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

Abstract

Polycystic ovary syndrome (PCOS) is a common endocrine disorder of women, characterized by hyperandrogenism and chronic anovulation. It is a leading cause of female infertility and is associated with polycystic ovaries, hirsutism, obesity, and insulin resistance. We tested a carefully chosen collection of 37 candidate genes for linkage and association with PCOS or hyperandrogenemia in data from 150 families. The strongest evidence for linkage was with the follistatin gene, for which affected sisters showed increased identity by descent (72%; 2 ‫؍‬ 12.97; nominal P ‫؍‬ 3.2 ؋ 10 ؊4 ). After correction for multiple testing (33 tests), the follistatin findings were still 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 transmission͞disequilibrium test ( 2 > 3.84; nominal P < 0.05). The strongest effect in the transmission͞disequilibrium test was observed in the INSR region (D19S884; allele 5; 2 ‫؍‬ 8.53) but was not significant after correction. Our study shows how a systematic screen of candidate genes can provide strong evidence for genetic linkage in complex diseases and can identify those genes that should have high (or low) priority for further study.

Polycystic ovary syndrome in adolescents

“…We found evidence for linkage and association with PCOS and testosterone levels at the CYP11A locus. 54 The preliminary findings of a subsequent study by Urbanek and colleagues 55 were consistent with our results. When, however, we repeated the analysis in two large case-control populations, we could no longer find evidence of association of the polymorphism with PCOS or serum testosterone.…”

No Association Between the Microsatellite Polymorphism (TTTTA) n in the Promoter of the CYP11A Gene and Ovarian Hyperstimulation Syndrome

“…We focused on investigating a possible association of the (TTTTA) n microsatellite polymorphism in the promoter of the CYP11A gene with the development of OHSS during COH. Namely, the CYP11A gene participates in the first, rate-limiting step in steroidogenesis (17) and it is one of the most promising candidate genes for abnormalities in androgen biosynthesis (8)(9)(10)(11)(12)(13)(14)(15)(16). Furthermore, the (TTTTA) n microsatellite polymorphism could regulate transcriptional activity of the CYP11A gene, as regulation of a gene transcription has been described as one of the major possible functions of variable number of tandem repeat (VNTR) polymorphisms, with a classical example of VNTR polymorphism in the insulin gene (21).…”

“…Women with BM-PCOS are mainly characterized by disturbances in androgen biosynthesis (8)(9)(10)(11)(12)(13)(14)(15)(16), before as well as during COH. On the other hand, women with US-PCOS have normal androgen status before COH; however, their androgen biochemical picture is changed during COH (7).…”

“…Namely, the CYP11A gene product, cholesterol side chain cleavage enzyme, catalyzes the first, rate-limiting step in steroidogenesis (17), and the gene itself is one of the candidate genes for hyperandrogenemia (8)(9)(10)(11)(12)(13)(14)(15)(16). Furthermore, the (TTTTA) n microsatellite polymorphism might influence the expression of the CYP11A gene and consequently cause abnormalities in steroidogenesis and androgen production.…”

Diagnosis of Polycystic Ovary Syndrome

“…(31) Finally, genes implicated in ovarian follicular development may have a role in the etiology of PCOS, as demonstrated by recent identification of the follistatin gene as a potential disease locus. (32) To date, although specific gene mutations affecting androgen synthesis, insulin secretion and insulin activity may explain most of the endocrine and metabolic symptoms, environmental risk factors (either during prenatal or postnatal life) seem to play an important role in converting an occult PCOS into a clinically manifest syndrome. (33) PCOS and Puberty PCOS usually has a menarchal age of onset.…”