March 24, 2025

Cure Health Life

Wellness Starts Here

Atlas of genetic and phenotypic associations across 42 female reproductive health diagnoses

Atlas of genetic and phenotypic associations across 42 female reproductive health diagnoses

  • Mercuri, N. D. & Cox, B. J. The need for more research into reproductive health and disease. eLife 11, e75061 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • A life-course approach to women’s health. Nat. Med. 30, 1 (2024).

  • Abdellaoui, A., Yengo, L., Verweij, K. J. H. & Visscher, P. M. 15 years of GWAS discovery: realizing the promise. Am. J. Hum. Genet. 110, 179–194 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Day, F. et al. Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria. PLoS Genet. 14, e1007813 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Moolhuijsen, L. M. E. et al. Genomic and proteomic evidence for hormonal and metabolic foundations of polycystic ovary syndrome. Preprint at medRxiv (2024).

  • Rahmioglu, N. et al. The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions. Nat. Genet. 55, 423–436 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • O’Mara, T. A. et al. Identification of nine new susceptibility loci for endometrial cancer. Nat. Commun. 9, 3166 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Phelan, C. M. et al. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer. Nat. Genet. 49, 680–691 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Koel, M. et al. GWAS meta-analyses clarify the genetics of cervical phenotypes and inform risk stratification for cervical cancer. Hum. Mol. Genet. 32, 2103–2116 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Honigberg, M. C. et al. Polygenic prediction of preeclampsia and gestational hypertension. Nat. Med. 29, 1540–1549 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Tyrmi, J. S. et al. Genetic risk factors associated with preeclampsia and hypertensive disorders of pregnancy. JAMA Cardiol. 8, 674–683 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Pervjakova, N. et al. Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes. Hum. Mol. Genet. 31, 3377–3391 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Elliott, A. et al. Distinct and shared genetic architectures of gestational diabetes mellitus and type 2 diabetes. Nat. Genet. 56, 377–382 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Fejzo, M. S. et al. Placenta and appetite genes GDF15 and IGFBP7 are associated with hyperemesis gravidarum. Nat. Commun. 9, 1178 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Pujol Gualdo, N., Estonian Biobank Research Team, Mägi, R. & Laisk, T. Genome-wide association study meta-analysis supports association between MUC1 and ectopic pregnancy. Hum. Reprod. 38, 2516–2525 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Solé-Navais, P. et al. Genetic effects on the timing of parturition and links to fetal birth weight. Nat. Genet. 55, 559–567 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kentistou, K. A. et al. Understanding the genetic complexity of puberty timing across the allele frequency spectrum. Nat. Genet. 56, 1397–1411 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Ruth, K. S. et al. Genetic insights into biological mechanisms governing human ovarian ageing. Nature 596, 393–397 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Xiao, B. et al. Inference of causal relationships between genetic risk factors for cardiometabolic phenotypes and female-specific health conditions. J. Am. Heart Assoc. 12, e026561 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Leitsalu, L. et al. Cohort profile: Estonian Biobank of the Estonian Genome Center, University of Tartu. Int. J. Epidemiol. 44, 1137–1147 (2015).

    Article 
    PubMed 

    Google Scholar 

  • Milani, L. et al. From biobanking to personalized medicine: the journey of the Estonian Biobank. Preprint at medRxiv (2024).

  • Kurki, M. I. et al. FinnGen provides genetic insights from a well-phenotyped isolated population. Nature 613, 508–518 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Gallagher, C. S. et al. Genome-wide association and epidemiological analyses reveal common genetic origins between uterine leiomyomata and endometriosis. Nat. Commun. 10, 4857 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Dixon, P. H. et al. GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements. Nat. Commun. 13, 4840 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Pathare, A. D. S. et al. A large-scale genome-wide association study on female genital tract polyps highlights role of DNA repair, cell proliferation, and cell growth. Hum. Reprod. deaf025 (2025).

  • Ghoussaini, M. et al. Open Targets Genetics: systematic identification of trait-associated genes using large-scale genetics and functional genomics. Nucleic Acids Res. 49, D1311–D1320 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Mountjoy, E. et al. An open approach to systematically prioritize causal variants and genes at all published human GWAS trait-associated loci. Nat. Genet. 53, 1527–1533 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Buyukcelebi, K. et al. Integrating leiomyoma genetics, epigenomics, and single-cell transcriptomics reveals causal genetic variants, genes, and cell types. Nat. Commun. 15, 1169 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Laisk, T. et al. Large-scale meta-analysis highlights the hypothalamic–pituitary–gonadal axis in the genetic regulation of menstrual cycle length. Hum. Mol. Genet. 27, 4323–4332 (2018).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Tyrmi, J. S. et al. Leveraging Northern European population history: novel low-frequency variants for polycystic ovary syndrome. Hum. Reprod. 37, 352–365 (2022).

    Article 
    PubMed 

    Google Scholar 

  • Sliz, E. et al. Evidence of a causal effect of genetic tendency to gain muscle mass on uterine leiomyomata. Nat. Commun. 14, 542 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Välimäki, N. et al. Genetic predisposition to uterine leiomyoma is determined by loci for genitourinary development and genome stability. eLife 7, e37110 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Bray, M. J. et al. Admixture mapping of uterine fibroid size and number in African American women. Fertil. Steril. 108, 1034–1042 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Ward, L. D. et al. Rare coding variants in DNA damage repair genes associated with timing of natural menopause. HGG Adv. 3, 100079 (2021).

    PubMed 
    PubMed Central 

    Google Scholar 

  • Zhang, W. et al. Overexpression of myosin is associated with the development of uterine myoma. J. Obstet. Gynaecol. Res. 40, 2051–2057 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Bulik-Sullivan, B. K. et al. LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat. Genet. 47, 291–295 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Pujol-Gualdo, N. et al. Advancing our understanding of genetic risk factors and potential personalized strategies for pelvic organ prolapse. Nat. Commun. 13, 3584 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Holland, D. et al. Beyond SNP heritability: polygenicity and discoverability of phenotypes estimated with a univariate Gaussian mixture model. PLoS Genet. 16, e1008612 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Venkatesh, S. S. et al. Genome-wide analyses identify 21 infertility loci and over 400 reproductive hormone loci across the allele frequency spectrum. Preprint at medRxiv (2024).

  • Bulik-Sullivan, B. et al. An atlas of genetic correlations across human diseases and traits. Nat. Genet. 47, 1236–1241 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Pan, M.-L., Chen, L.-R. & Chen, K.-H. Prepregnancy polycystic ovary syndrome as a risk factor of subsequent preterm labor: a national population-based cohort study. Int. J. Environ. Res. Public Health 19, 5470 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Roos, N. et al. Risk of adverse pregnancy outcomes in women with polycystic ovary syndrome: population based cohort study. BMJ 343, d6309 (2011).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Jin, L.-Y. et al. Overexpression of Pde4d in rat granulosa cells inhibits maturation and atresia of antral follicles to induce polycystic ovary. Biochim. Biophys. Acta Mol. Basis Dis. 1870, 166869 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Jensterle, M., Kocjan, T. & Janez, A. Phosphodiesterase 4 inhibition as a potential new therapeutic target in obese women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 99, E1476–E1481 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Lim, E. T. et al. Distribution and medical impact of loss-of-function variants in the Finnish founder population. PLoS Genet. 10, e1004494 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Chheda, H. et al. Whole-genome view of the consequences of a population bottleneck using 2926 genome sequences from Finland and United Kingdom. Eur. J. Hum. Genet. 25, 477–484 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kivisild, T. et al. Patterns of genetic connectedness between modern and medieval Estonian genomes reveal the origins of a major ancestry component of the Finnish population. Am. J. Hum. Genet. 108, 1792–1806 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Mitt, M. et al. Improved imputation accuracy of rare and low-frequency variants using population-specific high-coverage WGS-based imputation reference panel. Eur. J. Hum. Genet. 25, 869–876 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Day, F. R. et al. Causal mechanisms and balancing selection inferred from genetic associations with polycystic ovary syndrome. Nat. Commun. 6, 8464 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Varas Enriquez, P. J., McKerracher, L. J. & Elliot, M. G. Pre-eclampsia and maternal–fetal conflict. Evol. Med. Public Health 2018, 217–218 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Pavličev, M. et al. A common allele increases endometrial Wnt4 expression, with antagonistic implications for pregnancy, reproductive cancers, and endometriosis. Nat. Commun. 15, 1152 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Wilcox, N. et al. Exome sequencing identifies breast cancer susceptibility genes and defines the contribution of coding variants to breast cancer risk. Nat. Genet. 55, 1435–1439 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Breast Cancer Association Consortium et al. Breast cancer risk genes—association analysis in more than 113,000 women. N. Engl. J. Med. 384, 428–439 (2021).

    Article 

    Google Scholar 

  • Patel, A. P. et al. A multi-ancestry polygenic risk score improves risk prediction for coronary artery disease. Nat. Med. 29, 1793–1803 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Mars, N. et al. The role of polygenic risk and susceptibility genes in breast cancer over the course of life. Nat. Commun. 11, 6383 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Obstetrics Group of the Gynecology and Obstetrics Branch of Chinese Medical Association, Perinatal Medicine Branch of Chinese Medical Association, Yu, X., Yang, H. & Qi, H. Clinical management guidelines for intrahepatic cholestasis of pregnancy. Matern. Fetal Med. 6, 13–22 (2024).

  • Lennon, N. J. et al. Selection, optimization and validation of ten chronic disease polygenic risk scores for clinical implementation in diverse US populations. Nat. Med. 30, 480–487 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Khan, A. et al. Polygenic risk alters the penetrance of monogenic kidney disease. Nat. Commun. 14, 8318 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Fahed, A. C. et al. Polygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions. Nat. Commun. 11, 3635 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Krebs, K. et al. Genome-wide study identifies association between HLA-B55:01 and self-reported penicillin allergy. Am. J. Hum. Genet. 107, 612–621 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Leitsalu, L., Alavere, H., Tammesoo, M.-L., Leego, E. & Metspalu, A. Linking a population biobank with national health registries—the Estonian experience. J. Pers. Med. 5, 96–106 (2015).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Mbatchou, J. et al. Computationally efficient whole-genome regression for quantitative and binary traits. Nat. Genet. 53, 1097–1103 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Kent, W. J. et al. The human genome browser at UCSC. Genome Res. 12, 996–1006 (2002).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Mägi, R. & Morris, A. P. GWAMA: software for genome-wide association meta-analysis. BMC Bioinformatics 11, 288 (2010).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Watanabe, K., Taskesen, E., van Bochoven, A. & Posthuma, D. Functional mapping and annotation of genetic associations with FUMA. Nat. Commun. 8, 1826 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lee, S. H., Wray, N. R., Goddard, M. E. & Visscher, P. M. Estimating missing heritability for disease from genome-wide association studies. Am. J. Hum. Genet. 88, 294–305 (2011).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Pasman, J. A. et al. GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophrenia. Nat. Neurosci. 21, 1161–1170 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Romero, C. et al. Exploring the genetic overlap between twelve psychiatric disorders. Nat. Genet. 54, 1795–1802 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Watanabe, K. et al. A global overview of pleiotropy and genetic architecture in complex traits. Nat. Genet. 51, 1339–1348 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Kanai, M. et al. Genetic analysis of quantitative traits in the Japanese population links cell types to complex human diseases. Nat. Genet. 50, 390–400 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Ge, T., Chen, C.-Y., Ni, Y., Feng, Y.-C. A. & Smoller, J. W. Polygenic prediction via Bayesian regression and continuous shrinkage priors. Nat. Commun. 10, 1776 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Chang, C. C. et al. Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience 4, 7 (2015).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Carroll, R. J., Bastarache, L. & Denny, J. C. R PheWAS: data analysis and plotting tools for phenome-wide association studies in the R environment. Bioinformatics 30, 2375–2376 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Krokstad, S. et al. Cohort profile: the HUNT study, Norway. Int. J. Epidemiol. 42, 968–977 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Åsvold, B. O. et al. Cohort profile update: the HUNT study, Norway. Int. J. Epidemiol. 52, e80–e91 (2023).

    Article 
    PubMed 

    Google Scholar 

  • Brumpton, B. M. et al. The HUNT study: a population-based cohort for genetic research. Cell Genom. 2, 100193 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • McCarthy, S. et al. A reference panel of 64,976 haplotypes for genotype imputation. Nat. Genet. 48, 1279–1283 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lambert, S. A. et al. Enhancing the Polygenic Score Catalog with tools for score calculation and ancestry normalization. Nat. Genet. (2024).

    Article 
    PubMed 

    Google Scholar 

  • Lambert, S. A. et al. The Polygenic Score Catalog as an open database for reproducibility and systematic evaluation. Nat. Genet. 53, 420–425 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

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