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Genome-wide analyses identify 21 infertility loci and over 400 reproductive hormone loci across the allele frequency spectrum.

التفاصيل البيبلوغرافية
العنوان: Genome-wide analyses identify 21 infertility loci and over 400 reproductive hormone loci across the allele frequency spectrum.
المؤلفون: Venkatesh SS; Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 7LF, United Kingdom.; Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, United Kingdom., Wittemans LBL; Novo Nordisk Research Centre Oxford, Oxford, United Kingdom.; Nuffield Department of Women's and Reproductive Health, Medical Sciences Division, University of Oxford, United Kingdom., Palmer DS; Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 7LF, United Kingdom.; Nuffield Department of Population Health, Medical Sciences Division, University of Oxford, Oxford, United Kingdom., Baya NA; Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 7LF, United Kingdom.; Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, United Kingdom., Ferreira T; Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 7LF, United Kingdom., Hill B; Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 7LF, United Kingdom.; Nuffield Department of Population Health, Medical Sciences Division, University of Oxford, Oxford, United Kingdom., Lassen FH; Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 7LF, United Kingdom.; Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, United Kingdom., Parker MJ; Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 7LF, United Kingdom.; Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom., Reibe S; Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 7LF, United Kingdom.; Nuffield Department of Population Health, Medical Sciences Division, University of Oxford, Oxford, United Kingdom., Elhakeem A; MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom.; Population Health Science, Bristol Medical School, University of Bristol, Bristol, United Kingdom., Banasik K; Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark.; Department of Obstetrics and Gynecology, Copenhagen University Hospital, Hvidovre, Copenhagen, Denmark., Bruun MT; Department of Clinical Immunology, Odense University Hospital, Odense, Denmark., Erikstrup C; Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark.; Department of Clinical Medicine, Health, Aarhus University, Aarhus, Denmark., Jensen BA; Department of Clinical Immunology, Aalborg University Hospital, Aalborg, Denmark., Juul A; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen; Copenhagen, Denmark.; Department of Growth and Reproduction, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark., Mikkelsen C; Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Science, Copenhagen University, Copenhagen, Denmark., Nielsen HS; Department of Obstetrics and Gynecology, The Fertility Clinic, Hvidovre University Hospital, Copenhagen, Denmark.; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Ostrowski SR; Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Pedersen OB; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Department of Clinical Immunology, Zealand University Hospital, Kge, Denmark., Rohde PD; Genomic Medicine, Department of Health Science and Technology, Aalborg University, Aalborg, Denmark., Sorensen E; Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark., Ullum H; Statens Serum Institut, Copenhagen, Denmark., Westergaard D; Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark.; Department of Obstetrics and Gynecology, Copenhagen University Hospital, Hvidovre, Copenhagen, Denmark., Haraldsson A; Faculty of Medicine, University of Iceland, Reykjavik, Iceland.; Children's Hospital Iceland, Landspitali University Hospital, Reykjavik, Iceland., Holm H; deCODE genetics/Amgen, Inc., Reykjavik, Iceland., Jonsdottir I; Faculty of Medicine, University of Iceland, Reykjavik, Iceland.; deCODE genetics/Amgen, Inc., Reykjavik, Iceland., Olafsson I; Department of Clinical Biochemistry, Landspitali University Hospital, Reykjavik, Iceland., Steingrimsdottir T; Faculty of Medicine, University of Iceland, Reykjavik, Iceland.; Department of Obstetrics and Gynecology, Landspitali University Hospital, Reykjavik, Iceland., Steinthorsdottir V; deCODE genetics/Amgen, Inc., Reykjavik, Iceland., Thorleifsson G; deCODE genetics/Amgen, Inc., Reykjavik, Iceland., Figueredo J; Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia., Karjalainen MK; Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.; Research Unit of Population Health, Faculty of Medicine, University of Oulu, Finland.; Northern Finland Birth Cohorts, Arctic Biobank, Infrastructure for Population Studies, Faculty of Medicine, University of Oulu, Oulu, Finland., Pasanen A; Research Unit of Clinical Medicine, Medical Research Center Oulu, University of Oulu, and Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland., Jacobs BM; Centre for Preventive Neurology, Wolfson Institute of Population Health, Queen Mary University London, London, EC1M 6BQ, United Kingdom., Hubers N; Department of Biological Psychology, Netherlands Twin Register, Vrije Universiteit, Amsterdam, The Netherlands.; Amsterdam Reproduction and Development Institute, Amsterdam, The Netherlands., Lippincott M; Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, United States of America.; Harvard Medical School, Boston, Massachusetts, United States of America., Fraser A; MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom.; Population Health Science, Bristol Medical School, University of Bristol, Bristol, United Kingdom., Lawlor DA; MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom.; Population Health Science, Bristol Medical School, University of Bristol, Bristol, United Kingdom., Timpson NJ; MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom.; Population Health Science, Bristol Medical School, University of Bristol, Bristol, United Kingdom., Nyegaard M; Genomic Medicine, Department of Health Science and Technology, Aalborg University, Aalborg, Denmark., Stefansson K; Faculty of Medicine, University of Iceland, Reykjavik, Iceland.; deCODE genetics/Amgen, Inc., Reykjavik, Iceland., Magi R; Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia., Laivuori H; Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.; Medical and Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.; Department of Obstetrics and Gynecology, Tampere University Hospital, Finland.; Center for Child, Adolescent, and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University, Finland., van Heel DA; Blizard Institute, Queen Mary University London, London, E1 2AT, United Kingdom., Boomsma DI; Department of Biological Psychology, Netherlands Twin Register, Vrije Universiteit, Amsterdam, The Netherlands.; Amsterdam Reproduction and Development Institute, Amsterdam, The Netherlands., Balasubramanian R; Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, United States of America.; Harvard Medical School, Boston, Massachusetts, United States of America., Seminara SB; Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, United States of America.; Harvard Medical School, Boston, Massachusetts, United States of America., Chan YM; Harvard Medical School, Boston, Massachusetts, United States of America.; Division of Endocrinology, Department of Pediatrics, Boston Children's Hospital, Boston, Massachusetts, United States of America., Laisk T; Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia., Lindgren CM; Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 7LF, United Kingdom.; Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, United Kingdom.; Nuffield Department of Women's and Reproductive Health, Medical Sciences Division, University of Oxford, United Kingdom.; Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
مؤلفون مشاركون: Genes & Health Research Team, Estonian Biobank Research Team, Estonian Health Informatics Research Team, DBDS Genomic Consortium, FinnGen
المصدر: MedRxiv : the preprint server for health sciences [medRxiv] 2024 Mar 20. Date of Electronic Publication: 2024 Mar 20.
نوع المنشور: Preprint
اللغة: English
بيانات الدورية: Country of Publication: United States NLM ID: 101767986 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: medRxiv Subsets: PubMed not MEDLINE
مستخلص: Genome-wide association studies (GWASs) may help inform treatments for infertility, whose causes remain unknown in many cases. Here we present GWAS meta-analyses across six cohorts for male and female infertility in up to 41,200 cases and 687,005 controls. We identified 21 genetic risk loci for infertility ( P ≤5E-08), of which 12 have not been reported for any reproductive condition. We found positive genetic correlations between endometriosis and all-cause female infertility ( r g =0.585, P =8.98E-14), and between polycystic ovary syndrome and anovulatory infertility ( r g =0.403, P =2.16E-03). The evolutionary persistence of female infertility-risk alleles in EBAG9 may be explained by recent directional selection. We additionally identified up to 269 genetic loci associated with follicle-stimulating hormone (FSH), luteinising hormone, oestradiol, and testosterone through sex-specific GWAS meta-analyses (N=6,095-246,862). While hormone-associated variants near FSHB and ARL14EP colocalised with signals for anovulatory infertility, we found no r g between female infertility and reproductive hormones ( P >0.05). Exome sequencing analyses in the UK Biobank (N=197,340) revealed that women carrying testosterone-lowering rare variants in GPC2 were at higher risk of infertility (OR=2.63, P =1.25E-03). Taken together, our results suggest that while individual genes associated with hormone regulation may be relevant for fertility, there is limited genetic evidence for correlation between reproductive hormones and infertility at the population level. We provide the first comprehensive view of the genetic architecture of infertility across multiple diagnostic criteria in men and women, and characterise its relationship to other health conditions.
Competing Interests: Competing Interests Statement L.B.L.W. is currently employed by Novo Nordisk Research Centre Oxford but, while she conducted the research described in this manuscript, was only affiliated to the University of Oxford. V.S., G.T., H.H., I.J., and K.S. are employees of deCODE genetics, a subsidiary of Amgen. C.M.L. reports grants from Bayer AG and Novo Nordisk and has a partner who works at Vertex. The other authors declare no conflicts of interest.
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معلومات مُعتمدة: United Kingdom WT_ Wellcome Trust; INV-024200 United States GATES Bill & Melinda Gates Foundation; P50 HD104224 United States HD NICHD NIH HHS
تواريخ الأحداث: Date Created: 20240402 Latest Revision: 20240410
رمز التحديث: 20240410
مُعرف محوري في PubMed: PMC10984039
DOI: 10.1101/2024.03.19.24304530
PMID: 38562841
قاعدة البيانات: MEDLINE
الوصف
DOI:10.1101/2024.03.19.24304530