\u0026thinsp;\u0026plusmn;\u0026thinsp;4.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e4.88E-03\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14.60\u0026thinsp;\u0026plusmn;\u0026thinsp;3.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16.25\u0026thinsp;\u0026plusmn;\u0026thinsp;5.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15.00\u0026thinsp;\u0026plusmn;\u0026thinsp;3.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12.44\u0026thinsp;\u0026plusmn;\u0026thinsp;4.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e4.64E-03\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13.65\u0026thinsp;\u0026plusmn;\u0026thinsp;5.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13.67\u0026thinsp;\u0026plusmn;\u0026thinsp;4.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15.46\u0026thinsp;\u0026plusmn;\u0026thinsp;4.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12.65\u0026thinsp;\u0026plusmn;\u0026thinsp;4.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13.88\u0026thinsp;\u0026plusmn;\u0026thinsp;4.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.29\u0026thinsp;\u0026plusmn;\u0026thinsp;2.79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e8.84E-05\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13.25\u0026thinsp;\u0026plusmn;\u0026thinsp;4.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e10.75\u0026thinsp;\u0026plusmn;\u0026thinsp;3.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.04\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.00\u0026thinsp;\u0026plusmn;\u0026thinsp;4.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.71\u0026thinsp;\u0026plusmn;\u0026thinsp;4.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12.83\u0026thinsp;\u0026plusmn;\u0026thinsp;4.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8.83\u0026thinsp;\u0026plusmn;\u0026thinsp;2.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e1.95E-04\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13.92\u0026thinsp;\u0026plusmn;\u0026thinsp;3.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16.13\u0026thinsp;\u0026plusmn;\u0026thinsp;4.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15.25\u0026thinsp;\u0026plusmn;\u0026thinsp;3.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12.67\u0026thinsp;\u0026plusmn;\u0026thinsp;2.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.01\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.92\u0026thinsp;\u0026plusmn;\u0026thinsp;5.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14.29\u0026thinsp;\u0026plusmn;\u0026thinsp;5.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16.25\u0026thinsp;\u0026plusmn;\u0026thinsp;5.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e13.04\u0026thinsp;\u0026plusmn;\u0026thinsp;3.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.02\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003efemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13.75\u0026thinsp;\u0026plusmn;\u0026thinsp;5.54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10.17\u0026thinsp;\u0026plusmn;\u0026thinsp;4.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.02\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13.08\u0026thinsp;\u0026plusmn;\u0026thinsp;5.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e13.50\u0026thinsp;\u0026plusmn;\u0026thinsp;6.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.81\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.46\u0026thinsp;\u0026plusmn;\u0026thinsp;5.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.79\u0026thinsp;\u0026plusmn;\u0026thinsp;4.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11.21\u0026thinsp;\u0026plusmn;\u0026thinsp;4.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e10.75\u0026thinsp;\u0026plusmn;\u0026thinsp;5.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15.29\u0026thinsp;\u0026plusmn;\u0026thinsp;3.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16.38\u0026thinsp;\u0026plusmn;\u0026thinsp;6.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e14.75\u0026thinsp;\u0026plusmn;\u0026thinsp;3.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12.21\u0026thinsp;\u0026plusmn;\u0026thinsp;6.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15.38\u0026thinsp;\u0026plusmn;\u0026thinsp;5.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13.04\u0026thinsp;\u0026plusmn;\u0026thinsp;4.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e14.67\u0026thinsp;\u0026plusmn;\u0026thinsp;4.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12.25\u0026thinsp;\u0026plusmn;\u0026thinsp;5.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn the present study, the subjects were Han and Uygur; therefore, comparisons based on ethnicity are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e In the overall analyses, significant differences were detected in CpG 1 and CpG 3 in the control group (CpG 1: \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.02, CpG 3: \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5.65E-04). Stratified analyses based on sex showed that, for MCI patients, CpG 2 and CpG 4 harbored lower methylation levels in Uygur males than in Han males (CpG 2: \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.02, CpG 4: \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7.45E-03), whereas, for controls, CpG 3 in both sexes showed higher methylation in Uygur subgroups (male: CpG 3, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5.01E-03, female: CpG 3, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.03). However, when the analyses were adjusted for age, given the imbalance between the two ethnicities, the previous results were no longer significant except for CpG 4 in male patients and CpG 3 in male controls (CpG 4: \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.01, CpG 3: \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.03).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eEthnic comparisons of \u003cem\u003eDRD4\u003c/em\u003e methylation levels\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUygur\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHan\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eadjusted \u003cem\u003ep\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e13.81\u0026thinsp;\u0026plusmn;\u0026thinsp;4.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e13.17\u0026thinsp;\u0026plusmn;\u0026thinsp;4.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.37\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e10.73\u0026thinsp;\u0026plusmn;\u0026thinsp;4.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e12.02\u0026thinsp;\u0026plusmn;\u0026thinsp;4.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.38\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e14.60\u0026thinsp;\u0026plusmn;\u0026thinsp;3.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e15.00\u0026thinsp;\u0026plusmn;\u0026thinsp;3.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.85\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e13.65\u0026thinsp;\u0026plusmn;\u0026thinsp;5.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e15.46\u0026thinsp;\u0026plusmn;\u0026thinsp;4.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.14\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e13.88\u0026thinsp;\u0026plusmn;\u0026thinsp;4.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e13.25\u0026thinsp;\u0026plusmn;\u0026thinsp;4.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.64\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e10.00\u0026thinsp;\u0026plusmn;\u0026thinsp;4.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e12.83\u0026thinsp;\u0026plusmn;\u0026thinsp;4.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.02\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e13.92\u0026thinsp;\u0026plusmn;\u0026thinsp;3.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e15.25\u0026thinsp;\u0026plusmn;\u0026thinsp;3.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.37\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e11.92\u0026thinsp;\u0026plusmn;\u0026thinsp;5.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e16.25\u0026thinsp;\u0026plusmn;\u0026thinsp;5.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e7.45E-03\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.01\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003efemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e13.75\u0026thinsp;\u0026plusmn;\u0026thinsp;5.54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e13.08\u0026thinsp;\u0026plusmn;\u0026thinsp;5.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.47\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e11.46\u0026thinsp;\u0026plusmn;\u0026thinsp;5.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e11.21\u0026thinsp;\u0026plusmn;\u0026thinsp;4.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.71\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e15.29\u0026thinsp;\u0026plusmn;\u0026thinsp;3.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e14.75\u0026thinsp;\u0026plusmn;\u0026thinsp;3.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.51\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e15.38\u0026thinsp;\u0026plusmn;\u0026thinsp;5.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e14.67\u0026thinsp;\u0026plusmn;\u0026thinsp;4.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.28\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e9.73\u0026thinsp;\u0026plusmn;\u0026thinsp;3.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e12.13\u0026thinsp;\u0026plusmn;\u0026thinsp;5.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.02\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.02\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e9.75\u0026thinsp;\u0026plusmn;\u0026thinsp;4.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e9.79\u0026thinsp;\u0026plusmn;\u0026thinsp;4.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.95\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e16.25\u0026thinsp;\u0026plusmn;\u0026thinsp;5.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e12.44\u0026thinsp;\u0026plusmn;\u0026thinsp;4.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e5.65E-04\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.09\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e13.67\u0026thinsp;\u0026plusmn;\u0026thinsp;4.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e12.65\u0026thinsp;\u0026plusmn;\u0026thinsp;4.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.32\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e9.29\u0026thinsp;\u0026plusmn;\u0026thinsp;2.79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e10.75\u0026thinsp;\u0026plusmn;\u0026thinsp;3.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e9.71\u0026thinsp;\u0026plusmn;\u0026thinsp;4.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e8.83\u0026thinsp;\u0026plusmn;\u0026thinsp;2.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e16.13\u0026thinsp;\u0026plusmn;\u0026thinsp;4.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e12.67\u0026thinsp;\u0026plusmn;\u0026thinsp;2.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e5.01E-03\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.03\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e14.29\u0026thinsp;\u0026plusmn;\u0026thinsp;5.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e13.04\u0026thinsp;\u0026plusmn;\u0026thinsp;3.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003efemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e10.17\u0026thinsp;\u0026plusmn;\u0026thinsp;4.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e13.50\u0026thinsp;\u0026plusmn;\u0026thinsp;6.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e9.79\u0026thinsp;\u0026plusmn;\u0026thinsp;4.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e10.75\u0026thinsp;\u0026plusmn;\u0026thinsp;5.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.88\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e16.38\u0026thinsp;\u0026plusmn;\u0026thinsp;6.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e12.21\u0026thinsp;\u0026plusmn;\u0026thinsp;6.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.03\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e13.04\u0026thinsp;\u0026plusmn;\u0026thinsp;4.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e12.25\u0026thinsp;\u0026plusmn;\u0026thinsp;5.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003ePrevious findings concerning Han controls from the Zhejiang region were used for comparisons with the Xinjiang Han population. As shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, CpG 1 and CpG 4 in the male group were significantly different between the two regions (CpG 1: \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.01, CpG 4: \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.04).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparisons of \u003cem\u003eDRD4\u003c/em\u003e methylation levels of control from Xinjiang and Zhejiang\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003econtrol\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eZhejiang\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eXinjiang\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e13.37\u0026thinsp;\u0026plusmn;\u0026thinsp;4.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e12.13\u0026thinsp;\u0026plusmn;\u0026thinsp;5.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e10.26\u0026thinsp;\u0026plusmn;\u0026thinsp;4.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e9.79\u0026thinsp;\u0026plusmn;\u0026thinsp;4.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.57\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e12.69\u0026thinsp;\u0026plusmn;\u0026thinsp;9.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e12.44\u0026thinsp;\u0026plusmn;\u0026thinsp;4.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.87\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e11.10\u0026thinsp;\u0026plusmn;\u0026thinsp;5.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e12.65\u0026thinsp;\u0026plusmn;\u0026thinsp;4.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e14.00\u0026thinsp;\u0026plusmn;\u0026thinsp;4.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e10.75\u0026thinsp;\u0026plusmn;\u0026thinsp;3.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.01\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e10.56\u0026thinsp;\u0026plusmn;\u0026thinsp;3.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e8.83\u0026thinsp;\u0026plusmn;\u0026thinsp;2.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e12.69\u0026thinsp;\u0026plusmn;\u0026thinsp;11.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e12.67\u0026thinsp;\u0026plusmn;\u0026thinsp;2.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e10.62\u0026thinsp;\u0026plusmn;\u0026thinsp;4.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e13.04\u0026thinsp;\u0026plusmn;\u0026thinsp;3.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.04\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003efemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e11.71\u0026thinsp;\u0026plusmn;\u0026thinsp;4.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e13.50\u0026thinsp;\u0026plusmn;\u0026thinsp;6.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.35\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e9.47\u0026thinsp;\u0026plusmn;\u0026thinsp;4.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e10.75\u0026thinsp;\u0026plusmn;\u0026thinsp;5.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.45\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e12.71\u0026thinsp;\u0026plusmn;\u0026thinsp;5.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e12.21\u0026thinsp;\u0026plusmn;\u0026thinsp;6.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.80\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e12.35\u0026thinsp;\u0026plusmn;\u0026thinsp;5.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e12.25\u0026thinsp;\u0026plusmn;\u0026thinsp;5.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.95\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eMoreover, we performed analyses related to sex differences. As shown in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, the current results demonstrated that sex was only associated with CpG 4 in Uygur patients (CpG 4: \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.03). Given the age imbalance between the two ethnicities in the control group, corrected analyses indicated sex differences in CpG1 (CpG 1: adjusted \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.46E-02).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparisons of \u003cem\u003eDRD4\u003c/em\u003e methylation levels between male and female\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecase\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003emale\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003efemale\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e13.56\u0026thinsp;\u0026plusmn;\u0026thinsp;4.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e13.42\u0026thinsp;\u0026plusmn;\u0026thinsp;5.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.88\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e11.42\u0026thinsp;\u0026plusmn;\u0026thinsp;4.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e11.33\u0026thinsp;\u0026plusmn;\u0026thinsp;4.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.93\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e14.58\u0026thinsp;\u0026plusmn;\u0026thinsp;3.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e15.02\u0026thinsp;\u0026plusmn;\u0026thinsp;3.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.54\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e14.08\u0026thinsp;\u0026plusmn;\u0026thinsp;5.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e15.02\u0026thinsp;\u0026plusmn;\u0026thinsp;4.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.39\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUygur case\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e13.88\u0026thinsp;\u0026plusmn;\u0026thinsp;4.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e13.75\u0026thinsp;\u0026plusmn;\u0026thinsp;5.54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.93\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e10.00\u0026thinsp;\u0026plusmn;\u0026thinsp;4.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e11.46\u0026thinsp;\u0026plusmn;\u0026thinsp;5.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.29\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e13.92\u0026thinsp;\u0026plusmn;\u0026thinsp;3.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e15.29\u0026thinsp;\u0026plusmn;\u0026thinsp;3.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e11.92\u0026thinsp;\u0026plusmn;\u0026thinsp;5.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e15.38\u0026thinsp;\u0026plusmn;\u0026thinsp;5.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.03\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHan case\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e13.25\u0026thinsp;\u0026plusmn;\u0026thinsp;4.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e13.08\u0026thinsp;\u0026plusmn;\u0026thinsp;5.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.91\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e12.83\u0026thinsp;\u0026plusmn;\u0026thinsp;4.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e11.21\u0026thinsp;\u0026plusmn;\u0026thinsp;4.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e15.25\u0026thinsp;\u0026plusmn;\u0026thinsp;3.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e14.75\u0026thinsp;\u0026plusmn;\u0026thinsp;3.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.64\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e16.25\u0026thinsp;\u0026plusmn;\u0026thinsp;5.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e14.67\u0026thinsp;\u0026plusmn;\u0026thinsp;4.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eControl\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e10.02\u0026thinsp;\u0026plusmn;\u0026thinsp;3.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e11.83\u0026thinsp;\u0026plusmn;\u0026thinsp;5.92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e9.27\u0026thinsp;\u0026plusmn;\u0026thinsp;3.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e10.27\u0026thinsp;\u0026plusmn;\u0026thinsp;5.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.28\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e14.40\u0026thinsp;\u0026plusmn;\u0026thinsp;4.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e14.29\u0026thinsp;\u0026plusmn;\u0026thinsp;6.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.93\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e13.67\u0026thinsp;\u0026plusmn;\u0026thinsp;4.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e12.65\u0026thinsp;\u0026plusmn;\u0026thinsp;4.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUygur control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e9.29\u0026thinsp;\u0026plusmn;\u0026thinsp;2.79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e10.17\u0026thinsp;\u0026plusmn;\u0026thinsp;4.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.44\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e9.71\u0026thinsp;\u0026plusmn;\u0026thinsp;4.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e9.79\u0026thinsp;\u0026plusmn;\u0026thinsp;4.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.95\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e16.13\u0026thinsp;\u0026plusmn;\u0026thinsp;4.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e16.38\u0026thinsp;\u0026plusmn;\u0026thinsp;6.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.88\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e14.29\u0026thinsp;\u0026plusmn;\u0026thinsp;5.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e13.04\u0026thinsp;\u0026plusmn;\u0026thinsp;4.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.35\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHan control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e10.75\u0026thinsp;\u0026plusmn;\u0026thinsp;3.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e13.50\u0026thinsp;\u0026plusmn;\u0026thinsp;6.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e8.83\u0026thinsp;\u0026plusmn;\u0026thinsp;2.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e10.75\u0026thinsp;\u0026plusmn;\u0026thinsp;5.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.14\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e12.67\u0026thinsp;\u0026plusmn;\u0026thinsp;2.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e12.21\u0026thinsp;\u0026plusmn;\u0026thinsp;6.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCpG4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e13.04\u0026thinsp;\u0026plusmn;\u0026thinsp;3.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e12.25\u0026thinsp;\u0026plusmn;\u0026thinsp;5.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.55\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003cb\u003eNote\u003c/b\u003e: Significant difference was only detected in CpG 1 site (CpG 1: \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4.64E-02; CpG 2: \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.29; CpG 3: \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.68; CpG 4: \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.23) after adjusted by age given its imbalance between male controls and female controls (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.04)\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe correlation analyses between allelic methylation and physiobiochemical indices are shown in Supplementary Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e, and their visualization is shown in Figs.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e and \u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e. In the Han control group, HDL-C was significantly correlated with CpG 3 and CpG 1 methylation in males and females, respectively (CpG 3: r\u0026thinsp;=\u0026thinsp;0.46, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.02; CpG1: r\u0026thinsp;=\u0026thinsp;\u0026minus;0.46, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.02). Moreover, age positively correlated with CpG 4 methylation level in female patients (r\u0026thinsp;=\u0026thinsp;0.43, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.04). These correlations were distinct in the Uyghur population. Age, Glu, and TC in male controls were significantly correlated with CpG 1, CpG 2, and CpG 3 methylation, respectively (CpG 1: r\u0026thinsp;=\u0026thinsp;\u0026minus;0.45, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.03, CpG 2: r\u0026thinsp;=\u0026thinsp;0.45, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.03; CpG 3: r\u0026thinsp;=\u0026thinsp;0.43, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.04). Meanwhile, in the female group, Glu was significantly correlated with CpG 1 and CpG 4 methylation in the MCI and control groups, respectively (CpG 1: r\u0026thinsp;=\u0026thinsp;\u0026minus;0.43, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.04; CpG 4: r\u0026thinsp;=\u0026thinsp;0.55, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.01), while TG levels were positively correlated with CpG1 and CpG 2 (CpG1: r\u0026thinsp;=\u0026thinsp;0.64, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8.33E-04; CpG2: r\u0026thinsp;=\u0026thinsp;0.52, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.01).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn the present study, we performed pyrosequencing analysis of \u003cem\u003eDRD4\u003c/em\u003e promoter methylation in patients with MCI and controls from the Uygur and Han populations. More importantly, assessment of \u003cem\u003eDRD4\u003c/em\u003e methylation levels under the effects of age, sex, and ethnicity has been the focus of current research. MCI-related hypermethylation was detected in the Uygur (CpG 1) and Han (CpG 1\u0026ndash;3) population, and subgroup analyses by sex in the Uygur population indicated consistent results, while in the Han subgroup, \u003cem\u003eDRD4\u003c/em\u003e hypermethylation was only observed in the male group. Ethnic differences were detected in CpG 4 in male cases, CpG 1 in overall control, and CpG 3 in male controls. Regional distinctions were shown between CpG 1 and CpG 4 in the male subgroup. Diverse correlations were observed. CpG 1 methylation in the Uygur male control, Uygur female case, and Han female control groups was significantly correlated with age, Glu, and HDL-C, respectively. CpG 2 in Uygur male controls and Uygur female patients showed correlations with Glu and TG levels. CpG 3 in Uygur male and Han male controls was significantly correlated with TC and HDL-C levels. CpG 4 in Uygur female controls and Han female patients correlated with Glu and age.\u003c/p\u003e \u003cp\u003eMCI, multi-pathogenesis psychiatric disease, could progress to various diseases such as Alzheimer\u0026rsquo;s disease, frontotemporal dementia, Lewy body disease, or vascular disease among them, AD possessed the highest conversion rate.\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e Increasing studies demonstrated that methylation was an important mechanism in memory formation and involved in the pathology of psychiatry diseases.\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e Memory associated genes such as \u003cem\u003ePP1\u003c/em\u003e and \u003cem\u003ereelin\u003c/em\u003e showed different degrees of methylation, thus further influencing memory function through modulating their transcription and expression.\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e \u003cem\u003eDRD4\u003c/em\u003e explored in our study occupied an important role in mental disorders due to its modulation function in cognition and synaptic plasticity and pharmacological role in psychiatric disorders.\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e,\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e A study conducted by Unland et al. demonstrated that methylation of \u003cem\u003eDRD4\u003c/em\u003e ranging from 0.95\u0026ndash;95.46% was detected in CNS tumors of childhood.\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e Previous findings demonstrated that hypomethylation in the \u003cem\u003eDRD4\u003c/em\u003e gene associated with hyperactivity disorder,\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e moreover, lately results have further revealed that epigenetic modification in particular sites is associated with the disease.\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e In our current study, results indicated that all significant sites were hypermethylated in MCI; thus we may hypothesize there is \u003cem\u003eDRD4\u003c/em\u003e suppression in MCI. Previous studies that focused on schizophrenia using methylation-specific PCR showed that aberrant methylation of \u003cem\u003eDRD4\u003c/em\u003e scarcely existed in brain sample.\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e Besides, the impact of gender on methylation was detected in the Han population; therefore, we deduced that CpG 1 may play a critical role in increasing the risk of MCI by lowering the expression of \u003cem\u003eDRD4\u003c/em\u003e. Further investigation of the influence of \u003cem\u003eDRD4\u003c/em\u003e hypermethylation on MCI is warranted.\u003c/p\u003e \u003cp\u003eIn the present study, ethnic disparities were detected only in the male subgroup. In the Uygur population, CpG 4 in the MCI group showed hypomethylation while CpG 3 in the control group was hypermethylated compared to the control group. Regional discrepancy analyses indicated significant differences in CpGs 1 and 4 in the male subgroups. Men and women differed in the incidence and progression of MCI.\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e Lastly, a study in Caucasian populations indicated that males tended to suffer from multiple diseases that elevated the risk of MCI .\u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e Moreover, previous studies found that \u003cem\u003eDRD4\u003c/em\u003e polymorphism in the third exon had an effect on emotion-related behavior in a particular environment.\u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e,\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e Religious beliefs, particularly in men with \u003cem\u003eDRD4\u003c/em\u003e polymorphism, showed an effect on individual behaviors.\u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e Other than gender-specific differences, CpG 4 in Uygur cases and CpG 1 in overall controls showed gender differences.\u003c/p\u003e \u003cp\u003eMethylation of CpG 1 in Uygur male controls was negatively correlated with age, in contrast with the positive correlation of CpG 4 methylation in Han female patients with age; simultaneously, this tendency was consistent with the results of our study. In addition, a previous study indicated an increased risk of MCI with age.\u003csup\u003e\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e Glu, a known risk factor for MCI and AD,\u003csup\u003e\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e showed a negative correlation with methylation of CpG 1 in Uygur female patients, whereas positive correlations in CpG 2 and CpG 4 methylation were observed separately in male and female from Uygur controls. This has aroused much interest in the Glu methylation interactions in MCI. Methylation of 1 and 3 showed opposite changes with increasing HDL-C in females and males from the Han control groups. The methylation of 3 increased with TC treatment in the Uygur male controls. The methylation of 1 and 3 in Uygur females increased with increasing TG levels.\u003c/p\u003e \u003cp\u003eThis study had several limitations. First, fewer sites were investigated; therefore, other target fragments in the promoter should be sequenced in future studies. Second, we excluded other confounding factors. Third, the combined actions of various indices should be explored.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn summary, hypermethylation in \u003cem\u003eDRD4\u003c/em\u003e was associated with MCI risk. Other confounding factors, including age, sex, and ethnicity, showed a potential risk of the disease. Correlations between \u003cem\u003eDRD4\u003c/em\u003e methylation and hematological indicators indicated the role of \u003cem\u003eDRD4\u003c/em\u003e methylation.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMCI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMild cognitive impairment\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDRD4\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eDopamine Receptor D4\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAlzheimer\u0026rsquo;s Disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCpG\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCytosine-phosphate-Guanine site\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGlu\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGlucose\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHDL-C\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHigh-Density Lipoprotein Cholesterol\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTG\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTriglyceride\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTotal Cholesterol.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics Approval and Informed Consent\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from all participants, and the study was approved by the Ningbo University Medical Ethics Committee (No. NBU-2020-158).\u003c/p\u003e\n\u003cp\u003eAcknowledgments\u003c/p\u003e\n\u003cp\u003eWe gratefully acknowledge the support of the First Affiliated Hospital of Xinjiang Medical University and Ningbo University Medical Ethics Committee for their approval. Special thanks go to the patients who participated in this trial for entrusting us with their health and time. Their participation is the cornerstone of our research, and we honor their contribution to medical advancement. We extend our sincere thanks to the\u0026nbsp;pathophysiology graduate student team for their dedicated assistance and valuable insights throughout this research.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Zhejiang Key Research and Development Project (2024C03101) and the National Natural Science Foundation of China (U1503223, 32171035), which was also sponsored by K.\u0026nbsp;C. Wong Magna and funded\u0026nbsp;by Ningbo University.\u003c/p\u003e\n\u003cp\u003eDisclosure\u003c/p\u003e\n\u003cp\u003eThe authors report no conflicts of interest in this work.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAuthor Contributions：Conceptualization: Huihui Ji. Data acquisition: Guili Liu, Qi Yao, Xiaohui Zhou. Formal analysis: Chunshuang Xu，Wei Cui, Shujun Xu,. Writing\u0026mdash;original draft: Chunshuang Xu. Writing-review and editing: Jingbo Yu, Qinwen Wang.\u003c/p\u003e"},{"header":"References","content":"\u003col start=\"1\" type=\"1\"\u003e\n\u003cli\u003eAmini N, Ibn Hach M, Lapauw L, et al. Meta-analysis on the interrelationship between sarcopenia and mild cognitive impairment, Alzheimer\u0026rsquo;s disease and other forms of dementia. J Cachexia Sarcopenia Muscle 2024;15:1240\u0026ndash;1253. \u003c/li\u003e\n\u003cli\u003eMian M, Tahiri J, Eldin R, et al. Overlooked cases of mild cognitive impairment: Implications to early Alzheimer\u0026rsquo;s disease. Ageing Res Rev 2024;98:102335.\u003c/li\u003e\n\u003cli\u003eWu Y, Wang X, Gu C, et al. Investigating predictors of progression from mild cognitive impairment to Alzheimer\u0026rsquo;s disease based on different time intervals. Age Ageing 2023;52:afad182.\u003c/li\u003e\n\u003cli\u003eH\u0026ouml;nig M, Altomare D, Caprioglio C, et al. Association Between Years of Education and Amyloid Burden in Patients With Subjective Cognitive Decline, MCI, and Alzheimer Disease. Neurology 2024;102:e208053. \u003c/li\u003e\n\u003cli\u003eNiu Y-Y, Yan H-Y, Zhong J-F, et al. Association of dietary choline intake with incidence of dementia, Alzheimer disease, and mild cognitive impairment: a large population-based prospective cohort study. Am J Clin Nutr 2024;S0002-9165(24)00869\u0026ndash;4.\u003c/li\u003e\n\u003cli\u003eSmith RG, Pishva E, Kouhsar M, et al. Blood DNA methylomic signatures associated with CSF biomarkers of Alzheimer\u0026rsquo;s disease in the EMIF-AD study. Alzheimers Dement J Alzheimers Assoc 2024;20:6722\u0026ndash;6739. \u003c/li\u003e\n\u003cli\u003eKoetsier J, Cavill R, Reijnders R, et al. Blood‐based multivariate methylation risk score for cognitive impairment and dementia. Alzheimers Dement 2024;alz.14061.\u003c/li\u003e\n\u003cli\u003eHoang D-T, Shulman ED, Turakulov R, et al. Prediction of DNA methylation-based tumor types from histopathology in central nervous system tumors with deep learning. Nat Med 2024;30:1952\u0026ndash;1961. \u003c/li\u003e\n\u003cli\u003eZhang X-X, Wei M, Wang H-R, et al. Mitochondrial dysfunction gene expression, DNA methylation, and inflammatory cytokines interaction activate Alzheimer\u0026rsquo;s disease: a multi-omics Mendelian randomization study. J Transl Med 2024;22:893.\u003c/li\u003e\n\u003cli\u003eDe Plano LM, Saitta A, Oddo S, et al. Epigenetic Changes in Alzheimer\u0026rsquo;s Disease: DNA Methylation and Histone Modification. Cells 2024;13:719.\u003c/li\u003e\n\u003cli\u003eZhang Y, Shen S. Epigenome-wide DNA methylation analysis of late-stage mild cognitive impairment. Front Cell Dev Biol 2024;12:1276288.\u003c/li\u003e\n\u003cli\u003eMa W, Zhou X, Ji H, et al. Population difference in the association of BDNF promoter methylation with mild cognitive impairment in the Xinjiang Uygur and Han populations. Psychiatry Res 2015;229:926\u0026ndash;932.\u003c/li\u003e\n\u003cli\u003eLuo M, Zhou X, Ji H, et al. Population Difference in the Associations of KLOTH Promoter Methylation with Mild Cognitive Impairment in Xinjiang Uygur and Han Populations. PloS One 2015;10:e0132156.\u003c/li\u003e\n\u003cli\u003eFranco R, Reyes-Resina I, Navarro G. Dopamine in Health and Disease: Much More Than a Neurotransmitter. Biomedicines 2021;9:109.\u003c/li\u003e\n\u003cli\u003ePoulin J-F, Gaertner Z, Moreno-Ramos OA, et al. Classification of Midbrain Dopamine Neurons Using Single-Cell Gene Expression Profiling Approaches. Trends Neurosci 2020;43:155\u0026ndash;169.\u003c/li\u003e\n\u003cli\u003eZhao X, Huang Y, Chen K, et al. \u0026minus;141 C insertion/deletion polymorphism of the dopamine D 2 receptor gene is associated with schizophrenia in C hinese H an population: Evidence from an ethnic group‐specific meta‐analysis. Asia-Pac Psychiatry 2016;8:189\u0026ndash;198.\u003c/li\u003e\n\u003cli\u003eSu H, Wang X, Bai J, et al. Role of dopamine D3 receptors in methamphetamine-induced behavioural sensitization and the characterization of dopamine receptors (D1R-D5R) gene expression in the brain. Folia Neuropathol 2022;60:105\u0026ndash;113.\u003c/li\u003e\n\u003cli\u003eKiss B, Laszlovszky I, Kr\u0026aacute;mos B, et al. Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders. Biomolecules 2021;11:104.\u003c/li\u003e\n\u003cli\u003eFerr\u0026eacute; S, Belcher AM, Bonaventura J, et al. Functional and pharmacological role of the dopamine D4 receptor and its polymorphic variants. Front Endocrinol 2022;13:1014678. \u003c/li\u003e\n\u003cli\u003eK\u0026auml;ver L, Hinney A, Rajcsanyi LS, et al. Epigenetic alterations in patients with anorexia nervosa-a systematic review. Mol Psychiatry 2024;29:3900\u0026ndash;3914.\u003c/li\u003e\n\u003cli\u003eDai D, Cheng J, Zhou K, et al. Significant association between DRD3 gene body methylation and schizophrenia. Psychiatry Res 2014;220:772\u0026ndash;777.\u003c/li\u003e\n\u003cli\u003eKuang J, Kafetzopoulos V, Deth R, et al. Dopamine D4 Receptor Agonist Drastically Increases Delta Activity in the Thalamic Nucleus Reuniens: Potential Role in Communication between Prefrontal Cortex and Hippocampus. Int J Mol Sci 2023;24:15289.\u003c/li\u003e\n\u003cli\u003eLatif S, Jahangeer M, Maknoon Razia D, et al. Dopamine in Parkinson\u0026rsquo;s disease. Clin Chim Acta Int J Clin Chem 2021;522:114\u0026ndash;126.\u003c/li\u003e\n\u003cli\u003eKanarik M, Grimm O, Mota NR, et al. ADHD co-morbidities: A review of implication of gene environment effects with dopamine-related genes. Neurosci Biobehav Rev 2022;139:104757.\u003c/li\u003e\n\u003cli\u003eZhang R, Dang W, Zhang J, et al. Methylation quantitative locus rs3758653 in the DRD4 gene is associated with duration from first heroin exposure to addiction. Brain Res 2022;1775:147746.\u003c/li\u003e\n\u003cli\u003eBolat H, Ercan ES, \u0026Uuml;nsel-Bolat G, et al. DRD4 genotyping may differentiate symptoms of attention-deficit/hyperactivity disorder and sluggish cognitive tempo. Rev Bras Psiquiatr Sao Paulo Braz 1999 2020;42:630\u0026ndash;637.\u003c/li\u003e\n\u003cli\u003ePaudel P, Choi JS, Prajapati R, et al. In Vitro Human Monoamine Oxidase Inhibition and Human Dopamine D4 Receptor Antagonist Effect of Natural Flavonoids for Neuroprotection. Int J Mol Sci 2023;24:15859.\u003c/li\u003e\n\u003cli\u003eJi H, Wang Y, Jiang D, et al. Elevated DRD4 promoter methylation increases the risk of Alzheimer\u0026rsquo;s disease in males. Mol Med Rep 2016;14:2732\u0026ndash;2738.\u003c/li\u003e\n\u003cli\u003eUnland R, Kerl K, Schlosser S, et al. Epigenetic repression of the dopamine receptor D4 in pediatric tumors of the central nervous system. J Neurooncol 2014;116:237\u0026ndash;249.\u003c/li\u003e\n\u003cli\u003eAmini N, Ibn Hach M, Lapauw L, et al. Meta-analysis on the interrelationship between sarcopenia and mild cognitive impairment, Alzheimer\u0026rsquo;s disease and other forms of dementia. J Cachexia Sarcopenia Muscle 2024;15:1240\u0026ndash;1253.\u003c/li\u003e\n\u003cli\u003eHop PJ, Zwamborn RAJ, Hannon E, et al. Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS. Sci Transl Med 2022;14:eabj0264.\u003c/li\u003e\n\u003cli\u003eRudenko A, Tsai L-H. Epigenetic regulation in memory and cognitive disorders. Neuroscience 2014;264:51\u0026ndash;63.\u003c/li\u003e\n\u003cli\u003eGilman TL, Ford MT, Jasnow AM, et al. DRD4 polymorphism associated with greater positive affect in response to negative and neutral social stimuli. Ann Hum Genet 2022;86:218\u0026ndash;223.\u003c/li\u003e\n\u003cli\u003eTaheri N, Pirboveiri R, Sayyah M, et al. Association of DRD2, DRD4 and COMT genes variants and their gene-gene interactions with antipsychotic treatment response in patients with schizophrenia. BMC Psychiatry 2023;23:781.\u003c/li\u003e\n\u003cli\u003eUnland R, Kerl K, Schlosser S, et al. Epigenetic repression of the dopamine receptor D4 in pediatric tumors of the central nervous system. J Neurooncol 2014;116:237\u0026ndash;249.\u003c/li\u003e\n\u003cli\u003eBolat H, Ercan ES, \u0026Uuml;nsel-Bolat G, et al. DRD4 genotyping may differentiate symptoms of attention-deficit/hyperactivity disorder and sluggish cognitive tempo. Rev Bras Psiquiatr Sao Paulo Braz 1999 2020;42:630\u0026ndash;637.\u003c/li\u003e\n\u003cli\u003eThursina C, Nurputra DK, Harahap ISK, et al. Determining the association between polymorphisms of the DAT1 and DRD4 genes with attention deficit hyperactivity disorder in children from Java Island. Neurol Int 2020;12:8292.\u003c/li\u003e\n\u003cli\u003eAlel\u0026uacute;-Paz R, Gonz\u0026aacute;lez-Corpas A, Ashour N, et al. DNA methylation pattern of gene promoters of major neurotransmitter systems in older patients with schizophrenia with severe and mild cognitive impairment. Int J Geriatr Psychiatry 2015;30:558\u0026ndash;565.\u003c/li\u003e\n\u003cli\u003eGreenberg BD, Pettigrew C, Soldan A, et al. CSF Alzheimer Disease Biomarkers: Time-Varying Relationships With MCI Symptom Onset and Associations With Age, Sex, and ApoE4. Neurology 2022;99:e1640\u0026ndash;e1650.\u003c/li\u003e\n\u003cli\u003eBai W, Chen P, Cai H, et al. Worldwide prevalence of mild cognitive impairment among community dwellers aged 50 years and older: a meta-analysis and systematic review of epidemiology studies. Age Ageing 2022;51:afac173.\u003c/li\u003e\n\u003cli\u003eJiang Y, Bachner-Melman R, Chew SH, et al. Dopamine D4 receptor gene and religious affiliation correlate with dictator game altruism in males and not females: evidence for gender-sensitive gene \u0026times; culture interaction. Front Neurosci 2015;9:338.\u003c/li\u003e\n\u003cli\u003eUzefovsky F, Shalev I, Israel S, et al. The dopamine D4 receptor gene shows a gender-sensitive association with cognitive empathy: evidence from two independent samples. Emot Wash DC 2014;14:712\u0026ndash;721. \u003c/li\u003e\n\u003cli\u003eLi G, Toschi N, Devanarayan V, et al. The age-specific comorbidity burden of mild cognitive impairment: a US claims database study. Alzheimers Res Ther 2023;15:211.\u003c/li\u003e\n\u003cli\u003eZeng Z, He J, Yao T. Characteristic early changes of Glu and Cho in brain regions affected by different types of subjective cognitive decline and their clinical significance. Medicine (Baltimore) 2023;102:e36457.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-medical-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejmr","sideBox":"Learn more about [European Journal of Medical Research](http://eurjmedres.biomedcentral.com)","snPcode":"40001","submissionUrl":"https://submission.nature.com/new-submission/40001/3","title":"European Journal of Medical Research","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"mild cognitive impairment, dopamine receptor, DRD4, DNA methylation, peripheral blood","lastPublishedDoi":"10.21203/rs.3.rs-6939122/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6939122/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eMild cognitive impairment (MCI), the symptomatic pre-dementia phase of Alzheimer\u0026rsquo;s disease, is characterized by objective or subjective memory impairment without affecting daily activity. Dopamine receptors play a pivotal role in the modulation of memory and cognitive functions. Our study focused on the association between \u003cem\u003eDRD4\u003c/em\u003e methylation and MCI in Uygur and Han populations.\u003c/p\u003e\u003ch2\u003ePatients and methods:\u003c/h2\u003e \u003cp\u003eMethylation was measured using bisulfite pyrosequencing.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eOur results indicated that MCI-related hypermethylation was detected in the Uygur (CpG 1) and Han (CpG 1\u0026ndash;3) populations, and subgroup analyses by sex in the Uygur population indicated consistent results, while in the Han subgroup, \u003cem\u003eDRD4\u003c/em\u003e hypermethylation was only observed in the male group. Ethnic differences in CpG 4(CpG: Cytosine Phosphate Guanine)in male cases, CpG 1 in overall control and CpG 3 in male controls. Regional distinctions were shown between CpG 1 and CpG 4 in the male subgroup. Diverse correlations were observed. CpG 1 methylation in the Uygur male control, Uygur female case, and Han female control groups was significantly correlated with age, Glu, and HDL-C, respectively. CpG 2 in Uygur male controls and Uygur female patients showed correlations with Glu and TG levels. CpG 3 in Uygur male and Han male controls was significantly correlated with TC and HDL-C levels. CpG 4 in Uygur female controls and Han female patients correlated with Glu and age.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eOur findings provide novel insights into \u003cem\u003eDRD4\u003c/em\u003e methylation in Uygur and Han populations.\u003c/p\u003e","manuscriptTitle":"Association of DRD4 promoter-associated methylation with mild cognitive impairment in Han and Uygur populations","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-02 06:44:26","doi":"10.21203/rs.3.rs-6939122/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-07-22T01:43:01+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-10T20:09:46+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-10T00:43:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"111604164731359643003153808079322168406","date":"2025-07-03T17:11:57+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"100463461741517063146621663773855721630","date":"2025-06-29T12:34:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"143415617866460516612268673808091300003","date":"2025-06-29T08:57:56+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-24T08:10:35+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-21T12:36:17+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-06-21T10:25:38+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Medical Research","date":"2025-06-20T12:49:59+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-medical-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejmr","sideBox":"Learn more about [European Journal of Medical Research](http://eurjmedres.biomedcentral.com)","snPcode":"40001","submissionUrl":"https://submission.nature.com/new-submission/40001/3","title":"European Journal of Medical Research","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b6cb995d-5a61-48af-9c8c-b7aa4139ddfa","owner":[],"postedDate":"July 2nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-12-01T16:09:05+00:00","versionOfRecord":{"articleIdentity":"rs-6939122","link":"https://doi.org/10.1186/s40001-025-03416-3","journal":{"identity":"european-journal-of-medical-research","isVorOnly":false,"title":"European Journal of Medical Research"},"publishedOn":"2025-11-26 15:58:43","publishedOnDateReadable":"November 26th, 2025"},"versionCreatedAt":"2025-07-02 06:44:26","video":"","vorDoi":"10.1186/s40001-025-03416-3","vorDoiUrl":"https://doi.org/10.1186/s40001-025-03416-3","workflowStages":[]},"version":"v1","identity":"rs-6939122","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6939122","identity":"rs-6939122","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}