期刊
NATURE COMMUNICATIONS
卷 6, 期 -, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/ncomms9464
关键词
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资金
- Medical Research Council [U106179472, MC_U106179472, U106179471, MC_U106179471]
- National Human Genome Research Institute of the National Institutes of Health [R44HG006981]
- US National Institute of Health [R01 DK077659]
- University of Bristol
- UK Medical Research Council [MC_UU_12013/5]
- Medical Research Council [MC_UU_12015/2, MC_UU_12015/1, G0600717, MC_UU_12013/5, MC_U106179472, MC_PC_15018, MC_U106179471] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0513-10012, NF-SI-0508-10274, NF-SI-0512-10135] Funding Source: researchfish
- MRC [MC_U106179472, MC_UU_12013/5, MC_UU_12015/2, MC_UU_12015/1, G0600717] Funding Source: UKRI
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 similar to 2,000 clinically validated cases and similar to 100,000 controls. We identify six signals for PCOS at genome-wide statistical significance (P<5 x 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 x 10(-9)), higher insulin resistance (P = 6 x 10(-4)) and lower serum sex hormone binding globulin concentrations (P = 5 x 10(-4)). Furthermore, genetic susceptibility to later menopause is associated with higher PCOS risk (P = 1.6 x 10(-8)) and PCOS-susceptibility alleles are associated with higher serum anti-Mullerian hormone concentrations in girls (P = 8.9 x 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.
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