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

Felix R Day; David A Hinds; Joyce Y Tung; Lisette Stolk; Unnur Styrkarsdottir; Richa Saxena; Andrew Bjonnes; Linda Broer; David B Dunger; Bjarni V Halldorsson; Debbie A Lawlor; Guillaume Laval; Iain Mathieson; Wendy L McCardle; Yvonne Louwers; Cindy Meun; Susan Ring; Robert A Scott; Patrick Sulem; André G Uitterlinden; Nicholas J Wareham; Unnur Thorsteinsdottir; Corrine Welt; Kari Stefansson; Joop S E Laven; Ken K Ong; John R B Perry

doi:10.1038/ncomms9464

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

Felix R Day, David A Hinds, Joyce Y Tung, Lisette Stolk, Unnur Styrkarsdottir, Richa Saxena, Andrew Bjonnes, Linda Broer, David B Dunger, Bjarni V Halldorsson, Debbie A Lawlor, Guillaume Laval, Iain Mathieson, Wendy L McCardle, Yvonne Louwers, Cindy Meun, Susan Ring, Robert A Scott, Patrick Sulem, André G UitterlindenNicholas J Wareham, Unnur Thorsteinsdottir, Corrine Welt, Kari Stefansson, Joop S E Laven, Ken K Ong^*, John R B Perry^*

^*Corresponding author for this work

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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.

Original language	English
Pages (from-to)	8464
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms9464
Publication status	Published - 29 Sept 2015

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Day, F. R., Hinds, D. A., Tung, J. Y., Stolk, L., Styrkarsdottir, U., Saxena, R., Bjonnes, A., Broer, L., Dunger, D. B., Halldorsson, B. V., Lawlor, D. A., Laval, G., Mathieson, I., McCardle, W. L., Louwers, Y., Meun, C., Ring, S., Scott, R. A., Sulem, P., ... Perry, J. R. B. (2015). Causal mechanisms and balancing selection inferred from genetic associations with polycystic ovary syndrome. Nature Communications, 6, 8464. https://doi.org/10.1038/ncomms9464

@article{6dcfc6f460c44b699821db840498332f,

title = "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-M{\"u}llerian 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.",

author = "Day, {Felix R} and Hinds, {David A} and Tung, {Joyce Y} and Lisette Stolk and Unnur Styrkarsdottir and Richa Saxena and Andrew Bjonnes and Linda Broer and Dunger, {David B} and Halldorsson, {Bjarni V} and Lawlor, {Debbie A} and Guillaume Laval and Iain Mathieson and McCardle, {Wendy L} and Yvonne Louwers and Cindy Meun and Susan Ring and Scott, {Robert A} and Patrick Sulem and Uitterlinden, {Andr{\'e} G} and Wareham, {Nicholas J} and Unnur Thorsteinsdottir and Corrine Welt and Kari Stefansson and Laven, {Joop S E} and Ong, {Ken K} and Perry, {John R B}",

year = "2015",

month = sep,

day = "29",

doi = "10.1038/ncomms9464",

language = "English",

volume = "6",

pages = "8464",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

}

Day, FR, Hinds, DA, Tung, JY, Stolk, L, Styrkarsdottir, U, Saxena, R, Bjonnes, A, Broer, L, Dunger, DB, Halldorsson, BV, Lawlor, DA, Laval, G, Mathieson, I, McCardle, WL, Louwers, Y, Meun, C, Ring, S, Scott, RA, Sulem, P, Uitterlinden, AG, Wareham, NJ, Thorsteinsdottir, U, Welt, C, Stefansson, K, Laven, JSE, Ong, KK & Perry, JRB 2015, 'Causal mechanisms and balancing selection inferred from genetic associations with polycystic ovary syndrome', Nature Communications, vol. 6, pp. 8464. https://doi.org/10.1038/ncomms9464

TY - JOUR

T1 - Causal mechanisms and balancing selection inferred from genetic associations with polycystic ovary syndrome

AU - Day, Felix R

AU - Hinds, David A

AU - Tung, Joyce Y

AU - Stolk, Lisette

AU - Styrkarsdottir, Unnur

AU - Saxena, Richa

AU - Bjonnes, Andrew

AU - Broer, Linda

AU - Dunger, David B

AU - Halldorsson, Bjarni V

AU - Lawlor, Debbie A

AU - Laval, Guillaume

AU - Mathieson, Iain

AU - McCardle, Wendy L

AU - Louwers, Yvonne

AU - Meun, Cindy

AU - Ring, Susan

AU - Scott, Robert A

AU - Sulem, Patrick

AU - Uitterlinden, André G

AU - Wareham, Nicholas J

AU - Thorsteinsdottir, Unnur

AU - Welt, Corrine

AU - Stefansson, Kari

AU - Laven, Joop S E

AU - Ong, Ken K

AU - Perry, John R B

PY - 2015/9/29

Y1 - 2015/9/29

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 ∼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.

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 ∼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.

U2 - 10.1038/ncomms9464

DO - 10.1038/ncomms9464

M3 - Article

C2 - 26416764

SN - 2041-1723

VL - 6

SP - 8464

JO - Nature Communications

JF - Nature Communications

ER -

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

Abstract

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