Genome-wide analyses identify 25 infertility loci and relationships with reproductive traits across the allele frequency spectrum.
Venkatesh SS., Wittemans LBL., Palmer DS., Baya NA., Ferreira T., Hill B., Lassen FH., Parker MJ., Reibe S., Elhakeem A., Banasik K., Bruun MT., Erikstrup C., Aagard Jensen B., Juul A., Mikkelsen C., Nielsen HS., Ostrowski SR., Pedersen OB., Rohde PD., Sørensen E., Ullum H., Westergaard D., Haraldsson A., Holm H., Jonsdottir I., Olafsson I., Steingrimsdottir T., Steinthorsdottir V., Thorleifsson G., Figueredo J., Karjalainen MK., Pasanen A., Jacobs BM., Kalantzis G., Hubers N., Genes & Health Research Team None., Estonian Biobank Research Team None., Estonian Health Informatics Research Team None., DBDS Genomic Consortium None., FinnGen None., Lippincott M., Fraser A., Lawlor DA., Timpson NJ., Nyegaard M., Stefansson K., Magi R., Laivuori H., van Heel DA., Boomsma DI., Balasubramanian R., Seminara SB., Chan Y-M., Laisk T., Lindgren CM.
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.