Miscarriage is a common complex trait that affects 10-25% of clinically confirmed pregnancies. Here we present the first large-scale genetic association analyses with 69,118 cases from five different ancestries for sporadic miscarriage and 750 cases of European ancestry for recurrent miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association on chromosome 13 (rs146350366, minor allele frequency (MAF) 1.2%, Pmeta=3.2×10-8, odds ratio (OR) 1.4 (95% confidence interval (CI) 1.2-1.6) for sporadic miscarriage in our European ancestry meta-analysis (50,060 cases and 174,109 controls), located near FGF9 involved in pregnancy maintenance and progesterone production. Additionally, we identified three genome-wide significant associations for recurrent miscarriage, including a signal on chromosome 9 (rs7859844, MAF=6.4%, Pmeta=1.3×10-8, OR=1.7 (1.4-2.0)) physically interacting with TLE1/TLE4 involved in controlling extravillous trophoblast motility. We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability and, genetic correlation analyses. Our results implicate that miscarriage etiopathogenesis is partly driven by genetic variation related to gonadotropin regulation, placental biology and progesterone production.

The genetic architecture of sporadic and recurrent miscarriage