Systems-level genomic analyses reveal shared mechanisms underlying endometriosis and sleep disorders

We examined clinical, genetic, and molecular links between sleep disorders and endometriosis. Women aged 20–54 years in NHANES 2005–2006 were analyzed with survey-weighted logistic regression. Bidirectional two-sample Mendelian randomization (MR) was used to assess genetic directionality. Endometriosis-related genes were obtained from the Endometriosis eQTL analysis, whereas sleep disorder-related proteins were obtained from the sleep disorder pQTL analysis and mapped to their encoding genes. The two candidate lists were intersected by gene symbol, and shared candidates were evaluated by pathway enrichment, transcriptomic validation, machine-learning prioritization, single-cell localization, drug-gene annotation, and exploratory docking. Among 1,460 women, clinician-diagnosed sleep disorder was more common in those with endometriosis than in those without endometriosis (weighted prevalence, 13.4% vs 5.1%). In the core adjusted model, endometriosis was associated with higher odds of clinician-diagnosed sleep disorder (OR 2.64, 95% CI 1.03–6.76; P = 0.044). Forward MR suggested a modest association between genetic liability to sleep disorders and endometriosis risk (IVW OR 1.11, 95% CI 1.00–1.22; P = 0.040), whereas reverse MR provided no clear evidence for the opposite direction. Intersecting endometriosis-related eQTL genes with sleep disorder-related pQTL protein-coding genes yielded 37 shared xQTL-prioritized gene/protein candidates. Downstream analyses highlighted glucose metabolism, MAPK signaling, inflammatory pathways, and stromal-cell expression of SPARC and YEATS4. Sleep disorders and endometriosis showed convergent epidemiologic, genetic, and expression-based signals. The core clinical association remained positive after adjustment for major demographic and lifestyle covariates. The genetic and molecular findings should be interpreted as hypothesis-generating pending prospective and experimental validation. Similar content being viewed by others Data availability No new datasets were generated in this study. All data analyzed are publicly available: NHANES 2005–2006 data are available from the National Health and Nutrition Examination Survey (NHANES); genome-wide association summary statistics for sleep disorders (OpenGWAS id: finn-b-SLEEP) and endometriosis (details in Supplementary Table 1) were obtained from the OpenGWAS and Finn resources; transcriptomic and single-cell RNA-seq datasets were downloaded from the Gene Expression Omnibus (GEO) (GSE4888, GSE5108, GSE6364, GSE7846, GSE37837, GSE58178, GSE120103, and GSE214411). Additional information required to reproduce the analyses is provided in the Supplementary Materials, and analysis code is available from the corresponding author upon reasonable request.

Chen J, Shen L, Wu T, Yang Y (2024) Unraveling the significance of AGPAT4 for the pathogenesis of endometriosis via a multi-omics approach. Hum Genet 143:1163–1174 Chlenski A, Cohn SL (2010) Modulation of matrix remodeling by SPARC in neoplastic progression. Semin Cell Dev Biol 21:55–65 Chuang HH, Huang CG, Hsu JF, Chuang LP, Huang YS, Li HY, Lee LA (2024) Weight status, autonomic function, and systemic inflammation in children with obstructive sleep apnea. Int J Mol Sci. https://doi.org/10.3390/ijms25168951 Coxon L, Demetriou L, Vincent K (2024) Current developments in endometriosis-associated pain. Cell Rep Med 5:101769 de Souza RJ, Brollo LCS, Carrerette FB, Villela NR, Oliveira MAP (2024) Challenges in measuring sleep quality among women with endometriosis: a comparison of two questionnaires. Sleep Med 114:250–254 Facchin F, Buggio L, Roncella E, Somigliana E, Ottolini F, Dridi D, Roberto A, Vercellini P (2021) Sleep disturbances, fatigue and psychological health in women with endometriosis: a matched pair case-control study. Reprod Biomed Online 43:1027–1034 Frizell E, Liu SL, Abraham A, Ozaki I, Eghbali M, Sage EH, Zern MA (1995) Expression of SPARC in normal and fibrotic livers. Hepatology 21:847–854 Gazzinelli-Guimaraes PH, Dulek B, Swanson P, Lack J, Roederer M, Nutman TB (2024) ’Single-cell molecular signature of pathogenic T helper subsets in type 2-associated disorders in humans. JCI Insight 9:e177720 Henlon Y, Panir K, McIntyre I, Hogg C, Dhami P, Cuff AO, Senior A, Moolchandani-Adwani N, Courtois ET, Horne AW, Rosser M, Ott S, Greaves E (2024) Single-cell analysis identifies distinct macrophage phenotypes associated with prodisease and proresolving functions in the endometriotic niche. Proc Natl Acad Sci U S A 121:e2405474121 Huang W, Ramsey KM, Marcheva B, Bass J (2011) Circadian rhythms, sleep, and metabolism. J Clin Invest 121:2133–2141 Irwin MR (2015) Why sleep is important for health: a psychoneuroimmunology perspective. Annu Rev Psychol 66:143–172 Ishikura IA, Hachul H, Pires GN, Tufik S, Andersen ML (2020) The relationship between insomnia and endometriosis. J Clin Sleep Med 16:1387–1388 Kitchen DB, Decornez H, Furr JR, Bajorath J (2004) Docking and scoring in virtual screening for drug discovery: methods and applications. Nat Rev Drug Discov 3:935–949 Langenbach F, Handschel J (2013) Effects of dexamethasone, ascorbic acid and β-glycerophosphate on the osteogenic differentiation of stem cells in vitro. Stem Cell Res Ther 4:117 Lempesis IG, Georgakopoulou VE, Reiter RJ, Spandidos DA (2024) A mid-pandemic night’s dream: melatonin, from harbinger of anti-inflammation to mitochondrial savior in acute and long COVID-19 (review). Int J Mol Med 53:28 Leuenberger J, Kohl Schwartz AS, Geraedts K, Haeberlin F, Eberhard M, von Orellie S, Imesch P, Leeners B (2022) Living with endometriosis: comorbid pain disorders, characteristics of pain and relevance for daily life. Eur J Pain 26:1021–1038 Ligthart S, Vaez A, Võsa U, Stathopoulou MG, de Vries PS, Prins BP, Van der Most PJ, Tanaka T, Naderi E, Rose LM, Wu Y, Karlsson R, Barbalic M, Lin H, Pool R, Zhu G, Macé A, Sidore C, Trompet S, Mangino M, Sabater-Lleal M, Kemp JP, Abbasi A, Kacprowski T, Verweij N, Smith AV, Huang T, Marzi C, Feitosa MF, Lohman KK, Kleber ME, Milaneschi Y, Mueller C, Huq M, Vlachopoulou E, Lyytikäinen LP, Oldmeadow C, Deelen J, Perola M, Zhao JH, Feenstra B, Amini M, Lahti J, Schraut KE, Fornage M, Suktitipat B, Chen WM, Li X, Nutile T, Malerba G, Luan J, Bak T, Schork N, Del Greco MF, Thiering E, Mahajan A, Marioni RE, Mihailov E, Eriksson J, Ozel AB, Zhang W, Nethander M, Cheng YC, Aslibekyan S, Ang W, Gandin I, Yengo L, Portas L, Kooperberg C, Hofer E, Rajan KB, Schurmann C, den Hollander W, Ahluwalia TS, Zhao J, Draisma HHM, Ford I, Timpson N, Teumer A, Huang H, Wahl S, Liu Y, Huang J, Uh HW, Geller F, Joshi PK, Yanek LR, Trabetti E, Lehne B, Vozzi D, Verbanck M, Biino G, Saba Y, Meulenbelt I, O’Connell JR, Laakso M, Giulianini F, Magnusson PKE, Ballantyne CM, Hottenga JJ, Montgomery GW, Rivadineira F, Rueedi R, Steri M, Herzig KH, Stott DJ, Menni C, Frånberg M, St Pourcain B, Felix SB, Pers TH, Bakker SJL, Kraft P, Peters A, Vaidya D, Delgado G, Smit JH, Großmann V, Sinisalo J, Seppälä I, Williams SR, Holliday EG, Moed M, Langenberg C, Räikkönen K, Ding J, Campbell H, Sale MM, Chen YI, James AL, Ruggiero D, Soranzo N, Hartman CA, Smith EN, Berenson GS, Fuchsberger C, Hernandez D, Tiesler CMT, Giedraitis V, Liewald D, Fischer K, Mellström D, Larsson A, Wang Y, Scott WR, Lorentzon M, Beilby J, Ryan KA, Pennell CE, Vuckovic D, Balkau B, Concas MP, Schmidt R, Mendes de Leon CF, Bottinger EP, Kloppenburg M, Paternoster L, Boehnke M, Musk AW, Willemsen G, Evans DM, Madden PAF, Kähönen M, Kutalik Z, Zoledziewska M, Karhunen V, Kritchevsky SB, Sattar N, Lachance G, Clarke R, Harris TB, Raitakari OT, Attia JR, van Heemst D, Kajantie E, Sorice R, Gambaro G, Scott RA, Hicks AA, Ferrucci L, Standl M, Lindgren CM, Starr JM, Karlsson M, Lind L, Li JZ, Chambers JC, Mori TA, Ejcn de Geus AC, Heath NG, Martin J, Auvinen BM, de Buckley AJM, Craen M, Waldenberger K, Strauch T, Meitinger RJ, Scott M, McEvoy M, Beekman C, Bombieri PM, Ridker KL, Mohlke NL, Pedersen AC, Morrison DI, Boomsma JB, Whitfield DP, Strachan A, Hofman P, Vollenweider F, Cucca MR, Jarvelin JW, Jukema TD, Spector A, Hamsten T, Zeller AG, Uitterlinden M, Nauck V, Gudnason L, Qi H, Grallert IB, Borecki JI, Rotter W, März PS, Wild ML, Lokki M, Boyle V, Salomaa M, Melbye JG, Eriksson JF, Wilson BP, Becker DM, Worrall BB, Gibson G, Krauss RM, Ciullo M, Zaza G, Wareham NJ, Oldehinkel AJ, Palmer LJ, Murray SS, Pramstaller PP, Bandinelli S, Heinrich J, Ingelsson E, Deary IJ, Mägi R, Vandenput L, van der Harst P, Desch KC, Kooner JS, Ohlsson C, Hayward C, Lehtimäki T, Shuldiner AR, Arnett DK, Beilin LJ, Robino A, Froguel P, Pirastu M, Jess T, Koenig W, Loos RJF, Evans DA, Schmidt H, Smith GD, Slagboom PE, Eiriksdottir G, Morris AP, Psaty BM, Tracy RP, Nolte IM, Boerwinkle E, Visvikis-Siest S, Reiner AP, Gross M, Bis JC, Franke L, Franco OH, Benjamin EJ, Chasman DI, Dupuis J, Snieder H, Dehghan A, Alizadeh BZ (2018) Genome analyses of >200,000 individuals identify 58 loci for chronic inflammation and highlight pathways that link inflammation and complex disorders. Am J Hum Genet 103:691–706 Liu B, Yang L, Zhu X, Li H, Zhu P, Wu J, Lu T, He L, Liu N, Meng S, Zhou L, Ye B, Tian Y, Fan Z (2019) Yeats4 drives ILC lineage commitment via activation of Lmo4 transcription. J Exp Med 216:2653–2668 Morris GM, Lim-Wilby M (2008) Molecular docking. Methods Mol Biol 443:365–382 Park W, Jang H, Kim HS, Park SJ, Lim W, Song G, Park S (2024) Therapeutic efficacy and anti-inflammatory mechanism of baicalein on endometriosis progression in patient-derived cell line and mouse model. Phytomedicine 130:155469 Pascual-Pasto G, Castillo-Ecija H, Unceta N, Aschero R, Resa-Pares C, Gómez-Caballero A, Vila-Ubach M, Muñoz-Aznar O, Suñol M, Burgueño V, Gomez-Gonzalez S, Sosnik A, Ibarra M, Schaiquevich P, de Álava E, Tirado OM, Mora J, Carcaboso AM (2022) SPARC-mediated long-term retention of nab-paclitaxel in pediatric sarcomas. J Control Release 342:81–92 Ramu I, Buchholz SM, Patzak MS, Goetze RG, Singh SK, Richards FM, Jodrell DI, Sipos B, Ströbel P, Ellenrieder V, Hessmann E, Neesse A (2019) SPARC dependent collagen deposition and gemcitabine delivery in a genetically engineered mouse model of pancreas cancer. EBioMedicine 48:161–168 Reel PS, Reel S, Pearson E, Trucco E, Jefferson E (2021) Using machine learning approaches for multi-omics data analysis: a review. Biotechnol Adv 49:107739 Sekharan S, Morokuma K (2011) Why 11-cis-retinal? Why not 7-cis-, 9-cis-, or 13-cis-retinal in the eye? J Am Chem Soc 133:19052–19055 The Lancet (2024) Endometriosis: addressing the roots of slow progress. Lancet (London, England), 404(10460), 1279. https://doi.org/10.1016/S0140-6736(24)02179-2 Välimäki N, Jokinen V, Cajuso T, Kuisma H, Taira A, Dagnaud O, Ilves S, Kaukomaa J, Pasanen A, Palin K, Heikinheimo O, Bützow R, Aaltonen LA, Karhu A (2023) Inherited mutations affecting the SRCAP complex are central in moderate-penetrance predisposition to uterine leiomyomas. Am J Hum Genet 110:460–474 VanBuren W, Feldman M, Shenoy-Bhangle AS, Sakala MD, Young S, Chamie LP, Giudice L, Hindman NM, Tong A, Rabban JT, Yano M, Kilcoyne A, Dave HD, Poder L, Kho RM, Burnett TL, Khan Z, King C, Shen L, Colak C, Burk KS, Andrieu PIC, Franco IVP, Glanc P, Kielar AZ, Taffel MT, Kania LM, Bonde A, Pectasides M, Arif-Tiwari H, Laifer-Narin S, Nicola R, Jha P (2024) Radiology state-of-the-art review: endometriosis imaging interpretation and reporting. Radiology 312:e233482 Vandereyken K, Sifrim A, Thienpont B, Voet T (2023) Methods and applications for single-cell and spatial multi-omics. Nat Rev Genet 24:494–515 Wang XL, Yuan K, Zhang W, Li SX, Gao GF, Lu L (2020) Regulation of circadian genes by the MAPK pathway: implications for rapid antidepressant action. Neurosci Bull 36:66–76 Wang QS, Hasegawa T, Namkoong H, Saiki R, Edahiro R, Sonehara K, Tanaka H, Azekawa S, Chubachi S, Takahashi Y, Sakaue S, Namba S, Yamamoto K, Shiraishi Y, Chiba K, Tanaka H, Makishima H, Nannya Y, Zhang Z, Tsujikawa R, Koike R, Takano T, Ishii M, Kimura A, Inoue F, Kanai T, Fukunaga K, Ogawa S, Imoto S, Miyano S, Okada Y (2024) Statistically and functionally fine-mapped blood eQTLs and pQTLs from 1,405 humans reveal distinct regulation patterns and disease relevance. Nat Genet 56:2281 Xie M, Zhou L, Li T, Lin Y, Zhang R, Zheng X, Zeng C, Zheng L, Zhong L, Huang X, Zou Y, Kang T, Wu Y (2024) Targeting the KAT8/YEATS4 axis represses tumor growth and increases cisplatin sensitivity in bladder cancer. Adv Sci (Weinh) 11:e2310146 Zhang Y, Yu S, Chen Z, Liu H, Li H, Long X, Ye F, Luo W, Dai Y, Tu S, Chen W, Kong S, He Y, Xue L, Tan N, Liang H, Zhang Z, He P, Duan C, Liu Y (2024) Gestational diabetes and future cardiovascular diseases: associations by sex-specific genetic data. Eur Heart J. https://doi.org/10.1093/eurheartj/ehae706 Zhou M, Xu W, Wang J, Yan J, Shi Y, Zhang C, Ge W, Wu J, Du P, Chen Y (2018) Boosting mTOR-dependent autophagy via upstream TLR4-MyD88-MAPK signalling and downstream NF-κB pathway quenches intestinal inflammation and oxidative stress injury. EBioMedicine 35:345–360 Funding This study was supported by the Hunan Provincial Natural Science Foundation of China (2022JJ40839, 2022JJ30955, and 2023JJ40927). Author information Authors and Affiliations Contributions JC, LCS, and YWY conceptualized and designed the study. JC and LCS were responsible for data collection. JC and LCS conducted the analysis and interpreted the results. JC drafted the initial manuscript. All authors participated in reviewing and editing multiple versions of the manuscript. YWY, JC and LCS supervised the study and secured project funding. All authors reviewed the manuscript. Corresponding author Ethics declarations Ethics approval and consent to participate This study was a secondary analysis of de-identified, publicly available data. For the NHANES 2005–2006 component, the original NHANES protocols were approved by the National Center for Health Statistics Research Ethics Review Board, and all participants provided written informed consent. The present secondary analysis used publicly available de-identified data and therefore did not require additional institutional review board approval. Clinical trial number: not applicable. Consent for publication Not applicable. Competing interests The authors declare no competing interests. Additional information Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Supplementary Information Below is the link to the electronic supplementary material. Rights and permissions Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. About this article Cite this article Shen, L., Chen, J. & Yang, Y. Systems-level genomic analyses reveal shared mechanisms underlying endometriosis and sleep disorders. Funct Integr Genomics 26, 203 (2026). https://doi.org/10.1007/s10142-026-01979-w Received: Revised: Accepted: Published: Version of record: DOI: https://doi.org/10.1007/s10142-026-01979-w