Investigating the Associations between Neurodevelopmental and Psychiatric Genetic Liability and Adverse Social and Functional Outcomes across Childhood, Adolescence and Young-Adulthood

Investigating the Associations between Neurodevelopmental and Psychiatric Genetic Liability and Adverse Social and Functional Outcomes across Childhood, Adolescence and Young-Adulthood | 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 Article Investigating the Associations between Neurodevelopmental and Psychiatric Genetic Liability and Adverse Social and Functional Outcomes across Childhood, Adolescence and Young-Adulthood Beatrice Fury, Charlotte Dennison, Lucy Riglin*, Amy Shakeshaft* This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7217396/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 18 You are reading this latest preprint version Abstract Neurodevelopmental and psychiatric conditions often originate in youth and can lead to adverse social and functional outcomes. However, it is unclear whether these associations are driven by genetic liability to these conditions, with possible developmental differences. We examined multivariable associations between polygenic scores (PGS) for attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), schizophrenia, bipolar disorder, depression, anxiety and three outcomes: peer problems, educational attainment/NEET (not in education, employment or training) and suicidality, in childhood, adolescence and young-adulthood. Data were analysed from the Avon Longitudinal Study of Parents and Children, with outcomes at ages 10–13, 16 and 24–25 years. ADHD PGS was associated with peer problems in childhood, adolescence and young-adulthood, as well as with lower educational attainment in childhood/adolescence and NEET status in young-adulthood. ASD PGS was associated with greater educational attainment in childhood and adolescence, and increased likelihood of suicidality in childhood. Depression PGS was associated with peer problems in childhood and young-adulthood, and poorer educational attainment/NEET and suicidality in adolescence and young-adulthood. We did not find strong evidence of associations for schizophrenia, bipolar disorder or anxiety PGS. These findings suggest that genetic liability to neurodevelopmental and psychiatric conditions are associated with a range of social/functional outcomes, although the strength and direction of association varies by PGS, outcome and development stage. This highlights the importance of examining genetic liability to multiple neurodevelopmental and psychiatric conditions simultaneously and of a developmental perspective. Biological sciences/Genetics Health sciences/Diseases/Psychiatric disorders/ADHD Health sciences/Diseases/Psychiatric disorders/Autism spectrum disorders ALSPAC Polygenic scores Suicidality Educational attainment Peer problems Genetics Figures Figure 1 Figure 2 Figure 3 Introduction Neurodevelopmental and psychiatric conditions often originate early in development and are strongly associated with a range of adverse social and functional outcomes. Substantial evidence indicates that common neurodevelopmental and psychiatric conditions such as attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD) and schizophrenia as well as bipolar disorder, depression, and anxiety share some symptoms and comorbidities are common ( 1 , 2 ). Adverse outcomes associated with these conditions include peer problems, suicidality, and poor educational attainment ( 3 – 7 ). Importantly, referrals to mental health services are often driven not solely by the symptoms of the condition but by the broader challenges associated with these negative social, behavioural and functional outcomes. While evidence for phenotypic associations between neurodevelopmental and psychiatric conditions and these negative outcomes is clear, it is unclear whether these associations are driven by genetic liability to these conditions. The existing evidence base varies considerably depending on the specific condition, the type of outcome assessed, and the developmental stage examined (childhood, adolescence or young-adulthood). Research examining genetic liability to neurodevelopmental conditions – which onset early in development – such as ADHD and ASD, have found associations with a range of social and functional outcomes spanning childhood, adolescence and young-adulthood. For example, both ADHD and ASD PGS have shown evidence of associations with suicidality in a childhood high-risk population sample ( 8 ) and with peer problems in childhood and adolescence in a general population sample ( 9 ). ADHD PGS has also shown associations with poor educational attainment in childhood and adolescence ( 10 – 12 ) and with unemployment in young-adulthood ( 13 , 14 ), whereas evidence did not support strong associations between ASD PGS and educational attainment in childhood ( 12 ) or unemployment in young-adulthood ( 14 ), with limited research conducted in adolescence. Previous research has not identified strong evidence of an association between either ADHD or ASD PGS and suicidality in adulthood ( 14 , 15 ). While schizophrenia is not classified as a neurodevelopmental disorder in the DSM-V ( 16 ) or ICD-11, and typically does not onset until adolescence or young-adulthood, it is widely considered as neurodevelopmental given its early origins ( 17 , 18 ). Consistent with this, and akin to ASD and ADHD PGS, schizophrenia PGS has also been found to be associated with suicidality in childhood ( 8 ) and peer problems adolescence ( 19 ). However, unlike ADHD and ASD PGS, a recent study did not find strong evidence of associations between schizophrenia PGS with either suicidality or unemployment in adulthood ( 14 ). Whilst evidence suggests an association between the genetic liability to schizophrenia and the related construct of loneliness in adulthood ( 20 ), specific associations with peer problems in young-adulthood have not been examined. Unlike schizophrenia, bipolar disorder is classified as a mood disorder ( 15 ) and is not considered neurodevelopmental, given the relative lack of associated early life impairments ( 21 ). Nonetheless, both conditions tend to onset after puberty and have considerable genetic overlap ( 22 ). Genetic liability for both conditions have been associated with greater educational attainment across development ( 23 , 24 ). Unlike schizophrenia PGS, most research has not found strong evidence of an association between genetic liability to bipolar disorder and peer problems, suicidality or unemployment ( 25 ). Depression and anxiety each have a relatively low heritability, with SNP-based estimates around 20% ( 26 ) compared to that of the SNP-based estimates of neurodevelopmental conditions, like ASD, at 60% ( 27 ). Both depression and anxiety are considered emotional disorders, with a typical onset in adolescence or young-adulthood ( 28 ). Previous evidence suggests associations between depression PGS and peer problems in adolescence and young-adulthood ( 29 ). However, depression PGS show associations with suicidality across all developmental stages, including childhood ( 8 , 14 , 30 ). There is moderate genetic overlap between depression and anxiety and current evidence suggests both PGS are associated with unemployment in adulthood ( 26 ). There is limited literature on the associations between anxiety and depression PGS and educational attainment in childhood or adolescence. Unlike depression, associations between anxiety PGS and suicidality in adulthood are inconsistent ( 31 , 32 ) and there is limited research into associations with other outcomes in childhood and adolescence for anxiety PGS. Thus, research suggests genetic liability to neurodevelopmental and psychiatric conditions is associated with social and functional outcomes, but that associations likely vary for genetic liability to different conditions. However, research examining associations across different developmental periods – which appears to be one potentially source of heterogeneity – is limited. Research examining multiple PGS together is also limited, which is important given the genetic overlap between conditions. The aims of this study were to investigate associations between PGS for six neurodevelopmental/psychiatric conditions—ADHD, ASD, schizophrenia, bipolar disorder, depression and anxiety—and social and functional outcomes measured across childhood, adolescence, and young-adulthood: i) peer problems, ii) suicidality and iii) educational attainment and employment. We hypothesised that neurodevelopmental PGS (ADHD, ASD and schizophrenia) would be associated with all outcomes at all ages. For the mood/emotional PGS (bipolar disorder, depression and anxiety) we hypothesised that the presence of associations would depend on the developmental period. We hypothesised that depression PGS would be associated with suicidality at all ages, but with peer problems and educational attainment/employment in adolescence and young-adulthood only. For anxiety PGS, we hypothesised the presence of associations with suicidality, peer problems and educational attainment/employment in adolescence and young-adulthood. Finally, for bipolar disorder PGS, we hypothesised the presence of an association with suicidality and peer problems in young-adulthood, but with educational attainment/employment in adolescence and young-adulthood. Methods Participants We used data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a prospective population-based cohort study. This study recruited pregnant women who resided in Avon, UK with expected due dates between 1st April 1991 and 31st December 1992. Initially 14 541 pregnancies were enrolled with 13 988 children alive at 1 year of age. After further recruitment, the total sample size using any data collected after 7 years old is 15 447 pregnancies of which 14 901 children were alive at 1 year of age. There were 338 women of the initial 14 541 pregnancies who had already enrolled with a previous pregnancy, making 14 203 unique mothers. After another phase of recruitment, there was a total of 14 833 women as of September 2021 ( 33 – 35 ). For participants over the age of 22 years, study data were collected and managed using REDcap electronic data capture tools hosted at the University of Bristol. REDcap (Research Electronic Data Capture) is a secure, web-based software platform designed to support data capture for research studies ( 36 ). The study website contains details of all data available through a fully searchable data dictionary and variable search tool ( http://www.bristol.ac.uk/alspac/researchers/our-data/ ). For families with multiple births, we include the oldest sibling. Genetic data and Polygenic scores Blood samples for DNA extraction were collected at birth or during study clinics between ages 3 and 7. Genotyping of collected samples was done via the Illumina HumanHap550 quad platform and then imputed using the Haplotype Reference Consortium panel. For details of genetic QC see Supplementary material ( 37 ). After QC, 8 648 individuals remained. PGS were calculated using PGS-CS ( 38 ) and derived based on the largest and most recent genome-wide association studies (GWAS) for the 6 neurodevelopmental/psychiatric conditions: 1) ADHD (N = 38 691 cases and N = 186 843 controls) ( 39 ), 2) ASD (N = 18 381 cases and N = 27 969 controls) ( 40 ), 3) schizophrenia (N = 76 755 cases and N = 243 649 controls) ( 41 ) 4) bipolar disorder (N = 41 917 cases and N = 371 549 controls) ( 22 ) 5) depression (N = 688 808 cases and N = 4 364 225 controls) ( 42 ) and 6) anxiety (N = 25 453 cases and N = 58 113 controls) ( 43 ). Each PGS was residualised against ten ancestry-specific principal components and standardised to aid interpretation. Outcomes Peer Problems The peer problem subscale of the Strengths and Difficulties questionnaire (SDQ) ( 44 ) was parent-reported at ages 10 and 16 and self-reported at 25 years old. This subscale consists of 5 items which are scored as 0 (not true), 1 (somewhat true) and 2 (certainly true) to give a total score of 10. A standard cut-off score of ≥4 ( 45 ) was used to index the presence of peer problems. Educational Attainment and Employment To assess educational attainment in childhood, we used parent-reporting of the child’s Key Stage 3 SAT (Standard Assessment Tests) levels for Maths and English when offspring were around 14 years old. The Key Stage 3 SATs are national curriculum tests sat by UK pupils at the end of year 9 (age 13/14, 3rd year of secondary school). SATs levels ranged from 3 to 8; as per UK government guidelines, children are expected to achieve a level 5 or above ( 46 ). Thus, to dichotomise this variable, a level of ≥5 was considered as higher educational attainment and < 5 defined as lower educational attainment. For adolescent educational attainment, a self-reported retrospective questionnaire on GCSE grades obtained at 16 years old was reported at age 18. GCSEs are exams taken at the end of secondary school (in year 11, age 15/16), where students are examined on an average of 8 subjects. At the time of these questionnaires, GCSE grades range from A* to G. In accordance with UK government benchmark measures ( 47 , 48 ), those who did not achieve grades between A*-C in all the subjects they were studying were defined as lower educational attainment and those who achieved grades within A*-C for all subjects as higher educational attainment. For young-adulthood, participants self-reported whether they were currently engaged in any education, employment or training at age 25. In accordance with the UK Office of National Statistics, participants who were not in employment (full-time/part-time/occasional or self-employed), doing an apprenticeship or any other government supported training or work experience scheme or full-time education were defined as being NEET (not in education, employment or training) which also included those doing voluntary work, those who were a part or full-time carer or those who were unable to work due to sickness or disability ( 49 ). Suicidality Suicidality or risk of suicide encompassed questionnaire items describing suicidal thoughts, ideation and suicide attempts. For primary analyses, suicidality was defined as a lifetime report at age 11, whereas at ages 16 and 24, suicidality was present only if they had experienced suicidal thoughts within a year of completing the questionnaire. An answer of ‘yes’ to any suicidality item was defined as the presence of suicidality, as defined previously ( 50 ). At age 11, suicidality was assessed using the Childhood Interview for DSM-IV Borderline Personality Disorder (CI-BPD) ( 51 ). This is a semi-structured interview including a suicidal behaviours section of four binary (yes/no) items: i) “Told someone you will kill yourself”, ii) “thought about killing yourself”, iii) “made plans to kill yourself” and iv) “actually tried to kill yourself”. At age 16 years, suicidality was measured using a self-reported questionnaire on deliberate self-harm. The questions within this section were based on the Child and Adolescent Self-harm in Europe (CASE) study ( 52 ). We defined suicidality as answering ‘yes’ to both the following questions and reporting these actions within a year of survey completion: “have you ever hurt yourself on purpose in any way?” and “on any of the occasions where you have hurt yourself, have you ever seriously wanted to kill yourself?”. In addition, individuals answering ‘yes’ to “have you ever felt that life was not worth living?” in the past year since survey completion were also classified as experiencing suicidality. At age 24 years, suicidality was measured using the computerised Interview Schedule- Revised (CIS-R) questionnaire which is a self-reported interview that determines diagnoses for depression and anxiety disorder, based on ICD-10 criteria ( 53 , 54 ). Within this questionnaire were the following items: i) ‘ever self-harmed with suicidal intent’, ii) ‘ever attempted suicide’, iii) ‘ever had suicidal thoughts’ and iv) ‘when was the last time you had these thoughts?’. Analyses All analyses were conducted using stataSE (version 18). Initially, descriptive analyses were conducted to determine the prevalence of each outcome in the sample at each age. We then performed multivariable logistic regression models of each outcome at each age (9 models), including all PGS simultaneously. We used multiple imputation to account for missing data in our sample (those with genetic data), using the Stata package ‘ICE’. All outcomes were included in the imputation model, alongside the same phenotype at different ages (e.g. SDQ peer problems at ages 10 and 16 were used to predict SDQ peer problems at age 25, and suicidality at ages 11 and 16 were used to predict suicidality at age 24). Further auxiliary variables used to predict missingness in ALSPAC were also included in all models (socioeconomic status, multiple birth status, maternal age). 200 imputed data sets were created and results from regression analyses were pooled across all datasets. All other settings remained as the default option. Results using imputed data are presented in the main text, with analysis using unimputed data (listwise deletion) presented as sensitivity analysis. Sensitivity analyses were also conducted using parent-reported SDQ peer problems data at 25 years old and lifetime self-reports of suicidality at ages 16 and 24. We also performed univariable analysis examining the association of each PGS on each outcome. We used Benjamini-Hochberg false discovery rate (FDR) method to account for multiple comparisons ( 55 ). P-values for each PGS were corrected across the 9 multivariable models (across 9 outcomes). Both original p-values and corrected FDR q-values are presented in text and tables. Results In the imputed sample (N = 8,591), rates of peer problems increased across development (8.8% in childhood, 9.1% in adolescence and 18.5% in young-adulthood). Suicidality was highest in adolescence (24.3%), followed by young-adulthood (15.0%) and lowest in childhood (8.2%). For educational attainment, in childhood 17.5% of participants did not achieve a KS3 SAT grade 5 or above in both maths and English. In adolescence 7.5% did not achieve all GCSEs within A*-C. In young-adulthood 6.8% were not in education, employment or training. Association between neurodevelopmental/psychiatric PGS with social and functional outcomes Peer problems Figure 1 and Table S1 show multivariable associations between PGS and peer problems across development. ADHD PGS were associated with peer problems in childhood (OR = 1.13, 95% CI [1.02–1.25] p = 0.020, q = 0.030), adolescence (OR = 1.21 [1.02–1.34], p < 0.0001, q < 0.0005) and young-adulthood (OR = 1.14 [1.03–1.26], p = 0.010, q = 0.018), whereas we only found strong evidence of associations between ASD PGS and peer problems in childhood (OR = 1.12 [1.02–1.23], p = 0.017, q = 0.038). Depression PGS were associated with peer problems in childhood (OR = 1.18 [1.06–1.31], p = 0.003, q = 0.007) and young-adulthood (OR = 1.21 [1.09–1.35], p < 0.0001, q < 0.0005). There was also weaker evidence of association between bipolar disorder PGS and peer problems in adolescence (OR = 1.10 [1.00-1.21], p = 0.038, q = 0.342). Finally, there was weaker evidence of association between schizophrenia PGS and the absence of peer problems in young-adulthood (OR = 0.91, [0.83–1.01], p = 0.070, q = 0.315). There was not strong evidence of association between anxiety PGS and peer problems at any developmental stage. Educational Attainment/ Employment As shown in Fig. 2 and Table S2 , ADHD PGS were associated with poor educational attainment in childhood (OR = 1.40 [1.29–1.52], p < 0.0001, q < 0.0005) and adolescence (OR = 1.62 [1.33–1.98], p < 0.0001, q < 0.0005) as well as NEET in young-adulthood (OR = 1.29 [1.08–1.54], p = 0.005, q = 0.011). The opposite relationship was seen for ASD PGS, which was associated with greater educational attainment in childhood (OR = 0.88 [0.81–0.96], p = 0.004, q = 0.018) and adolescence (OR = 0.77 [0.64–0.93], p = 0.007, q = 0.021). Depression PGS were associated with poor educational attainment in adolescence (OR = 1.39 [1.11–1.73], p = 0.004, q = 0.007) and NEET in young-adulthood (OR = 1.26 [1.04–1.51], p = 0.017, q = 0.026), with weaker evidence of an association in childhood (OR = 1.07 [0.98–1.18], p = 0.120, q = 0.135). There was not strong evidence of an association with educational attainment or employment for schizophrenia PGS, bipolar disorder PGS or anxiety PGS at any age. Suicidality As shown in Fig. 3 and Table S3 , both ADHD PGS (OR = 1.13 [1.01–1.26], p = 0.030, q = 0.039) and ASD PGS (OR = 1.24 [1.12–1.37], p < 0.0001, q < 0.0005) were associated with suicidality in childhood, with weaker evidence of an association in adolescence (ADHD PGS OR = 1.07 [0.99–1.15], p = 0.095, q = 0.107; ASD PGS OR = 1.07 [0.10–1.15], p = 0.063, q = 0.113). Depression PGS was associated with suicidality in adolescence (OR = 1.28 [1.18–1.39], p < 0.0001, q < 0.0005) and young-adulthood (OR = 1.42 [1.26–1.58], p < 0.0001, q < 0.0005). There was also weaker evidence, that did not survive correction for multiple testing, of associations between anxiety PGS and suicidality in childhood (OR = 1.12 [1.00-1.25], p = 0.047, q = 0.423) and between schizophrenia PGS and suicidality in young-adulthood (OR = 1.14 [1.029–1.266], p = 0.013, q = 0.117). There was no evidence of association with suicidality and bipolar disorder PGS at any developmental stage. Sensitivity Analyses Analyses using parent-reported peer problems in young-adulthood showed a consistent pattern of results as the primary self-reported analyses (see supplementary Table S4 ). Analyses investigating lifetime suicidality in adolescence were consistent with those in the primary analyses (suicidality within one year of assessment, see supplementary Table S5 ). However, results investigating lifetime suicidality in young-adulthood found weaker evidence of association for schizophrenia PGS (OR = 1.06, 95% CI = 0.98–1.15, p = 0.161) and found evidence of association for ASD PGS (OR = 1.11, 95% CI = 1.02–1.20, p = 0.013), see supplementary Table S6 . Analyses run using listwise deletion were consistent with primary analyses using imputed data (supplementary Tables S7-9 ). Finally, the results of univariate analyses between each PGS with each outcome was largely consistent with the primary analyses (see supplementary tables, S10-12 ). Stronger evidence of an association compared to multivariable analyses was found for both depression and anxiety PGS and peer problems in adolescence as well as poor educational attainment in childhood. There was also stronger evidence of an association between anxiety PGS and unemployment in young-adulthood. Weaker evidence of an association compared to multivariable analyses was found between ASD PGS and greater educational attainment in childhood and adolescence. Discussion This study used data from a longitudinal birth cohort to examine associations between PGS for six neurodevelopmental/psychiatric conditions (ADHD, ASD, schizophrenia, bipolar disorder, depression and anxiety) and adverse outcomes (peer problems, educational attainment/employment and suicidality) across childhood, adolescence and young-adulthood. ADHD and ASD PGS were more associated with outcomes in childhood and adolescence, while depression PGS showed stronger associations in adolescence and young-adulthood. We did not find strong evidence of associations for schizophrenia, bipolar disorder and anxiety PGS. Findings in relation to the hypotheses are discussed below. Consistent with the first neurodevelopmental hypothesis, ADHD PGS was associated with peer problems and lower educational attainment/unemployment across development as well as suicidality in childhood. There was not strong evidence of an association between ADHD PGS and suicidality in young-adulthood, which corroborates findings from a previous study ( 14 ). A potential explanation for this may be that ADHD PGS show greater associations with cognitive traits, like educational attainment, in young-adulthood than psychological traits, like suicidality ( 56 ). However, inconsistent with our neurodevelopmental hypothesis, we did not find consistent evidence of an associations with PGS for ASD and schizophrenia across development. ASD PGS was associated with peer problems and suicidality in childhood only, as well as greater educational attainment in childhood and adolescence. Previous research suggests that childhood peer problems associated with ASD PGS remain elevated and developmentally stable, indicating that an association would likely persist across development ( 9 ). Previous works found evidence of an association between ASD PGS and peer problems during adolescence ( 9 ); however, this analysis was based on univariate analyses, which may have also captured associations with genetic liability for other genetically correlated conditions, such as ADHD. A similar pattern was observed in the present study, where univariate analyses also identified an association between ASD PGS and peer problems in adolescence, highlighting that previous associations between ASD PGS and peer problems after childhood were likely driven by genetic correlation with other conditions, likely ADHD. Additionally, due to genetic overlap between ADHD and ASD, it was hypothesised that both ADHD and ASD PGS would be associated with worse educational attainment and unemployment across development. However, we identified an association between ADHD PGS and lower educational attainment across development, but in contrast, an association between ASD PGS and greater educational attainment in childhood and adolescence. Both the multivariable and univariate analyses are consistent with previous work showing that the shared genetic liability to ADHD and ASD, and genetic liability specific to ADHD, are associated with lower educational attainment, whereas genetic liability specific to ASD is associated with higher educational attainment ( 55 ). This highlights the importance of studying the genetic liability of multiple conditions together and underscores the complexity of the genetic liability for each condition with intricate genetic underpinnings that require careful interpretation. It was also hypothesised that schizophrenia PGS would be associated with suicidality across development, due to the neurodevelopmental origins of the condition and previous findings of such associations in both childhood ( 8 ) and adulthood ( 57 ). Yet in the current study, only weak evidence of an association was identified in young-adulthood, which did not survive correction for multiple testing. The lack of associations with childhood suicidality is consistent with findings by Lee et al. ( 25 ), who did not observe associations between schizophrenia PGS and suicidality in The Adolescent Brain and Cognitive Development (ABCD) Study. These findings thus provide some evidence that schizophrenia PGS may be associated with suicidality in young-adulthood, rather than earlier in development. Studies that are not sensitive to the developmental context may therefore miss these more specific associations which emphasises the significance of the developmental approach. The current study found decreasing effect sizes for the association between schizophrenia PGS and peer problems across development, consistent with a previous study ( 9 ), who reported similar declines from ages 7 to 17 in ALSPAC. Notably, the current findings extend this trend to young-adulthood and provide weak evidence of an association with the absence of peer problems during this period. One possible explanation involves developmental change in social-emotional cognition: individuals with schizophrenia often shown reduced cognitive empathy (e.g. recognising others’ emotions) but preserved or heightened social empathy (e.g. affective empathy and emotional contagion) compared to controls ( 58 ). These findings may suggest that the genetic liability to schizophrenia may be more associated with preserved social empathy later in development, potentially resulting in intact peer relationships, and again, underscores the importance of a developmental perspective. Consistent with our depression hypothesis, depression PGS was associated with poor educational attainment/unemployment and suicidality in adolescence and young-adulthood. Unexpectedly, we did not find evidence of an association between depression PGS and suicidality in childhood. This contrasts with previous research ( 8 ) which reports an association in a similarly aged cohort. One possible cause for this discrepancy is the use of different GWAS datasets to derive the depression PGS. The current study used a GWAS based on clinically defined MDD diagnoses (DSM-IV/V or ICD-9/10), whereas the previous study ( 8 ) used a GWAS that did not rely on standard diagnostic criteria, potentially capturing a broader phenotype, which may explain why an association was identified in childhood. Unlike for depression PGS, in multivariable analyses for anxiety PGS we did not find strong evidence of an association with peer problems, suicidality or educational attainment/unemployment in childhood, adolescence or young-adulthood. These results support a previous study ( 59 ) which also did not find strong evidence of association between anxiety PGS and adult suicidality. However, in this current study, univariate analyses did show associations with suicidality at all three developmental stages for both depression and anxiety PGS. Taken together with the multivariable analyses, this highlights the genetic overlap between depression and anxiety and the importance of analyses that investigate the genetic liability for both conditions together. The multivariable analyses suggest that both the genetic liability for anxiety and depression is associated with suicidality, but that the genetic liability to anxiety may play a stronger role for suicidality in childhood and depression genetic lability to suicidality after puberty. Finally, findings for bipolar disorder PGS were not consistent with our hypotheses (that bipolar disorder PGS would be associated with greater educational attainment/unemployment in adolescence and young-adulthood, as well as peer problems and suicidality in young-adulthood). Strong evidence was not found in support of any of these: only weak evidence of an association with peer problems in adolescence was identified. One explanation of these results may lie within the developmental pattern of the manifestations of social problems in bipolar disorder, and therefore potentially bipolar PGS, whereby certain aspects, like emotional dysregulation ( 60 ) may be more pronounced in childhood and therefore influencing peer rejection, whereas more internalising aspects ( 22 ) being more apparent in adulthood, influencing feelings of loneliness. Thus, it is possible that this study did not find evidence of an association between bipolar disorder PGS and peer problems in adulthood due to the SDQ peer problems measure broadly encompassing several sub-constructs, like peer victimisation (“picked on or bulled by others”) and popularity (“liked by other children”) instead of focussing on aspects like loneliness. Strengths and Limitations This study has several important strengths. The longitudinal study design allowed us to examine outcomes assessed prospectively across three developmental periods. Further, the use of both multivariable and univariate models to examine genetic liability means that that we are able to assess the impact of genetic liability specific to individual neurodevelopmental/psychiatric disorders on outcomes of interest. Additionally, this study focussed on a general population sample, reducing the sampling bias often seen in clinical samples. Since genetic liability to these conditions is continuous, population samples better capture associations between varying genetic risk levels and adverse outcomes, improving generalisability. The results of this study should be viewed considering methodological limitations. Firstly, except for the SDQ peer problems subscale, outcome measures varied across development. This somewhat limits comparability of suicidality and educational attainment across ages. To improve validity, future longitudinal studies should use consistent measures where possible to distinguish true developmental changes from measurement variation. However, this may not always be feasible, as some tools may not be appropriate for all age groups. Similarly, we used cross-sectional analyses, limiting our ability to assess changes over time, Consequently, we cannot infer how neurodevelopmental/psychiatric PGS may relate to developmental trajectories of educational attainment, suicidality and peer problems. Future research could used trajectory-based methods, to identify developmental patterns which may inform more targeted interventions. Conclusions This study provides novel insights into how genetic liability to neurodevelopmental/psychiatric conditions relates to adverse social and functional outcomes across development. We found variation in the strength and direction of associations across conditions, outcomes and development stage. Our results showed that ADHD and depression PGS were linked to all examined outcomes, suggesting broad and potentially negative influences of genetic liability to these conditions. However while ADHD PGS showed association across development, associations for depression PGS were more common from adolescence. ASD PGS showed association specifically with suicidality in childhood, and with greater educational attainment in childhood and adolescence. We did not find strong evidence of associations for schizophrenia, bipolar disorder or anxiety PGS. Our findings highlight the importance of examining genetic liability to multiple neurodevelopmental/psychiatric conditions simultaneous and of a developmental perspective. Declarations Ethical Approval Ethical approval for this study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees. Consent for biological samples has been collected in accordance with the Human Tissue Act (2004). Informed consent for the use of data collected via questionnaires and clinics was obtained from participants following the recommendations of the ALSPAC Ethics and Law Committee at the time. Acknowledgements The authors are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/ 19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and AS will serve as guarantor for the contents of this paper. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). This research was specifically funded by the Wolfson Centre for Young People’s Mental Health, established with support from the Wolfson Foundation. We also acknowledge the support of the Supercomputing Wales project, which is part-funded by the European Regional Development Fund (ERDF) via Welsh Government. ALSPAC GWAS data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. Conflicts of Interest The authors report no conflicts of interest. References Gidziela A, Ahmadzadeh YI, Michelini G, Allegrini AG, Agnew-Blais J, Lau LY, et al. A meta-analysis of genetic effects associated with neurodevelopmental disorders and co-occurring conditions. Nature Human Behaviour. 2023 Feb 20;7. Available from: https://www.nature.com/articles/s41562-023-01530-y Waszczuk MA, Zavos HMS, Gregory AM, Eley TC. The Phenotypic and Genetic Structure of Depression and Anxiety Disorder Symptoms in Childhood, Adolescence, and Young Adulthood. 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JAMA Psychiatry. 2019 Jul 1;76(7):730. doi: https://doi.org/10.1001/jamapsychiatry.2019.0310 Additional Declarations The authors have declared there is NO conflict of interest to disclose Supplementary Files SupplementaryMaterialsPGSsocialandfunctionaloutcomes.docx Supplementary Materials Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: revise 27 Jan, 2026 Review # 6 received at journal 22 Jan, 2026 Review # 5 received at journal 20 Jan, 2026 Reviewer # 7 agreed at journal 20 Dec, 2025 Reviewer # 6 agreed at journal 17 Dec, 2025 Reviewer # 5 agreed at journal 17 Dec, 2025 Review # 4 received at journal 27 Oct, 2025 Reviewer # 4 agreed at journal 15 Oct, 2025 Reviewer # 3 agreed at journal 15 Oct, 2025 Review # 2 received at journal 29 Sep, 2025 Reviewer # 2 agreed at journal 15 Sep, 2025 Review # 1 received at journal 09 Sep, 2025 Reviewer # 1 agreed at journal 27 Aug, 2025 Reviewers invited by journal 22 Aug, 2025 Editor assigned by journal 31 Jul, 2025 Submission checks completed at journal 31 Jul, 2025 First submitted to journal 30 Jul, 2025 Unknown event 28 Jul, 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. 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Abbreviations - ASD, autism spectrum disorder; SZ, schizophrenia; BD, bipolar disorder; MDD, major depressive disorder; ANX, anxiety; 95% CI, 95% confidence interval; PGS, polygenic score\u003c/em\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7217396/v1/17651d13b12cdcfc987cddb6.png"},{"id":90381093,"identity":"e33f630e-f809-43a4-84ed-b19372bd00cd","added_by":"auto","created_at":"2025-09-02 06:46:20","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":52319,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eAssociations between PGS and educational attainment in childhood/adolescence and NEET status in young-adulthood. Abbreviations - ASD, autism spectrum disorder; SZ, schizophrenia; BD, bipolar disorder; MDD, major depressive disorder; ANX, anxiety; 95% CI, 95% confidence interval; PGS, polygenic score\u003c/em\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7217396/v1/e02ba0b12845d3e50438334c.png"},{"id":90381095,"identity":"7432eed7-9fac-41cf-a05a-92e540d5b211","added_by":"auto","created_at":"2025-09-02 06:46:20","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":55511,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eAssociations between PGS and suicidality across development. Abbreviations - ASD, autism spectrum disorder; SZ, schizophrenia; BD, bipolar disorder; MDD, major depressive disorder; ANX, anxiety; 95% CI, 95% confidence interval; PGS, polygenic score\u003c/em\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7217396/v1/54ee45ade08e282d75258256.png"},{"id":90540375,"identity":"0c6c7ca0-672f-4a54-9654-2cfc306bbffb","added_by":"auto","created_at":"2025-09-03 23:41:08","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":724681,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7217396/v1/8cdc19da-02e9-4d38-a3cc-fbc8c1c85766.pdf"},{"id":90383735,"identity":"6fdce419-2cfe-45e3-87a2-5de243a33876","added_by":"auto","created_at":"2025-09-02 07:02:29","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":59831,"visible":true,"origin":"","legend":"Supplementary Materials","description":"","filename":"SupplementaryMaterialsPGSsocialandfunctionaloutcomes.docx","url":"https://assets-eu.researchsquare.com/files/rs-7217396/v1/0b5e78bc3c6e1883fe5fd5af.docx"}],"financialInterests":"The authors have declared there is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose","formattedTitle":"Investigating the Associations between Neurodevelopmental and Psychiatric Genetic Liability and Adverse Social and Functional Outcomes across Childhood, Adolescence and Young-Adulthood","fulltext":[{"header":"Introduction","content":"\u003cp\u003eNeurodevelopmental and psychiatric conditions often originate early in development and are strongly associated with a range of adverse social and functional outcomes. Substantial evidence indicates that common neurodevelopmental and psychiatric conditions such as attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD) and schizophrenia as well as bipolar disorder, depression, and anxiety share some symptoms and comorbidities are common (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Adverse outcomes associated with these conditions include peer problems, suicidality, and poor educational attainment (\u003cspan additionalcitationids=\"CR4 CR5 CR6\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Importantly, referrals to mental health services are often driven not solely by the symptoms of the condition but by the broader challenges associated with these negative social, behavioural and functional outcomes. While evidence for phenotypic associations between neurodevelopmental and psychiatric conditions and these negative outcomes is clear, it is unclear whether these associations are driven by genetic liability to these conditions. The existing evidence base varies considerably depending on the specific condition, the type of outcome assessed, and the developmental stage examined (childhood, adolescence or young-adulthood).\u003c/p\u003e\u003cp\u003eResearch examining genetic liability to neurodevelopmental conditions \u0026ndash; which onset early in development \u0026ndash; such as ADHD and ASD, have found associations with a range of social and functional outcomes spanning childhood, adolescence and young-adulthood. For example, both ADHD and ASD PGS have shown evidence of associations with suicidality in a childhood high-risk population sample (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) and with peer problems in childhood and adolescence in a general population sample (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). ADHD PGS has also shown associations with poor educational attainment in childhood and adolescence (\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) and with unemployment in young-adulthood (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e), whereas evidence did not support strong associations between ASD PGS and educational attainment in childhood (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) or unemployment in young-adulthood (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e), with limited research conducted in adolescence. Previous research has not identified strong evidence of an association between either ADHD or ASD PGS and suicidality in adulthood (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eWhile schizophrenia is not classified as a neurodevelopmental disorder in the DSM-V (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) or ICD-11, and typically does not onset until adolescence or young-adulthood, it is widely considered as neurodevelopmental given its early origins (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Consistent with this, and akin to ASD and ADHD PGS, schizophrenia PGS has also been found to be associated with suicidality in childhood (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) and peer problems adolescence (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). However, unlike ADHD and ASD PGS, a recent study did not find strong evidence of associations between schizophrenia PGS with either suicidality or unemployment in adulthood (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Whilst evidence suggests an association between the genetic liability to schizophrenia and the related construct of loneliness in adulthood (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e), specific associations with peer problems in young-adulthood have not been examined. Unlike schizophrenia, bipolar disorder is classified as a mood disorder (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) and is not considered neurodevelopmental, given the relative lack of associated early life impairments (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Nonetheless, both conditions tend to onset after puberty and have considerable genetic overlap (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Genetic liability for both conditions have been associated with greater educational attainment across development (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Unlike schizophrenia PGS, most research has not found strong evidence of an association between genetic liability to bipolar disorder and peer problems, suicidality or unemployment (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eDepression and anxiety each have a relatively low heritability, with SNP-based estimates around 20% (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e) compared to that of the SNP-based estimates of neurodevelopmental conditions, like ASD, at 60% (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). Both depression and anxiety are considered emotional disorders, with a typical onset in adolescence or young-adulthood (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). Previous evidence suggests associations between depression PGS and peer problems in adolescence and young-adulthood (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). However, depression PGS show associations with suicidality across all developmental stages, including childhood (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). There is moderate genetic overlap between depression and anxiety and current evidence suggests both PGS are associated with unemployment in adulthood (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). There is limited literature on the associations between anxiety and depression PGS and educational attainment in childhood or adolescence. Unlike depression, associations between anxiety PGS and suicidality in adulthood are inconsistent (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e) and there is limited research into associations with other outcomes in childhood and adolescence for anxiety PGS.\u003c/p\u003e\u003cp\u003eThus, research suggests genetic liability to neurodevelopmental and psychiatric conditions is associated with social and functional outcomes, but that associations likely vary for genetic liability to different conditions. However, research examining associations across different developmental periods \u0026ndash; which appears to be one potentially source of heterogeneity \u0026ndash; is limited. Research examining multiple PGS together is also limited, which is important given the genetic overlap between conditions.\u003c/p\u003e\u003cp\u003eThe aims of this study were to investigate associations between PGS for six neurodevelopmental/psychiatric conditions\u0026mdash;ADHD, ASD, schizophrenia, bipolar disorder, depression and anxiety\u0026mdash;and social and functional outcomes measured across childhood, adolescence, and young-adulthood: i) peer problems, ii) suicidality and iii) educational attainment and employment. We hypothesised that neurodevelopmental PGS (ADHD, ASD and schizophrenia) would be associated with all outcomes at all ages. For the mood/emotional PGS (bipolar disorder, depression and anxiety) we hypothesised that the presence of associations would depend on the developmental period. We hypothesised that depression PGS would be associated with suicidality at all ages, but with peer problems and educational attainment/employment in adolescence and young-adulthood only. For anxiety PGS, we hypothesised the presence of associations with suicidality, peer problems and educational attainment/employment in adolescence and young-adulthood. Finally, for bipolar disorder PGS, we hypothesised the presence of an association with suicidality and peer problems in young-adulthood, but with educational attainment/employment in adolescence and young-adulthood.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cb\u003eParticipants\u003c/b\u003e\u003c/p\u003e\u003cp\u003eWe used data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a prospective population-based cohort study. This study recruited pregnant women who resided in Avon, UK with expected due dates between 1st April 1991 and 31st December 1992. Initially 14 541 pregnancies were enrolled with 13 988 children alive at 1 year of age. After further recruitment, the total sample size using any data collected after 7 years old is 15 447 pregnancies of which 14 901 children were alive at 1 year of age. There were 338 women of the initial 14 541 pregnancies who had already enrolled with a previous pregnancy, making 14 203 unique mothers. After another phase of recruitment, there was a total of 14 833 women as of September 2021 (\u003cspan additionalcitationids=\"CR34\" citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e). For participants over the age of 22 years, study data were collected and managed using REDcap electronic data capture tools hosted at the University of Bristol. REDcap (Research Electronic Data Capture) is a secure, web-based software platform designed to support data capture for research studies (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). The study website contains details of all data available through a fully searchable data dictionary and variable search tool (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.bristol.ac.uk/alspac/researchers/our-data/\u003c/span\u003e\u003cspan address=\"http://www.bristol.ac.uk/alspac/researchers/our-data/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). For families with multiple births, we include the oldest sibling.\u003c/p\u003e\u003cp\u003e\u003cb\u003eGenetic data and Polygenic scores\u003c/b\u003e\u003c/p\u003e\u003cp\u003eBlood samples for DNA extraction were collected at birth or during study clinics between ages 3 and 7. Genotyping of collected samples was done via the Illumina HumanHap550 quad platform and then imputed using the Haplotype Reference Consortium panel. For details of genetic QC see Supplementary material (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eAfter QC, 8 648 individuals remained. PGS were calculated using PGS-CS (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e) and derived based on the largest and most recent genome-wide association studies (GWAS) for the 6 neurodevelopmental/psychiatric conditions: 1) ADHD (N\u0026thinsp;=\u0026thinsp;38 691 cases and N\u0026thinsp;=\u0026thinsp;186 843 controls) (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e), 2) ASD (N\u0026thinsp;=\u0026thinsp;18 381 cases and N\u0026thinsp;=\u0026thinsp;27 969 controls) (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e), 3) schizophrenia (N\u0026thinsp;=\u0026thinsp;76 755 cases and N\u0026thinsp;=\u0026thinsp;243 649 controls) (\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e) 4) bipolar disorder (N\u0026thinsp;=\u0026thinsp;41 917 cases and N\u0026thinsp;=\u0026thinsp;371 549 controls) (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) 5) depression (N\u0026thinsp;=\u0026thinsp;688 808 cases and N\u0026thinsp;=\u0026thinsp;4 364 225 controls) (\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e) and 6) anxiety (N\u0026thinsp;=\u0026thinsp;25 453 cases and N\u0026thinsp;=\u0026thinsp;58 113 controls) (\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e). Each PGS was residualised against ten ancestry-specific principal components and standardised to aid interpretation.\u003c/p\u003e\u003cp\u003e\u003cb\u003eOutcomes\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003ePeer Problems\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe peer problem subscale of the Strengths and Difficulties questionnaire (SDQ) (\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e) was parent-reported at ages 10 and 16 and self-reported at 25 years old. This subscale consists of 5 items which are scored as 0 (not true), 1 (somewhat true) and 2 (certainly true) to give a total score of 10. A standard cut-off score of \u0026ge;4 (\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e) was used to index the presence of peer problems.\u003c/p\u003e\u003cp\u003e\u003cb\u003eEducational Attainment and Employment\u003c/b\u003e\u003c/p\u003e\u003cp\u003eTo assess educational attainment in childhood, we used parent-reporting of the child\u0026rsquo;s Key Stage 3 SAT (Standard Assessment Tests) levels for Maths and English when offspring were around 14 years old. The Key Stage 3 SATs are national curriculum tests sat by UK pupils at the end of year 9 (age 13/14, 3rd year of secondary school). SATs levels ranged from 3 to 8; as per UK government guidelines, children are expected to achieve a level 5 or above (\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e). Thus, to dichotomise this variable, a level of \u0026ge;5 was considered as higher educational attainment and \u0026lt;\u0026thinsp;5 defined as lower educational attainment.\u003c/p\u003e\u003cp\u003eFor adolescent educational attainment, a self-reported retrospective questionnaire on GCSE grades obtained at 16 years old was reported at age 18. GCSEs are exams taken at the end of secondary school (in year 11, age 15/16), where students are examined on an average of 8 subjects. At the time of these questionnaires, GCSE grades range from A* to G. In accordance with UK government benchmark measures (\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e), those who did not achieve grades between A*-C in all the subjects they were studying were defined as lower educational attainment and those who achieved grades within A*-C for all subjects as higher educational attainment.\u003c/p\u003e\u003cp\u003eFor young-adulthood, participants self-reported whether they were currently engaged in any education, employment or training at age 25. In accordance with the UK Office of National Statistics, participants who were not in employment (full-time/part-time/occasional or self-employed), doing an apprenticeship or any other government supported training or work experience scheme or full-time education were defined as being NEET (not in education, employment or training) which also included those doing voluntary work, those who were a part or full-time carer or those who were unable to work due to sickness or disability (\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cb\u003eSuicidality\u003c/b\u003e\u003c/p\u003e\u003cp\u003eSuicidality or risk of suicide encompassed questionnaire items describing suicidal thoughts, ideation and suicide attempts. For primary analyses, suicidality was defined as a lifetime report at age 11, whereas at ages 16 and 24, suicidality was present only if they had experienced suicidal thoughts within a year of completing the questionnaire. An answer of \u0026lsquo;yes\u0026rsquo; to any suicidality item was defined as the presence of suicidality, as defined previously (\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eAt age 11, suicidality was assessed using the Childhood Interview for DSM-IV Borderline Personality Disorder (CI-BPD) (\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e). This is a semi-structured interview including a suicidal behaviours section of four binary (yes/no) items: i) \u0026ldquo;Told someone you will kill yourself\u0026rdquo;, ii) \u0026ldquo;thought about killing yourself\u0026rdquo;, iii) \u0026ldquo;made plans to kill yourself\u0026rdquo; and iv) \u0026ldquo;actually tried to kill yourself\u0026rdquo;.\u003c/p\u003e\u003cp\u003eAt age 16 years, suicidality was measured using a self-reported questionnaire on deliberate self-harm. The questions within this section were based on the Child and Adolescent Self-harm in Europe (CASE) study (\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e). We defined suicidality as answering \u0026lsquo;yes\u0026rsquo; to both the following questions and reporting these actions within a year of survey completion: \u0026ldquo;have you ever hurt yourself on purpose in any way?\u0026rdquo; and \u0026ldquo;on any of the occasions where you have hurt yourself, have you ever seriously wanted to kill yourself?\u0026rdquo;. In addition, individuals answering \u0026lsquo;yes\u0026rsquo; to \u0026ldquo;have you ever felt that life was not worth living?\u0026rdquo; in the past year since survey completion were also classified as experiencing suicidality.\u003c/p\u003e\u003cp\u003eAt age 24 years, suicidality was measured using the computerised Interview Schedule- Revised (CIS-R) questionnaire which is a self-reported interview that determines diagnoses for depression and anxiety disorder, based on ICD-10 criteria (\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e, \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e). Within this questionnaire were the following items: i) \u0026lsquo;ever self-harmed with suicidal intent\u0026rsquo;, ii) \u0026lsquo;ever attempted suicide\u0026rsquo;, iii) \u0026lsquo;ever had suicidal thoughts\u0026rsquo; and iv) \u0026lsquo;when was the last time you had these thoughts?\u0026rsquo;.\u003c/p\u003e\u003cp\u003e\u003cb\u003eAnalyses\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAll analyses were conducted using stataSE (version 18). Initially, descriptive analyses were conducted to determine the prevalence of each outcome in the sample at each age. We then performed multivariable logistic regression models of each outcome at each age (9 models), including all PGS simultaneously. We used multiple imputation to account for missing data in our sample (those with genetic data), using the Stata package \u0026lsquo;ICE\u0026rsquo;. All outcomes were included in the imputation model, alongside the same phenotype at different ages (e.g. SDQ peer problems at ages 10 and 16 were used to predict SDQ peer problems at age 25, and suicidality at ages 11 and 16 were used to predict suicidality at age 24). Further auxiliary variables used to predict missingness in ALSPAC were also included in all models (socioeconomic status, multiple birth status, maternal age). 200 imputed data sets were created and results from regression analyses were pooled across all datasets. All other settings remained as the default option. Results using imputed data are presented in the main text, with analysis using unimputed data (listwise deletion) presented as sensitivity analysis.\u003c/p\u003e\u003cp\u003eSensitivity analyses were also conducted using parent-reported SDQ peer problems data at 25 years old and lifetime self-reports of suicidality at ages 16 and 24. We also performed univariable analysis examining the association of each PGS on each outcome.\u003c/p\u003e\u003cp\u003eWe used Benjamini-Hochberg false discovery rate (FDR) method to account for multiple comparisons (\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e). P-values for each PGS were corrected across the 9 multivariable models (across 9 outcomes). Both original p-values and corrected FDR q-values are presented in text and tables.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eIn the imputed sample (N\u0026thinsp;=\u0026thinsp;8,591), rates of peer problems increased across development (8.8% in childhood, 9.1% in adolescence and 18.5% in young-adulthood). Suicidality was highest in adolescence (24.3%), followed by young-adulthood (15.0%) and lowest in childhood (8.2%). For educational attainment, in childhood 17.5% of participants did not achieve a KS3 SAT grade 5 or above in both maths and English. In adolescence 7.5% did not achieve all GCSEs within A*-C. In young-adulthood 6.8% were not in education, employment or training.\u003c/p\u003e\u003cp\u003e\u003cb\u003eAssociation between neurodevelopmental/psychiatric PGS with social and functional outcomes\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003ePeer problems\u003c/b\u003e\u003c/p\u003e\u003cp\u003eFigure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cem\u003eTable \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e\u003c/em\u003e show multivariable associations between PGS and peer problems across development. ADHD PGS were associated with peer problems in childhood (OR\u0026thinsp;=\u0026thinsp;1.13, 95% CI [1.02\u0026ndash;1.25] p\u0026thinsp;=\u0026thinsp;0.020, q\u0026thinsp;=\u0026thinsp;0.030), adolescence (OR\u0026thinsp;=\u0026thinsp;1.21 [1.02\u0026ndash;1.34], p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, q\u0026thinsp;\u0026lt;\u0026thinsp;0.0005) and young-adulthood (OR\u0026thinsp;=\u0026thinsp;1.14 [1.03\u0026ndash;1.26], p\u0026thinsp;=\u0026thinsp;0.010, q\u0026thinsp;=\u0026thinsp;0.018), whereas we only found strong evidence of associations between ASD PGS and peer problems in childhood (OR\u0026thinsp;=\u0026thinsp;1.12 [1.02\u0026ndash;1.23], p\u0026thinsp;=\u0026thinsp;0.017, q\u0026thinsp;=\u0026thinsp;0.038). Depression PGS were associated with peer problems in childhood (OR\u0026thinsp;=\u0026thinsp;1.18 [1.06\u0026ndash;1.31], p\u0026thinsp;=\u0026thinsp;0.003, q\u0026thinsp;=\u0026thinsp;0.007) and young-adulthood (OR\u0026thinsp;=\u0026thinsp;1.21 [1.09\u0026ndash;1.35], p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, q\u0026thinsp;\u0026lt;\u0026thinsp;0.0005). There was also weaker evidence of association between bipolar disorder PGS and peer problems in adolescence (OR\u0026thinsp;=\u0026thinsp;1.10 [1.00-1.21], p\u0026thinsp;=\u0026thinsp;0.038, q\u0026thinsp;=\u0026thinsp;0.342). Finally, there was weaker evidence of association between schizophrenia PGS and the absence of peer problems in young-adulthood (OR\u0026thinsp;=\u0026thinsp;0.91, [0.83\u0026ndash;1.01], p\u0026thinsp;=\u0026thinsp;0.070, q\u0026thinsp;=\u0026thinsp;0.315). There was not strong evidence of association between anxiety PGS and peer problems at any developmental stage.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eEducational Attainment/ Employment\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cem\u003eTable S2\u003c/em\u003e, ADHD PGS were associated with poor educational attainment in childhood (OR\u0026thinsp;=\u0026thinsp;1.40 [1.29\u0026ndash;1.52], p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, q\u0026thinsp;\u0026lt;\u0026thinsp;0.0005) and adolescence (OR\u0026thinsp;=\u0026thinsp;1.62 [1.33\u0026ndash;1.98], p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, q\u0026thinsp;\u0026lt;\u0026thinsp;0.0005) as well as NEET in young-adulthood (OR\u0026thinsp;=\u0026thinsp;1.29 [1.08\u0026ndash;1.54], p\u0026thinsp;=\u0026thinsp;0.005, q\u0026thinsp;=\u0026thinsp;0.011). The opposite relationship was seen for ASD PGS, which was associated with greater educational attainment in childhood (OR\u0026thinsp;=\u0026thinsp;0.88 [0.81\u0026ndash;0.96], p\u0026thinsp;=\u0026thinsp;0.004, q\u0026thinsp;=\u0026thinsp;0.018) and adolescence (OR\u0026thinsp;=\u0026thinsp;0.77 [0.64\u0026ndash;0.93], p\u0026thinsp;=\u0026thinsp;0.007, q\u0026thinsp;=\u0026thinsp;0.021). Depression PGS were associated with poor educational attainment in adolescence (OR\u0026thinsp;=\u0026thinsp;1.39 [1.11\u0026ndash;1.73], p\u0026thinsp;=\u0026thinsp;0.004, q\u0026thinsp;=\u0026thinsp;0.007) and NEET in young-adulthood (OR\u0026thinsp;=\u0026thinsp;1.26 [1.04\u0026ndash;1.51], p\u0026thinsp;=\u0026thinsp;0.017, q\u0026thinsp;=\u0026thinsp;0.026), with weaker evidence of an association in childhood (OR\u0026thinsp;=\u0026thinsp;1.07 [0.98\u0026ndash;1.18], p\u0026thinsp;=\u0026thinsp;0.120, q\u0026thinsp;=\u0026thinsp;0.135). There was not strong evidence of an association with educational attainment or employment for schizophrenia PGS, bipolar disorder PGS or anxiety PGS at any age.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eSuicidality\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and \u003cem\u003eTable S3\u003c/em\u003e, both ADHD PGS (OR\u0026thinsp;=\u0026thinsp;1.13 [1.01\u0026ndash;1.26], p\u0026thinsp;=\u0026thinsp;0.030, q\u0026thinsp;=\u0026thinsp;0.039) and ASD PGS (OR\u0026thinsp;=\u0026thinsp;1.24 [1.12\u0026ndash;1.37], p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, q\u0026thinsp;\u0026lt;\u0026thinsp;0.0005) were associated with suicidality in childhood, with weaker evidence of an association in adolescence (ADHD PGS OR\u0026thinsp;=\u0026thinsp;1.07 [0.99\u0026ndash;1.15], p\u0026thinsp;=\u0026thinsp;0.095, q\u0026thinsp;=\u0026thinsp;0.107; ASD PGS OR\u0026thinsp;=\u0026thinsp;1.07 [0.10\u0026ndash;1.15], p\u0026thinsp;=\u0026thinsp;0.063, q\u0026thinsp;=\u0026thinsp;0.113). Depression PGS was associated with suicidality in adolescence (OR\u0026thinsp;=\u0026thinsp;1.28 [1.18\u0026ndash;1.39], p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, q\u0026thinsp;\u0026lt;\u0026thinsp;0.0005) and young-adulthood (OR\u0026thinsp;=\u0026thinsp;1.42 [1.26\u0026ndash;1.58], p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, q\u0026thinsp;\u0026lt;\u0026thinsp;0.0005). There was also weaker evidence, that did not survive correction for multiple testing, of associations between anxiety PGS and suicidality in childhood (OR\u0026thinsp;=\u0026thinsp;1.12 [1.00-1.25], p\u0026thinsp;=\u0026thinsp;0.047, q\u0026thinsp;=\u0026thinsp;0.423) and between schizophrenia PGS and suicidality in young-adulthood (OR\u0026thinsp;=\u0026thinsp;1.14 [1.029\u0026ndash;1.266], p\u0026thinsp;=\u0026thinsp;0.013, q\u0026thinsp;=\u0026thinsp;0.117). There was no evidence of association with suicidality and bipolar disorder PGS at any developmental stage.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eSensitivity Analyses\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAnalyses using parent-reported peer problems in young-adulthood showed a consistent pattern of results as the primary self-reported analyses (see supplementary \u003cem\u003eTable S4\u003c/em\u003e). Analyses investigating lifetime suicidality in adolescence were consistent with those in the primary analyses (suicidality within one year of assessment, see supplementary \u003cem\u003eTable S5\u003c/em\u003e). However, results investigating lifetime suicidality in young-adulthood found weaker evidence of association for schizophrenia PGS (OR\u0026thinsp;=\u0026thinsp;1.06, 95% CI\u0026thinsp;=\u0026thinsp;0.98\u0026ndash;1.15, p\u0026thinsp;=\u0026thinsp;0.161) and found evidence of association for ASD PGS (OR\u0026thinsp;=\u0026thinsp;1.11, 95% CI\u0026thinsp;=\u0026thinsp;1.02\u0026ndash;1.20, p\u0026thinsp;=\u0026thinsp;0.013), see supplementary \u003cem\u003eTable S6\u003c/em\u003e.\u003c/p\u003e\u003cp\u003eAnalyses run using listwise deletion were consistent with primary analyses using imputed data (supplementary \u003cem\u003eTables S7-9\u003c/em\u003e).\u003c/p\u003e\u003cp\u003eFinally, the results of univariate analyses between each PGS with each outcome was largely consistent with the primary analyses (see supplementary tables, \u003cem\u003eS10-12\u003c/em\u003e). Stronger evidence of an association compared to multivariable analyses was found for both depression and anxiety PGS and peer problems in adolescence as well as poor educational attainment in childhood. There was also stronger evidence of an association between anxiety PGS and unemployment in young-adulthood. Weaker evidence of an association compared to multivariable analyses was found between ASD PGS and greater educational attainment in childhood and adolescence.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study used data from a longitudinal birth cohort to examine associations between PGS for six neurodevelopmental/psychiatric conditions (ADHD, ASD, schizophrenia, bipolar disorder, depression and anxiety) and adverse outcomes (peer problems, educational attainment/employment and suicidality) across childhood, adolescence and young-adulthood. ADHD and ASD PGS were more associated with outcomes in childhood and adolescence, while depression PGS showed stronger associations in adolescence and young-adulthood. We did not find strong evidence of associations for schizophrenia, bipolar disorder and anxiety PGS. Findings in relation to the hypotheses are discussed below.\u003c/p\u003e\u003cp\u003eConsistent with the first neurodevelopmental hypothesis, ADHD PGS was associated with peer problems and lower educational attainment/unemployment across development as well as suicidality in childhood. There was not strong evidence of an association between ADHD PGS and suicidality in young-adulthood, which corroborates findings from a previous study (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). A potential explanation for this may be that ADHD PGS show greater associations with cognitive traits, like educational attainment, in young-adulthood than psychological traits, like suicidality (\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e). However, inconsistent with our neurodevelopmental hypothesis, we did not find consistent evidence of an associations with PGS for ASD and schizophrenia across development. ASD PGS was associated with peer problems and suicidality in childhood only, as well as greater educational attainment in childhood and adolescence.\u003c/p\u003e\u003cp\u003ePrevious research suggests that childhood peer problems associated with ASD PGS remain elevated and developmentally stable, indicating that an association would likely persist across development (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Previous works found evidence of an association between ASD PGS and peer problems during adolescence (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e); however, this analysis was based on univariate analyses, which may have also captured associations with genetic liability for other genetically correlated conditions, such as ADHD. A similar pattern was observed in the present study, where univariate analyses also identified an association between ASD PGS and peer problems in adolescence, highlighting that previous associations between ASD PGS and peer problems after childhood were likely driven by genetic correlation with other conditions, likely ADHD.\u003c/p\u003e\u003cp\u003eAdditionally, due to genetic overlap between ADHD and ASD, it was hypothesised that both ADHD and ASD PGS would be associated with worse educational attainment and unemployment across development. However, we identified an association between ADHD PGS and lower educational attainment across development, but in contrast, an association between ASD PGS and greater educational attainment in childhood and adolescence. Both the multivariable and univariate analyses are consistent with previous work showing that the shared genetic liability to ADHD and ASD, and genetic liability specific to ADHD, are associated with lower educational attainment, whereas genetic liability specific to ASD is associated with higher educational attainment (\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e). This highlights the importance of studying the genetic liability of multiple conditions together and underscores the complexity of the genetic liability for each condition with intricate genetic underpinnings that require careful interpretation.\u003c/p\u003e\u003cp\u003eIt was also hypothesised that schizophrenia PGS would be associated with suicidality across development, due to the neurodevelopmental origins of the condition and previous findings of such associations in both childhood (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) and adulthood (\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e). Yet in the current study, only weak evidence of an association was identified in young-adulthood, which did not survive correction for multiple testing. The lack of associations with childhood suicidality is consistent with findings by Lee et al. (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e), who did not observe associations between schizophrenia PGS and suicidality in The Adolescent Brain and Cognitive Development (ABCD) Study. These findings thus provide some evidence that schizophrenia PGS may be associated with suicidality in young-adulthood, rather than earlier in development. Studies that are not sensitive to the developmental context may therefore miss these more specific associations which emphasises the significance of the developmental approach.\u003c/p\u003e\u003cp\u003eThe current study found decreasing effect sizes for the association between schizophrenia PGS and peer problems across development, consistent with a previous study (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e), who reported similar declines from ages 7 to 17 in ALSPAC. Notably, the current findings extend this trend to young-adulthood and provide weak evidence of an association with the absence of peer problems during this period. One possible explanation involves developmental change in social-emotional cognition: individuals with schizophrenia often shown reduced cognitive empathy (e.g. recognising others\u0026rsquo; emotions) but preserved or heightened social empathy (e.g. affective empathy and emotional contagion) compared to controls (\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e). These findings may suggest that the genetic liability to schizophrenia may be more associated with preserved social empathy later in development, potentially resulting in intact peer relationships, and again, underscores the importance of a developmental perspective.\u003c/p\u003e\u003cp\u003eConsistent with our depression hypothesis, depression PGS was associated with poor educational attainment/unemployment and suicidality in adolescence and young-adulthood. Unexpectedly, we did not find evidence of an association between depression PGS and suicidality in childhood. This contrasts with previous research (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) which reports an association in a similarly aged cohort. One possible cause for this discrepancy is the use of different GWAS datasets to derive the depression PGS. The current study used a GWAS based on clinically defined MDD diagnoses (DSM-IV/V or ICD-9/10), whereas the previous study (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) used a GWAS that did not rely on standard diagnostic criteria, potentially capturing a broader phenotype, which may explain why an association was identified in childhood.\u003c/p\u003e\u003cp\u003eUnlike for depression PGS, in multivariable analyses for anxiety PGS we did not find strong evidence of an association with peer problems, suicidality or educational attainment/unemployment in childhood, adolescence or young-adulthood. These results support a previous study (\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e) which also did not find strong evidence of association between anxiety PGS and adult suicidality. However, in this current study, univariate analyses did show associations with suicidality at all three developmental stages for both depression and anxiety PGS. Taken together with the multivariable analyses, this highlights the genetic overlap between depression and anxiety and the importance of analyses that investigate the genetic liability for both conditions together. The multivariable analyses suggest that both the genetic liability for anxiety and depression is associated with suicidality, but that the genetic liability to anxiety may play a stronger role for suicidality in childhood and depression genetic lability to suicidality after puberty.\u003c/p\u003e\u003cp\u003eFinally, findings for bipolar disorder PGS were not consistent with our hypotheses (that bipolar disorder PGS would be associated with greater educational attainment/unemployment in adolescence and young-adulthood, as well as peer problems and suicidality in young-adulthood). Strong evidence was not found in support of any of these: only weak evidence of an association with peer problems in adolescence was identified. One explanation of these results may lie within the developmental pattern of the manifestations of social problems in bipolar disorder, and therefore potentially bipolar PGS, whereby certain aspects, like emotional dysregulation (\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e) may be more pronounced in childhood and therefore influencing peer rejection, whereas more internalising aspects (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) being more apparent in adulthood, influencing feelings of loneliness. Thus, it is possible that this study did not find evidence of an association between bipolar disorder PGS and peer problems in adulthood due to the SDQ peer problems measure broadly encompassing several sub-constructs, like peer victimisation (\u0026ldquo;picked on or bulled by others\u0026rdquo;) and popularity (\u0026ldquo;liked by other children\u0026rdquo;) instead of focussing on aspects like loneliness.\u003c/p\u003e\u003cp\u003e\u003cb\u003eStrengths and Limitations\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThis study has several important strengths. The longitudinal study design allowed us to examine outcomes assessed prospectively across three developmental periods. Further, the use of both multivariable and univariate models to examine genetic liability means that that we are able to assess the impact of genetic liability specific to individual neurodevelopmental/psychiatric disorders on outcomes of interest. Additionally, this study focussed on a general population sample, reducing the sampling bias often seen in clinical samples. Since genetic liability to these conditions is continuous, population samples better capture associations between varying genetic risk levels and adverse outcomes, improving generalisability.\u003c/p\u003e\u003cp\u003eThe results of this study should be viewed considering methodological limitations. Firstly, except for the SDQ peer problems subscale, outcome measures varied across development. This somewhat limits comparability of suicidality and educational attainment across ages. To improve validity, future longitudinal studies should use consistent measures where possible to distinguish true developmental changes from measurement variation. However, this may not always be feasible, as some tools may not be appropriate for all age groups. Similarly, we used cross-sectional analyses, limiting our ability to assess changes over time, Consequently, we cannot infer how neurodevelopmental/psychiatric PGS may relate to developmental trajectories of educational attainment, suicidality and peer problems. Future research could used trajectory-based methods, to identify developmental patterns which may inform more targeted interventions.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis study provides novel insights into how genetic liability to neurodevelopmental/psychiatric conditions relates to adverse social and functional outcomes across development. We found variation in the strength and direction of associations across conditions, outcomes and development stage. Our results showed that ADHD and depression PGS were linked to all examined outcomes, suggesting broad and potentially negative influences of genetic liability to these conditions. However while ADHD PGS showed association across development, associations for depression PGS were more common from adolescence. ASD PGS showed association specifically with suicidality in childhood, and with greater educational attainment in childhood and adolescence. We did not find strong evidence of associations for schizophrenia, bipolar disorder or anxiety PGS. Our findings highlight the importance of examining genetic liability to multiple neurodevelopmental/psychiatric conditions simultaneous and of a developmental perspective.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEthical Approval\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical approval for this study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees. Consent for biological samples has been collected in accordance with the Human Tissue Act (2004). Informed consent for the use of data collected via questionnaires and clinics was obtained from participants following the recommendations of the ALSPAC Ethics and Law Committee at the time.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAcknowledgements\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/ 19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and AS will serve as guarantor for the contents of this paper. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf).\u003c/p\u003e\n\u003cp\u003eThis research was specifically funded by the Wolfson Centre for Young People\u0026rsquo;s Mental Health, established with support from the Wolfson Foundation. We also acknowledge the support of the Supercomputing Wales project, which is part-funded by the European Regional Development Fund (ERDF) via Welsh Government. ALSPAC GWAS data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors report no conflicts of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eGidziela A, Ahmadzadeh YI, Michelini G, Allegrini AG, Agnew-Blais J, Lau LY, et al. A meta-analysis of genetic effects associated with neurodevelopmental disorders and co-occurring conditions. Nature Human Behaviour. 2023 Feb 20;7. Available from: https://www.nature.com/articles/s41562-023-01530-y\u003c/li\u003e\n \u003cli\u003eWaszczuk MA, Zavos HMS, Gregory AM, Eley TC. The Phenotypic and Genetic Structure of Depression and Anxiety Disorder Symptoms in Childhood, Adolescence, and Young Adulthood. 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JAMA Psychiatry. 2019 Jul 1;76(7):730. doi: https://doi.org/10.1001/jamapsychiatry.2019.0310\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"molecular-psychiatry","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"mp","sideBox":"Learn more about [Molecular Psychiatry](http://www.nature.com/mp/)","snPcode":"41380","submissionUrl":"https://mts-mp.nature.com/cgi-bin/main.plex","title":"Molecular Psychiatry","twitterHandle":"@molpsychiatry","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"ALSPAC, Polygenic scores, Suicidality, Educational attainment, Peer problems, Genetics","lastPublishedDoi":"10.21203/rs.3.rs-7217396/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7217396/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eNeurodevelopmental and psychiatric conditions often originate in youth and can lead to adverse social and functional outcomes. However, it is unclear whether these associations are driven by genetic liability to these conditions, with possible developmental differences. We examined multivariable associations between polygenic scores (PGS) for attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), schizophrenia, bipolar disorder, depression, anxiety and three outcomes: peer problems, educational attainment/NEET (not in education, employment or training) and suicidality, in childhood, adolescence and young-adulthood. Data were analysed from the Avon Longitudinal Study of Parents and Children, with outcomes at ages 10\u0026ndash;13, 16 and 24\u0026ndash;25 years. ADHD PGS was associated with peer problems in childhood, adolescence and young-adulthood, as well as with lower educational attainment in childhood/adolescence and NEET status in young-adulthood. ASD PGS was associated with greater educational attainment in childhood and adolescence, and increased likelihood of suicidality in childhood. Depression PGS was associated with peer problems in childhood and young-adulthood, and poorer educational attainment/NEET and suicidality in adolescence and young-adulthood. We did not find strong evidence of associations for schizophrenia, bipolar disorder or anxiety PGS. These findings suggest that genetic liability to neurodevelopmental and psychiatric conditions are associated with a range of social/functional outcomes, although the strength and direction of association varies by PGS, outcome and development stage. This highlights the importance of examining genetic liability to multiple neurodevelopmental and psychiatric conditions simultaneously and of a developmental perspective.\u003c/p\u003e","manuscriptTitle":"Investigating the Associations between Neurodevelopmental and Psychiatric Genetic Liability and Adverse Social and Functional Outcomes across Childhood, Adolescence and Young-Adulthood","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-02 06:46:15","doi":"10.21203/rs.3.rs-7217396/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2026-01-27T15:38:47+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-01-22T20:16:51+00:00","index":6,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-01-20T14:21:35+00:00","index":5,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-12-20T07:53:41+00:00","index":7,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-12-17T17:06:43+00:00","index":6,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-12-17T12:00:10+00:00","index":5,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2025-10-27T10:14:30+00:00","index":4,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-10-15T12:48:09+00:00","index":4,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-10-15T08:46:04+00:00","index":3,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2025-09-29T11:41:08+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-09-15T08:03:35+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2025-09-09T16:36:59+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-08-27T09:51:24+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2025-08-22T17:30:20+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-31T11:40:37+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-31T11:28:39+00:00","index":"","fulltext":""},{"type":"submitted","content":"Molecular Psychiatry","date":"2025-07-30T10:39:17+00:00","index":"","fulltext":""},{"type":"checksFailed","content":"","date":"2025-07-28T10:31:11+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"molecular-psychiatry","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"mp","sideBox":"Learn more about [Molecular Psychiatry](http://www.nature.com/mp/)","snPcode":"41380","submissionUrl":"https://mts-mp.nature.com/cgi-bin/main.plex","title":"Molecular Psychiatry","twitterHandle":"@molpsychiatry","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"08cd3e7a-c645-42cc-b737-197bd6fdf4b8","owner":[],"postedDate":"September 2nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":53585959,"name":"Biological sciences/Genetics"},{"id":53585960,"name":"Health sciences/Diseases/Psychiatric disorders/ADHD"},{"id":53585961,"name":"Health sciences/Diseases/Psychiatric disorders/Autism spectrum disorders"}],"tags":[],"updatedAt":"2026-04-30T09:04:37+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-02 06:46:15","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7217396","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7217396","identity":"rs-7217396","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}