Causal mechanisms and balancing selection inferred from genetic associations with polycystic ovary syndrome

Abstract

Polycystic ovary syndrome (PCOS) is the most common reproductive disorder in women, yet there is little consensus regarding its aetiology. Here we perform a genome-wide association study of PCOS in up to 5,184 self-reported cases of White European ancestry and 82,759 controls, with follow-up in a further ∼2,000 clinically validated cases and ∼100,000 controls. We identify six signals for PCOS at genome-wide statistical significance (P<5 × 10−8), in/near genes ERBB4/HER4, YAP1, THADA, FSHB, RAD50 and KRR1. Variants in/near three of the four epidermal growth factor receptor genes (ERBB2/HER2, ERBB3/HER3 and ERBB4/HER4) are associated with PCOS at or near genome-wide significance. Mendelian randomization analyses indicate causal roles in PCOS aetiology for higher BMI (P=2.5 × 10−9), higher insulin resistance (P=6 × 10−4) and lower serum sex hormone binding globulin concentrations (P=5 × 10−4). Furthermore, genetic susceptibility to later menopause is associated with higher PCOS risk (P=1.6 × 10−8) and PCOS-susceptibility alleles are associated with higher serum anti-Müllerian hormone concentrations in girls (P=8.9 × 10−5). This large-scale study implicates an aetiological role of the epidermal growth factor receptors, infers causal mechanisms relevant to clinical management and prevention, and suggests balancing selection mechanisms involved in PCOS risk.

Neuroendocrine androgen action is a key extraovarian mediator in the development of polycystic ovary syndrome

“…Our data demonstrate that, in particular, extraovarian neuroendocrine AR sites of androgen action are predominantly involved in the pathogenesis of multiple key PCOS characteristics. This provides strong experimental support for recent GWAS findings that highlight the importance of gonadotropin action in the genetic origins of susceptibility to PCOS (24)(25)(26). In concert, these Serum concentrations of dihydrotestosterone, testosterone, dehydroepiandrosterone, 5α-androstane-3α,17β-diol, 5α-androstane-3β,17β-diol, progesterone, luteinizing hormone, and follicle-stimulating hormone.…”

“…1). Our findings highlight the importance of extraovarian AR-mediated androgen actions in the origins of PCOS features, which is strongly supported by findings from recent genome-wide association studies (GWAS) of PCOS highlighting the importance of gonadotropins in PCOS (24)(25)(26).…”

An International Consortium Update: Pathophysiology, Diagnosis, and Treatment of Polycystic Ovarian Syndrome in Adolescence

“…As noted above, the role of DENND1A splice transcripts in ovarian theca cell steroidogenesis is being investigated. The PCOS susceptibility allele in the FSHB gene is also associated robustly with lower circulating FSH levels [94, 95], and with other phenotypes indicative of diminished ovarian follicle stimulation: later onset of puberty, and lower risk for dizygotic twinning [96]. Together, these genetic findings indicate a co-primary neuroendocrine pathogenesis of PCOS, alongside its likely ovarian etiology.…”

“…The advent of large-scale GWAS with their stringent statistical thresholds has brought robust new insights, although as yet these have been limited to adult PCOS cases and their direct relevance to adolescent PCOS is yet to be established. The first GWAS for PCOS were performed in Han Chinese populations [92, 93]; while the identified genomic loci were replicable in that population, their effects estimates are consistently smaller in Caucasian PCOS cases, possibly due to population differences in genetic architecture or even PCOS sub-phenotypes [94, 95]. …”

Increased serum neuregulin 4 levels in women with polycystic ovary syndrome: A case-control study

“…In mice with neuregulin-ErbB4/2 receptor deficiency the required LHRH failed to be secreted so the sex development of mice was impaired [20]. Day et al reported in their genetic study that ErbB2, ErbB3 and ErbB4 receptors may be associated with PCOS [21]. In another animal study, overexpressed NRG4 has been shown to cause an increase in insulin sensitivity while NRG4 deficiency has been shown to cause insulin resistance.…”