Looking for polycystic ovary syndrome genes: rational and best strategy

Polycystic ovary syndrome (PCOS) is a common, complex genetic disorder. Its inherited basis was established by studies demonstrating an increased prevalence of PCOS and hyperandrogenemia, insulin resistance, and disordered insulin secretion in relatives of women with PCOS. To date, efforts in elucidating the genetic basis of PCOS have focused on candidate genes chosen from logical pathways, such as steroid synthesis or insulin signaling. Whereas several positive results have been reported, no genes are universally accepted as important in PCOS pathogenesis, largely due to lack of replication of positive results. This has resulted, in part, from various factors, most importantly lack of a universally accepted diagnostic scheme for PCOS, ability to assign PCOS diagnosis only in women of reproductive age, inadequate coverage of genes by the analysis of only one or two variants, and of small case-control cohorts in most studies. Candidate gene selection has been limited by our incomplete knowledge of the pathophysiology of PCOS. In the future, strict and uniform diagnostic criteria, improved application of the candidate gene approach using haplotype-based analyses, intermediate phenotypes, replication of positive results in large cohorts, more family-based studies, gene selection from expression studies, and whole-genome approaches will enhance gene discovery in PCOS.