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

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 A Jensen, Anders Juul, Christina Mikkelsen, Henriette S Nielsen, Sisse R Ostrowski, Ole B Pedersen, Palle D RohdeErik Sorensen, 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, 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, Genes & Health Research Team


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 (rg=0.585, P=8.98E-14), and between polycystic ovary syndrome and anovulatory infertility (rg=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 rg 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.

Original languageEnglish
Publication statusPublished - 20 Mar 2024
SeriesmedRxiv : the preprint server for health sciences


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