SynthesisNature genetics2025
Genome-wide analyses identify 25 infertility loci and relationships with reproductive traits across the allele frequency spectrum.
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Synthesis in Nature genetics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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20citing papers in PubMed
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Who cites it
20 citing papers in PubMed.
- Shared genetic architecture and cellular convergence between female reproductive disorders and pulmonary function: a genome-wide cross-trait analysis.Functional & integrative genomics · 2026Article
- Current gene panels for female infertility: gaps between evidence and clinical application.Journal of assisted reproduction and genetics · 2026Review
- Isoprostanes and Isofurans in Infertility and Assisted Reproduction: What Do We Know So Far?International journal of molecular sciences · 2026Review
- Shared Risk Genes and Casual Relationships across Sex Hormone Related Traits and Alzheimer's Disease.medRxiv : the preprint server for health sciences · 2026Article
- Tet methylcytosine dioxygenase 2(TET2)-dependent epigenetic regulation in the pathogenesis of polycystic ovary syndrome.Cellular and molecular life sciences : CMLS · 2026Article
- Sharing approaches in predictive genomics across animals, plants and humans.Nature genetics · 2026Review
- Article
- Comparative Single-Cell Transcriptomic Atlas Reveals the Genetic Regulation of Reproductive Traits.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Article
- Sex-Stratified Genetic Analyses Mapping the Influences of Sedentary Behaviors and Physical Activity on Female Reproductive Health.Research (Washington, D.C.) · 2026Article
- An Integrative Genome-Wide Analysis Reveals Shared and Subtype-Specific Genetic Links Between Endometriosis and Menstrual-Cycle-Related Traits.International journal of women's health · 2026Article
- Surface-enhanced Raman spectroscopy analysis of glucose in spent embryo culture medium: correlation with embryo developmental potential.Frontiers in cell and developmental biology · 2026Article
- Advanced maternal age and assisted reproductive technologies: outcomes, genomics, and real-world evidence.Frontiers in reproductive health · 2026Review
- The role of social and genetic factors in partnership trajectories and later life health.Scientific reports · 2025Article
- Statistical methods to disentangle genetic effects influencing infertility and early fetal viability with a genome-wide application.PLoS genetics · 2025Article
- Article
- Regulatory Effects of Endometriosis-Associated Genetic Variants: A Multi-Tissue eQTL Analysis.Diseases (Basel, Switzerland) · 2025Article
- Beyond BMI: A Mendelian Randomization Study of the Causal Effects and Mediating Pathways of Regional Adipose Tissue Depots on Polycystic Ovary Syndrome.International journal of women's health · 2025Article
- The functional ovarian anatomy of 492 women aged 18-22 years: a population-based study in Norway.Human reproduction open · 2025Article
- Inherited infertility: Mapping loci associated with impaired female reproduction.American journal of human genetics · 2024Article
Corrections and comments
- Update of
Authors and funding
56 authors.
Samvida S VenkateshBig Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK. samvida.venkatesh@gmail.com.ORCID http://orcid.org/0000-0001-7680-1208
Laura B L WittemansNovo Nordisk Research Centre Oxford, Oxford, UK.
Duncan S PalmerBig Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK.ORCID http://orcid.org/0000-0002-0824-0047
Nikolas A BayaBig Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK.ORCID http://orcid.org/0000-0002-4681-374X
Teresa FerreiraBig Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK.
Barney HillBig Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK.
Frederik Heymann LassenBig Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK.
Melody J ParkerBig Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK.ORCID http://orcid.org/0009-0002-9829-2816
Saskia ReibeBig Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK.
Ahmed ElhakeemMRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.
Karina BanasikNovo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark.
Mie T BruunDepartment of Clinical Immunology, Odense University Hospital, Odense, Denmark.ORCID http://orcid.org/0000-0002-8819-5388
Christian ErikstrupDepartment of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark.ORCID http://orcid.org/0000-0001-6551-6647
Bitten Aagard JensenDepartment of Clinical Immunology, Aalborg University Hospital, Aalborg, Denmark.ORCID http://orcid.org/0000-0001-8306-1332
Anders JuulDepartment of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.ORCID http://orcid.org/0000-0002-0534-4350
Christina MikkelsenDepartment of Clinical Immunology, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.ORCID http://orcid.org/0000-0002-2945-6197
Henriette S NielsenDepartment of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.ORCID http://orcid.org/0000-0003-2106-8103
Sisse R OstrowskiDepartment of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.ORCID http://orcid.org/0000-0001-5288-3851
Ole B PedersenDepartment of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.ORCID http://orcid.org/0000-0003-2312-5976
Palle Duun RohdeGenomic Medicine, Department of Health Science and Technology, Aalborg University, Aalborg, Denmark.ORCID http://orcid.org/0000-0003-4347-8656
Erik SørensenDepartment of Clinical Immunology, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.ORCID http://orcid.org/0000-0002-5002-9077
Henrik UllumStatens Serum Institut, Copenhagen, Denmark.
David WestergaardNovo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark.ORCID http://orcid.org/0000-0003-0128-8432
Asgeir HaraldssonFaculty of Medicine, University of Iceland, Reykjavik, Iceland.ORCID http://orcid.org/0000-0001-5364-7877
Hilma HolmdeCODE genetics/Amgen Inc., Reykjavik, Iceland.ORCID http://orcid.org/0000-0002-9517-6636
Ingileif JonsdottirFaculty of Medicine, University of Iceland, Reykjavik, Iceland.ORCID http://orcid.org/0000-0001-8339-150X
Isleifur OlafssonDepartment of Clinical Biochemistry, Landspitali University Hospital, Reykjavik, Iceland.
Thora SteingrimsdottirFaculty of Medicine, University of Iceland, Reykjavik, Iceland.
Valgerdur SteinthorsdottirdeCODE genetics/Amgen Inc., Reykjavik, Iceland.ORCID http://orcid.org/0000-0003-1846-6274
Gudmar ThorleifssondeCODE genetics/Amgen Inc., Reykjavik, Iceland.ORCID http://orcid.org/0000-0003-4623-9087
Jessica FigueredoEstonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
Minna K KarjalainenInstitute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.ORCID http://orcid.org/0000-0003-3184-3775
Anu PasanenResearch Unit of Clinical Medicine, Medical Research Center Oulu, University of Oulu, and Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland.
Benjamin M JacobsCentre for Preventive Neurology, Wolfson Institute of Population Health, Queen Mary University London, London, UK.ORCID http://orcid.org/0000-0002-6023-6010
Georgios KalantzisWellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.ORCID http://orcid.org/0000-0002-0729-1125
Nikki HubersDepartment of Biological Psychology, Netherlands Twin Register, Vrije Universiteit, Amsterdam, The Netherlands.ORCID http://orcid.org/0000-0001-6030-9235
Genes & Health Research Team
Estonian Biobank Research Team
Estonian Health Informatics Research Team
DBDS Genomic Consortium
FinnGen
Margaret LippincottReproductive Endocrine Unit, Massachusetts General Hospital, Boston, MA, USA.ORCID http://orcid.org/0000-0002-3533-1999
Abigail FraserMRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.
Deborah A LawlorMRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.ORCID http://orcid.org/0000-0002-6793-2262
Nicholas J TimpsonMRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.ORCID http://orcid.org/0000-0002-7141-9189
Mette NyegaardGenomic Medicine, Department of Health Science and Technology, Aalborg University, Aalborg, Denmark.ORCID http://orcid.org/0000-0003-4973-8543
Kari StefanssonFaculty of Medicine, University of Iceland, Reykjavik, Iceland.ORCID http://orcid.org/0000-0003-1676-864X
Reedik MagiEstonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.ORCID http://orcid.org/0000-0002-2964-6011
Hannele LaivuoriInstitute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.ORCID http://orcid.org/0000-0003-3212-7826
David A van HeelBlizard Institute, Queen Mary University London, London, UK.ORCID http://orcid.org/0000-0002-0637-2265
Dorret I BoomsmaAmsterdam Reproduction and Development Institute, Amsterdam, The Netherlands.ORCID http://orcid.org/0000-0002-7099-7972
Ravikumar BalasubramanianReproductive Endocrine Unit, Massachusetts General Hospital, Boston, MA, USA.ORCID http://orcid.org/0000-0001-6008-5585
Stephanie B SeminaraReproductive Endocrine Unit, Massachusetts General Hospital, Boston, MA, USA.
Yee-Ming ChanHarvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0003-0554-8502
Triin LaiskEstonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.ORCID http://orcid.org/0000-0003-1501-9030
Cecilia M LindgrenBig Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK. cecilia.lindgren@bdi.ox.ac.uk.ORCID http://orcid.org/0000-0002-4903-9374
Funding
The Massachusetts General Hospital Harvard Center for Reproductive MedicineP50HD104224 · NICHD · MASSACHUSETTS GENERAL HOSPITAL · PI TALKOWSKI, MICHAEL E · 2021 to 2025
$7.8MTowards Curative Therapies for Hypogonadotropic DiseasesR37HD043341 · NICHD · MASSACHUSETTS GENERAL HOSPITAL · PI Stephanie Beth Seminara · 2020 to 2026
$5.8MDissection of the Molecular Basis of Pleiotropy Between GnRH Neuronal Development and Cranial Suture FusionR01DE031452 · NIDCR · MASSACHUSETTS GENERAL HOSPITAL · PI Erica Ellen Davis, Stephanie Beth Seminara · 2022 to 2026
$3.9MKisspeptin: A Novel Regulator of Insulin in PregnancyK23HD097296 · NICHD · MASSACHUSETTS GENERAL HOSPITAL · PI LIPPINCOTT, MARGARET FLYNN · 2019 to 2023
$864kEesti Teadusagentuur (Estonian Research Council) PRG1911FDA HHS R01 FD007843Gates Foundation INV-024200NICHD NIH HHS K23 HD097296NICHD NIH HHS P50 HD104224NICHD NIH HHS R37 HD043341NIDCR NIH HHS R01 DE031452RCUK | Medical Research Council (MRC) M009017, MR/X009777/1, MR/X009920/1RCUK | Medical Research Council (MRC) MR/V028766/1Wellcome TrustWellcome Trust (Wellcome) 220540/Z/20/AWellcome Trust (Wellcome) 221782/Z/20/ZWellcome Trust (Wellcome) WT102627, WT210561
Abstract
Genome-wide association studies (GWASs) may help inform the etiology of infertility. Here, we perform GWAS meta-analyses across seven cohorts in up to 42,629 cases and 740,619 controls and identify 25 genetic risk loci for male and female infertility. We additionally identify up to 269 genetic loci associated with follicle-stimulating hormone, luteinizing hormone, estradiol and testosterone through sex-specific GWAS meta-analyses (n = 6,095-246,862). Exome sequencing analyses reveal that women carrying testosterone-lowering rare variants in some genes are at risk of infertility. However, we find no local or genome-wide genetic correlation between female infertility and reproductive hormones. While infertility is genetically correlated with endometriosis and polycystic ovary syndrome, we find limited genetic overlap between infertility and obesity. Finally, we show that the evolutionary persistence of infertility-risk alleles may be explained by directional selection. Taken together, we provide a comprehensive view of the genetic determinants of infertility across multiple diagnostic criteria.
Indexed as
Gene FrequencyInfertilityInfertility, FemaleInfertility, MaleReproductionFemaleFollicle Stimulating HormoneGenetic Predisposition to DiseaseGenome-Wide Association StudyHumansLuteinizing HormoneMalePolycystic Ovary SyndromePolymorphism, Single NucleotideFollicle Stimulating HormoneLuteinizing Hormone
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