Trans-ancestral Genome Wide Association Study of Sporadic and Recurrent Miscarriage

Abstract

Miscarriage is a common adverse pregnancy outcome, impacting approximately 15% of pregnancies. Herein, we present results of the largest trans-ancestral genome wide association study for miscarriage to date, based on 334,593 cases of sporadic, and 52,087 cases of recurrent miscarriage in the 23andMe, Inc. Research Cohort. We identified 10 novel genome-wide significant associations for sporadic miscarriage, and one for recurrent miscarriage. These loci mapped to genes with roles in neural development and telomere length, and to developmental disorders including autism spectrum disorder. Three variants, with similar directionality and magnitude of effect, replicated in a previously published GWAS. Using Mendelian randomization and triangulation, robust evidence was found for smoking causally increasing the risk of sporadic (genetic liability to ever vs never smoking: OR 1.13; 95%CI: 1.11-1.15; P=2.61e-42) and recurrent (OR 1.25; 95%CI: 1.21-1.30; P=5.47e-34) miscarriage, with moderate, yet triangulating, evidence identified for a potential etiological role of caffeine consumption.