After discovering three loci that present a risk for polycystic ovary syndrome in Han Chinese women in a genome-wide association study, researchers replicated risk variants and found that women with European ancestry were also at risk for the disorder.
“Previous studies have demonstrated association between variants in more than 70 candidate genes and risk for PCOS, although the majority of these have not been replicated,” the researchers wrote.
Corrine K. Welt, MD, a researcher in the reproductive endocrine unit at Massachusetts General Hospital, and colleagues conducted a case-control study at deCODE Genetics in Iceland and two academic medical centers in the United States.
They examined 376 Icelandic women, 565 women in Boston and 203 women in Chicago, all of whom were diagnosed with PCOS according to NIH criteria. Control groups were 16,947 women in Iceland, 483 women in Boston (aged 18-45 years with regular menses between 21 and 35 days and no hyperandrogenism) and 189 (healthy reproductive-aged women, aged at least 18 years) in Chicago.
Researchers replicated two strongly correlated Han Chinese PCOS risk variants on chromosome 9q33.3: rs10986105[C] (OR=1.68; P=.00033) and rs10818854[A] (OR=1.53; P=.0019) in samples of European ancestry.
Other risk variants at alternate chromosomes were not related to PCOS, the researchers wrote. Additionally, the same allele of rs10986105[C], which increased the risk for PCOS, also put women without PCOS from Iceland at risk for hyperandrogenism and displayed a heightened risk for PCOS according to NIH criteria rather than Rotterdam criteria, the researchers wrote.
They said the variants found may be involved in the hyperandrogenism and irregular menses associated with PCOS. Despite impressive findings linking women with European ancestry to risk for PCOS based on variants found in this study, further studies should be considered to determine the role of the variant in the pathogenesis of PCOS.
Disclosure: Four of the 12 researchers are employed by deCODE Genetics. All other researchers report no relevant financial disclosures.
- This is the second study that has replicated findings in a genome-wide association study done in Chinese women with polycystic ovary syndrome. What’s exciting is that the Chinese study confirmed what’s been hypothesized now since the early ‘90s; that there is a genetic susceptibility to PCOS by mapping a couple of gene regions. To then replicate it in a distinct ethnic population in European women suggests that some of the same susceptibility variants are contributing to the disease in two very different populations.
It was suggested many years ago, in 1998, in a landmark paper by Rick Legro and colleagues (Legro RS. Proc Natl Acad Sci USA. 1998;95:14956-14960), that elevated testosterone levels were the underlying trait in PCOS families that most likely had a genetic basis. In this current study, they find that the gene variants are associated with testosterone levels in these populations.
The syndrome has been a disorder that we still don’t know the etiology of. We know that there’s a genetic component, and this is showing how genetic analyses can focus on what is causing all the other features, and again suggesting maybe it’s the testosterone and elevated androgen levels rather than the way the ovaries look.
Could we now do a genotype in a girl and predict whether or not she was going to have PCOS? Could it be used for personalized medicine? Unfortunately, none of these genes in these common, yet complex diseases have enough of the effect. Even if you had these variants that were associated with a 50% to 60% increased risk, that’s still not really enough to say that you’re going to have a disease or not. So, we really can’t use these gene variants for prediction. However, they’re very helpful in beginning to understand causality.
The strength of these studies is that they’re using rigorous new technology, the appropriate statistics, and these are meaningful findings, and hopefully, we’ll be seeing more of these related to other endocrine diseases of interest. This has certainly been the approach that’s been used in type 1 and 2 diabetes, where a number of genetic variants have been discovered.
- Andrea Dunaif, MD
- Professor of Endocrinology and Metabolism
Vice Chair for Research in the Department of Medicine
Northwestern University, Feinberg School of Medicine