Family-Based Analysis of Candidate Genes for Polycystic Ovary Syndrome

Abstract

Studies on familial aggregation of hyperandrogenemia in polycystic ovary syndrome (PCOS) have provided evidence consistent with a genetic contribution of hyperandrogenemia to risk of the disease. Numerous association studies have investigated possible PCOS candidate genes but there is no consensus on any proposed candidate gene. Few of the positive reported PCOS genetic associations have been confirmed or followed up in replication studies. Previous studies have provided strong evidence that D19S884, a polymorphic marker in fibrillin 3, or a nearby determinant, are associated with risk of PCOS. This strong association has been replicated in 3 independent association studies. The aim of this study was to replicate previous findings showing a strong association between single nucleotide polymorphisms (SNPs) in the region of D19S884 and PCOS and to confirm and extend published data on other putative candidate genes. The transmission disequilibrium test (TDT) was used to study the association and linkage of putative candidate genes with PCOS. Overexpression of a gene marker in TDT testing indicated positive association with PCOS. SNP markers were genotyped in 453 families having a proband with PCOS; the total number was 502, including 49 affected sisters. The primary study outcome was transmission frequency of SNP alleles. A 6-SNP haplotype allele (designated allele-C) identified within a 6.7 kb region including D19S884 was significantly associated with PCOS. Allele-C was overtransmitted to offspring with PCOS: allele-C TDTχ2 = 10.0 (P = 0.0016). Combination of allele-C with D19S884-allele 8 was also overtransmitted: allele-C/A8 TDTχ2 = 7.6 (P = 0.006). Of the other 26 putative candidate genes tested using the TDT, 4 SNPs had a nominally significant association (ACVR2A, POMC, FEM1B, and SGTA). After correction for multiple testing, only one SNP in POMC (rs12473543) remained significant (χ2 = 9.1; Pcorrected = 0.036). These findings confirm other studies showing that the D19S884 region is associated with risk of PCOS and suggest that the putative candidate gene POMC should be investigated.