Thirty-seven candidate genes for polycystic ovary syndrome: Strongest evidence for linkage is with follistatin

Polycystic ovary syndrome (PCOS) is a common endocrine disorder of women, c haracterized by hyperandrogenism and chronic anovulation. It is a leading c ause of female infertility and is associated with polycystic ovaries, hirsu tism, obesity, and insulin resistance. We tested a carefully chosen collect ion of 37 candidate genes for linkage and association with PCOS or hyperand rogenemia in data from 150 families. The strongest evidence for linkage was with the follistatin gene, for which affected sisters showed increased ide ntity by descent (72%; chi(2) = 12.97; nominal P = 3.2 x 10(-4)). After cor rection for multiple testing (33 tests), the follistatin findings were stil l highly significant (P-c = 0.01). Although the linkage results for CYP11A were also nominally significant (P = 0.02), they were no longer significant after correction. In 11 candidate gene regions, at least one allele showed nominally significant evidence for population association with PCOS in the transmission/disequilibrium test (chi(2) greater than or equal to 3.84; no minal P < 0.05). The strongest effect in the transmission/disequilibrium te st was observed in the INSR region (D19S884; allele 5; chi(2) = 8.53) but w as not significant after correction. Our study shows how a systematic scree n of candidate genes can provide strong evidence for genetic linkage in com plex diseases and can identify those genes that should have high (or low) p riority for further study.