Genome-wide analyses identify 25 infertility loci and relationships with reproductive traits across the allele frequency spectrum

IF 31.7 1区生物学 Q1 GENETICS & HEREDITY

Nature genetics Pub Date : 2025-04-14 DOI:10.1038/s41588-025-02156-8

Samvida S. Venkatesh, Laura B. L. Wittemans, Duncan S. Palmer, Nikolas A. Baya, Teresa Ferreira, Barney Hill, Frederik Heymann Lassen, Melody J. Parker, Saskia Reibe, Ahmed Elhakeem, Karina Banasik, Mie T. Bruun, Christian Erikstrup, Bitten Aagard Jensen, Anders Juul, Christina Mikkelsen, Henriette S. Nielsen, Sisse R. Ostrowski, Ole B. Pedersen, Palle Duun Rohde, Erik Sørensen, Henrik Ullum, David Westergaard, Asgeir Haraldsson, Hilma Holm, Ingileif Jonsdottir, Isleifur Olafsson, Thora Steingrimsdottir, Valgerdur Steinthorsdottir, Gudmar Thorleifsson, Jessica Figueredo, Minna K. Karjalainen, Anu Pasanen, Benjamin M. Jacobs, Georgios Kalantzis, Nikki Hubers, Margaret Lippincott, Abigail Fraser, Deborah A. Lawlor, Nicholas J. Timpson, Mette Nyegaard, Kari Stefansson, Reedik Magi, Hannele Laivuori, David A. van Heel, Dorret I. Boomsma, Ravikumar Balasubramanian, Stephanie B. Seminara, Yee-Ming Chan, Triin Laisk, Cecilia M. Lindgren

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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.

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来源期刊

Nature genetics 生物-遗传学

CiteScore

43.00

自引率

2.60%

发文量

241

审稿时长

3 months

期刊介绍： Nature Genetics publishes the very highest quality research in genetics. It encompasses genetic and functional genomic studies on human and plant traits and on other model organisms. Current emphasis is on the genetic basis for common and complex diseases and on the functional mechanism, architecture and evolution of gene networks, studied by experimental perturbation. Integrative genetic topics comprise, but are not limited to: -Genes in the pathology of human disease -Molecular analysis of simple and complex genetic traits -Cancer genetics -Agricultural genomics -Developmental genetics -Regulatory variation in gene expression -Strategies and technologies for extracting function from genomic data -Pharmacological genomics -Genome evolution