Day Felix R, Hinds David A, Tung Joyce Y, Stolk Lisette, Styrkarsdottir Unnur, Saxena Richa, Bjonnes Andrew, Broer Linda, Dunger David B, Halldorsson Bjarni V, Lawlor Debbie A, Laval Guillaume, Mathieson Iain, McCardle Wendy L, Louwers Yvonne, Meun Cindy, Ring Susan, Scott Robert A, Sulem Patrick, Uitterlinden André G, Wareham Nicholas J, Thorsteinsdottir Unnur, Welt Corrine, Stefansson Kari, Laven Joop S E, Ong Ken K, Perry John R B
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Box 285 Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
23andMe Inc., Mountain View, California 94043, USA.
Nat Commun. 2015 Sep 29;6:8464. doi: 10.1038/ncomms9464.
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.
多囊卵巢综合征（PCOS）是女性中最常见的生殖系统疾病，但其病因却几乎没有定论。在此，我们对多达5184例自我报告的具有欧洲白人血统的PCOS病例和82759例对照进行了全基因组关联研究，并在另外约2000例经临床验证的病例和约100000例对照中进行了随访。我们在全基因组统计学显著性水平（P<5×10^(-8)）下，在ERBB4/HER4、YAP1、THADA、FSHB、RAD50和KRR1基因内部或附近鉴定出6个与PCOS相关的信号。四个表皮生长因子受体基因（ERBB2/HER2、ERBB3/HER3和ERBB4/HER4）中的三个基因内部或附近的变异在全基因组水平或接近全基因组水平上与PCOS相关。孟德尔随机化分析表明，较高的体重指数（P=2.5×10^(-9)）、较高的胰岛素抵抗（P=6×10^(-4)）和较低的血清性激素结合球蛋白浓度（P=5×10^(-4)）在PCOS病因中具有因果作用。此外，绝经较晚的遗传易感性与较高的PCOS风险相关（P=1.6×10^(-8)），而PCOS易感等位基因与女孩较高的血清抗苗勒管激素浓度相关（P=8.9×10^(-5)）。这项大规模研究表明表皮生长因子受体在病因学上发挥作用，推断出与临床管理和预防相关的因果机制，并提示了参与PCOS风险的平衡选择机制。
