Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits

Joshua C Randall; Thomas W Winkler; Zoltán Kutalik; Sonja I Berndt; Anne U Jackson; Keri L Monda; Tuomas Oskari Kilpeläinen; Tõnu Esko; Reedik Mägi; Shengxu Li; Tsegaselassie Workalemahu; Mary F Feitosa; Damien C Croteau-Chonka; Felix R Day; Tove Fall; Teresa Ferreira; Stefan Gustafsson; Adam E Locke; Iain Mathieson; Andre Scherag; Sailaja Vedantam; Andrew R Wood; Liming Liang; Valgerdur Steinthorsdottir; Gudmar Thorleifsson; Emmanouil T Dermitzakis; Antigone S Dimas; Fredrik Karpe; Josine L Min; George Nicholson; Deborah J Clegg; Thomas Person; Jon P Krohn; Sabrina Bauer; Christa Buechler; Kristina Eisinger; Amélie Bonnefond; Philippe Froguel; Jouke-Jan Hottenga; Inga Prokopenko; Lindsay L Waite; Tamara B Harris; Albert Vernon Smith; Alan R Shuldiner; Wendy L McArdle; Mark J Caulfield; Peter Kovacs; Peter E H Schwarz; Lars Lind; Inger Njølstad; DIAGRAM Consortium

doi:10.1371/journal.pgen.1003500

Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits

Joshua C Randall, Thomas W Winkler, Zoltán Kutalik, Sonja I Berndt, Anne U Jackson, Keri L Monda, Tuomas Oskari Kilpeläinen, Tõnu Esko, Reedik Mägi, Shengxu Li, Tsegaselassie Workalemahu, Mary F Feitosa, Damien C Croteau-Chonka, Felix R Day, Tove Fall, Teresa Ferreira, Stefan Gustafsson, Adam E Locke, Iain Mathieson, Andre ScheragSailaja Vedantam, Andrew R Wood, Liming Liang, Valgerdur Steinthorsdottir, Gudmar Thorleifsson, Emmanouil T Dermitzakis, Antigone S Dimas, Fredrik Karpe, Josine L Min, George Nicholson, Deborah J Clegg, Thomas Person, Jon P Krohn, Sabrina Bauer, Christa Buechler, Kristina Eisinger, Amélie Bonnefond, Philippe Froguel, Jouke-Jan Hottenga, Inga Prokopenko, Lindsay L Waite, Tamara B Harris, Albert Vernon Smith, Alan R Shuldiner, Wendy L McArdle, Mark J Caulfield, Peter Kovacs, Peter E H Schwarz, Lars Lind, Inger Njølstad, DIAGRAM Consortium

223 Citations (Scopus)

Abstract

Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10^-8), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.

Original language	English
Article number	e1003500
Journal	P L o S Genetics
Volume	9
Issue number	6
Pages (from-to)	1-19
Number of pages	20
ISSN	1553-7390
DOIs	https://doi.org/10.1371/journal.pgen.1003500
Publication status	Published - Jun 2013

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Randall, J. C., Winkler, T. W., Kutalik, Z., Berndt, S. I., Jackson, A. U., Monda, K. L., Oskari Kilpeläinen, T., Esko, T., Mägi, R., Li, S., Workalemahu, T., Feitosa, M. F., Croteau-Chonka, D. C., Day, F. R., Fall, T., Ferreira, T., Gustafsson, S., Locke, A. E., Mathieson, I., ... DIAGRAM Consortium (2013). Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits. P L o S Genetics, 9(6), 1-19. Article e1003500. https://doi.org/10.1371/journal.pgen.1003500

Randall, JC, Winkler, TW, Kutalik, Z, Berndt, SI, Jackson, AU, Monda, KL, Oskari Kilpeläinen, T, Esko, T, Mägi, R, Li, S, Workalemahu, T, Feitosa, MF, Croteau-Chonka, DC, Day, FR, Fall, T, Ferreira, T, Gustafsson, S, Locke, AE, Mathieson, I, Scherag, A, Vedantam, S, Wood, AR, Liang, L, Steinthorsdottir, V, Thorleifsson, G, Dermitzakis, ET, Dimas, AS, Karpe, F, Min, JL, Nicholson, G, Clegg, DJ, Person, T, Krohn, JP, Bauer, S, Buechler, C, Eisinger, K, Bonnefond, A, Froguel, P, Hottenga, J-J, Prokopenko, I, Waite, LL, Harris, TB, Smith, AV, Shuldiner, AR, McArdle, WL, Caulfield, MJ, Kovacs, P, Schwarz, PEH, Lind, L, Njølstad, I & DIAGRAM Consortium 2013, 'Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits', P L o S Genetics, vol. 9, no. 6, e1003500, pp. 1-19. https://doi.org/10.1371/journal.pgen.1003500

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title = "Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits",

abstract = "Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10-8), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.",

author = "Randall, {Joshua C} and Winkler, {Thomas W} and Zolt{\'a}n Kutalik and Berndt, {Sonja I} and Jackson, {Anne U} and Monda, {Keri L} and {Oskari Kilpel{\"a}inen}, Tuomas and T{\~o}nu Esko and Reedik M{\"a}gi and Shengxu Li and Tsegaselassie Workalemahu and Feitosa, {Mary F} and Croteau-Chonka, {Damien C} and Day, {Felix R} and Tove Fall and Teresa Ferreira and Stefan Gustafsson and Locke, {Adam E} and Iain Mathieson and Andre Scherag and Sailaja Vedantam and Wood, {Andrew R} and Liming Liang and Valgerdur Steinthorsdottir and Gudmar Thorleifsson and Dermitzakis, {Emmanouil T} and Dimas, {Antigone S} and Fredrik Karpe and Min, {Josine L} and George Nicholson and Clegg, {Deborah J} and Thomas Person and Krohn, {Jon P} and Sabrina Bauer and Christa Buechler and Kristina Eisinger and Am{\'e}lie Bonnefond and Philippe Froguel and Jouke-Jan Hottenga and Inga Prokopenko and Waite, {Lindsay L} and Harris, {Tamara B} and Smith, {Albert Vernon} and Shuldiner, {Alan R} and McArdle, {Wendy L} and Caulfield, {Mark J} and Peter Kovacs and Schwarz, {Peter E H} and Lars Lind and Inger Nj{\o}lstad and {DIAGRAM Consortium}",

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AU - Randall, Joshua C

AU - Winkler, Thomas W

AU - Kutalik, Zoltán

AU - Berndt, Sonja I

AU - Jackson, Anne U

AU - Monda, Keri L

AU - Oskari Kilpeläinen, Tuomas

AU - Esko, Tõnu

AU - Mägi, Reedik

AU - Li, Shengxu

AU - Workalemahu, Tsegaselassie

AU - Feitosa, Mary F

AU - Croteau-Chonka, Damien C

AU - Day, Felix R

AU - Fall, Tove

AU - Ferreira, Teresa

AU - Gustafsson, Stefan

AU - Locke, Adam E

AU - Mathieson, Iain

AU - Scherag, Andre

AU - Vedantam, Sailaja

AU - Wood, Andrew R

AU - Liang, Liming

AU - Steinthorsdottir, Valgerdur

AU - Thorleifsson, Gudmar

AU - Dermitzakis, Emmanouil T

AU - Dimas, Antigone S

AU - Karpe, Fredrik

AU - Min, Josine L

AU - Nicholson, George

AU - Clegg, Deborah J

AU - Person, Thomas

AU - Krohn, Jon P

AU - Bauer, Sabrina

AU - Buechler, Christa

AU - Eisinger, Kristina

AU - Bonnefond, Amélie

AU - Froguel, Philippe

AU - Hottenga, Jouke-Jan

AU - Prokopenko, Inga

AU - Waite, Lindsay L

AU - Harris, Tamara B

AU - Smith, Albert Vernon

AU - Shuldiner, Alan R

AU - McArdle, Wendy L

AU - Caulfield, Mark J

AU - Kovacs, Peter

AU - Schwarz, Peter E H

AU - Lind, Lars

AU - Njølstad, Inger

AU - DIAGRAM Consortium

PY - 2013/6

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N2 - Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10-8), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.

AB - Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10-8), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.

U2 - 10.1371/journal.pgen.1003500

DO - 10.1371/journal.pgen.1003500

M3 - Journal article

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SN - 1553-7390

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EP - 19

JO - P L o S Genetics

JF - P L o S Genetics

IS - 6

M1 - e1003500

ER -

Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits

Abstract

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