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<p>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 (<i>n</i> = 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月14日

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  • 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,
  • David A. van Heel,
  • Reedik Mägi,
  • Andres Metspalu,
  • Lili Milani,
  • Tõnu Esko,
  • Mari Nelis,
  • Georgi Hudjashov,
  • Raivo Kolde,
  • Sven Laur,
  • Sulev Reisberg,
  • Jaak Vilo,
  • Bitten Aagard Jensen,
  • Minna K. Karjalainen,
  • 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

摘要

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.