Further investigation in europeans of susceptibility variants for polycystic ovary syndrome discovered in genomewide association studies of chinese individuals

Context: Two genome-wide association studies (GWAS) of polycystic ovary syndrome (PCOS) have identified 11 susceptibility loci in Chinese individuals. Some of the risk loci identified in Chinese cohorts, mostly from the first GWAS, have been replicated in Europeans. Replication of the loci from the second GWAS in European cohorts is necessary to determine whether the same variants confer risk for PCOS in multiple ethnicities. Objective: The objective of the study was to determine the effects of the Chinese GWAS loci in European-origin individuals. Design: This was a genetic association study. Setting: The study was conducted at a tertiary care academic center. Patients: Eighthundredforty-fiveEuropeansubjects withPCOSand845controls participated in the study. Interventions: Interventions included blood sampling and genotyping. Main Outcome Measure: The association between PCOS and 12 independent single-nucleotide polymorphisms mapping to seven of the Chinese GWAS loci in a European cohort was measured. Results: Variants inDENND1A(P=.0002),THADA(P=.035), FSHR (P=.007), and INSR (P=.046) were associatedwithPCOSinEuropeans.Thegeneticrisk score,generatedforeachsubjectbasedonthetotal number of risk alleles, was associated with the diagnosis of PCOS (P<.0001) and remained associated (P = .02), even after exclusion of the four variants individually associated with PCOS. Conclusions: At least four of the PCOS susceptibility loci identified in the Chinese GWAS are associated with PCOS in Europeans. The overall genetic burden for PCOS, as demonstrated by the risk score, is also associated with the diagnosis of PCOS in Europeans. The PCOS susceptibility loci identified in the Chinese GWAS are thus likely to play an important role in the etiology of PCOS across ethnicities.