TY - JOUR
T1 - Causal mechanisms and balancing selection inferred from genetic associations with polycystic ovary syndrome
AU - Day, FR
AU - Hinds, DA
AU - Tung, JY
AU - Stolk, Lisette
AU - Styrkarsdottir, U
AU - Saxena, R
AU - Bjonnes, A
AU - Broer, Linda
AU - Dunger, DB
AU - Halldorsson, BV
AU - Lawlor, DA
AU - Laval, G
AU - Mathieson, I
AU - McCardle, WL
AU - Louwers, Y
AU - Meun, Cindy
AU - Ring, S
AU - Scott, RA
AU - Sulem, P
AU - Uitterlinden, André
AU - Wareham, NJ
AU - Thorsteinsdottir, U
AU - Welt, C
AU - Stefansson, K
AU - Laven, Joop
AU - Ong, KK
AU - Perry, JRB
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
U2 - 10.1038/ncomms9464
DO - 10.1038/ncomms9464
M3 - Article
VL - 6
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
ER -