A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple loci implicated in sex steroid hormone regulation

Andrea D. Coviello, Robin Haring, Melissa Wellons, Dhananjay Vaidya, Terho Lehtimäki, Sarah Keildson, Kathryn L. Lunetta, Chunyan He, Myriam Fornage, Vasiliki Lagou, Massimo Mangino, N. Charlotte Onland-Moret, Brian Chen, Joel Eriksson, Melissa Garcia, Yong Mei Liu, Annemarie Koster, Kurt Lohman, Leo Pekka Lyytikäinen, Ann Kristin Petersen & 79 others Jennifer Prescott, Lisette Stolk, Liesbeth Vandenput, Andrew R. Wood, Wei Vivian Zhuang, Aimo Ruokonen, Anna Liisa Hartikainen, Anneli Pouta, Stefania Bandinelli, Reiner Biffar, Georg Brabant, David G. Cox, Yuhui Chen, Steven Cummings, Luigi Ferrucci, Marc J. Gunter, Susan E. Hankinson, Hannu Martikainen, Albert Hofman, Georg Homuth, Thomas Illig, John Olov Jansson, Andrew D. Johnson, David Karasik, Magnus Karlsson, Johannes Kettunen, Douglas P. Kiel, Peter Kraft, Jingmin Liu, Östen Ljunggren, Mattias Lorentzon, Marcello Maggio, Marcello R P Markus, Dan Mellström, Iva Miljkovic, Daniel Mirel, Sarah Nelson, Laure Morin Papunen, Petra H M Peeters, Inga Prokopenko, Leslie Raffel, Martin Reincke, Alex P. Reiner, Kathryn Rexrode, Fernando Rivadeneira, Stephen M. Schwartz, David Siscovick, Nicole Soranzo, Doris Stöckl, Shelley Tworoger, André G. Uitterlinden, Carla H. van Gils, Ramachandran S. Vasan, H. Erich Wichmann, Guangju Zhai, Shalender Bhasin, Martin Bidlingmaier, Stephen J. Chanock, Immaculata de Vivo, Tamara B. Harris, David J. Hunter, Mika Kähönen, Simin Liu, Pamela Ouyang, Tim D. Spector, Yvonne T. van der Schouw, Jorma Viikari, Henri Wallaschofski, Mark I. McCarthy, Timothy M. Frayling, Anna Murray, Steve Franks, Marjo Riitta Järvelin, Frank H. de Jong, Olli Raitakari, Alexander Teumer, Claes Ohlsson, Joanne M. Murabito, John R B Perry

Research output: Contribution to journalArticle

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Abstract

Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8×10-106), PRMT6 (rs17496332, 1p13.3, p = 1.4×10-11), GCKR (rs780093, 2p23.3, p = 2.2×10-16), ZBTB10 (rs440837, 8q21.13, p = 3.4×10-09), JMJD1C (rs7910927, 10q21.3, p = 6.1×10-35), SLCO1B1 (rs4149056, 12p12.1, p = 1.9×10-08), NR2F2 (rs8023580, 15q26.2, p = 8.3×10-12), ZNF652 (rs2411984, 17q21.32, p = 3.5×10-14), TDGF3 (rs1573036, Xq22.3, p = 4.1×10-14), LHCGR (rs10454142, 2p16.3, p = 1.3×10-07), BAIAP2L1 (rs3779195, 7q21.3, p = 2.7×10-08), and UGT2B15 (rs293428, 4q13.2, p = 5.5×10-06). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5×10-08, women p = 0.66, heterogeneity p = 0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained ~15.6% and ~8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance.

Original languageEnglish
Article numbere1002805
JournalPLoS Genetics
Volume8
Issue number7
DOIs
StatePublished - Jul 2012
Externally publishedYes

Fingerprint

sex hormone
Sex Hormone-Binding Globulin
sex hormones
Genome-Wide Association Study
meta-analysis
Gonadal Steroid Hormones
steroid hormones
steroid
hormone
Meta-Analysis
genome
loci
cancer
gender
Single Nucleotide Polymorphism
Prostatic Neoplasms
diabetes
prostatic neoplasms
Breast Neoplasms
noninsulin-dependent diabetes mellitus

All Science Journal Classification (ASJC) codes

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple loci implicated in sex steroid hormone regulation. / Coviello, Andrea D.; Haring, Robin; Wellons, Melissa; Vaidya, Dhananjay; Lehtimäki, Terho; Keildson, Sarah; Lunetta, Kathryn L.; He, Chunyan; Fornage, Myriam; Lagou, Vasiliki; Mangino, Massimo; Onland-Moret, N. Charlotte; Chen, Brian; Eriksson, Joel; Garcia, Melissa; Liu, Yong Mei; Koster, Annemarie; Lohman, Kurt; Lyytikäinen, Leo Pekka; Petersen, Ann Kristin; Prescott, Jennifer; Stolk, Lisette; Vandenput, Liesbeth; Wood, Andrew R.; Zhuang, Wei Vivian; Ruokonen, Aimo; Hartikainen, Anna Liisa; Pouta, Anneli; Bandinelli, Stefania; Biffar, Reiner; Brabant, Georg; Cox, David G.; Chen, Yuhui; Cummings, Steven; Ferrucci, Luigi; Gunter, Marc J.; Hankinson, Susan E.; Martikainen, Hannu; Hofman, Albert; Homuth, Georg; Illig, Thomas; Jansson, John Olov; Johnson, Andrew D.; Karasik, David; Karlsson, Magnus; Kettunen, Johannes; Kiel, Douglas P.; Kraft, Peter; Liu, Jingmin; Ljunggren, Östen; Lorentzon, Mattias; Maggio, Marcello; Markus, Marcello R P; Mellström, Dan; Miljkovic, Iva; Mirel, Daniel; Nelson, Sarah; Morin Papunen, Laure; Peeters, Petra H M; Prokopenko, Inga; Raffel, Leslie; Reincke, Martin; Reiner, Alex P.; Rexrode, Kathryn; Rivadeneira, Fernando; Schwartz, Stephen M.; Siscovick, David; Soranzo, Nicole; Stöckl, Doris; Tworoger, Shelley; Uitterlinden, André G.; van Gils, Carla H.; Vasan, Ramachandran S.; Wichmann, H. Erich; Zhai, Guangju; Bhasin, Shalender; Bidlingmaier, Martin; Chanock, Stephen J.; de Vivo, Immaculata; Harris, Tamara B.; Hunter, David J.; Kähönen, Mika; Liu, Simin; Ouyang, Pamela; Spector, Tim D.; van der Schouw, Yvonne T.; Viikari, Jorma; Wallaschofski, Henri; McCarthy, Mark I.; Frayling, Timothy M.; Murray, Anna; Franks, Steve; Järvelin, Marjo Riitta; de Jong, Frank H.; Raitakari, Olli; Teumer, Alexander; Ohlsson, Claes; Murabito, Joanne M.; Perry, John R B.

In: PLoS Genetics, Vol. 8, No. 7, e1002805, 07.2012.

Research output: Contribution to journalArticle

Coviello, AD, Haring, R, Wellons, M, Vaidya, D, Lehtimäki, T, Keildson, S, Lunetta, KL, He, C, Fornage, M, Lagou, V, Mangino, M, Onland-Moret, NC, Chen, B, Eriksson, J, Garcia, M, Liu, YM, Koster, A, Lohman, K, Lyytikäinen, LP, Petersen, AK, Prescott, J, Stolk, L, Vandenput, L, Wood, AR, Zhuang, WV, Ruokonen, A, Hartikainen, AL, Pouta, A, Bandinelli, S, Biffar, R, Brabant, G, Cox, DG, Chen, Y, Cummings, S, Ferrucci, L, Gunter, MJ, Hankinson, SE, Martikainen, H, Hofman, A, Homuth, G, Illig, T, Jansson, JO, Johnson, AD, Karasik, D, Karlsson, M, Kettunen, J, Kiel, DP, Kraft, P, Liu, J, Ljunggren, Ö, Lorentzon, M, Maggio, M, Markus, MRP, Mellström, D, Miljkovic, I, Mirel, D, Nelson, S, Morin Papunen, L, Peeters, PHM, Prokopenko, I, Raffel, L, Reincke, M, Reiner, AP, Rexrode, K, Rivadeneira, F, Schwartz, SM, Siscovick, D, Soranzo, N, Stöckl, D, Tworoger, S, Uitterlinden, AG, van Gils, CH, Vasan, RS, Wichmann, HE, Zhai, G, Bhasin, S, Bidlingmaier, M, Chanock, SJ, de Vivo, I, Harris, TB, Hunter, DJ, Kähönen, M, Liu, S, Ouyang, P, Spector, TD, van der Schouw, YT, Viikari, J, Wallaschofski, H, McCarthy, MI, Frayling, TM, Murray, A, Franks, S, Järvelin, MR, de Jong, FH, Raitakari, O, Teumer, A, Ohlsson, C, Murabito, JM & Perry, JRB 2012, 'A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple loci implicated in sex steroid hormone regulation', PLoS Genetics, vol. 8, no. 7, e1002805. https://doi.org/10.1371/journal.pgen.1002805
Coviello, Andrea D. ; Haring, Robin ; Wellons, Melissa ; Vaidya, Dhananjay ; Lehtimäki, Terho ; Keildson, Sarah ; Lunetta, Kathryn L. ; He, Chunyan ; Fornage, Myriam ; Lagou, Vasiliki ; Mangino, Massimo ; Onland-Moret, N. Charlotte ; Chen, Brian ; Eriksson, Joel ; Garcia, Melissa ; Liu, Yong Mei ; Koster, Annemarie ; Lohman, Kurt ; Lyytikäinen, Leo Pekka ; Petersen, Ann Kristin ; Prescott, Jennifer ; Stolk, Lisette ; Vandenput, Liesbeth ; Wood, Andrew R. ; Zhuang, Wei Vivian ; Ruokonen, Aimo ; Hartikainen, Anna Liisa ; Pouta, Anneli ; Bandinelli, Stefania ; Biffar, Reiner ; Brabant, Georg ; Cox, David G. ; Chen, Yuhui ; Cummings, Steven ; Ferrucci, Luigi ; Gunter, Marc J. ; Hankinson, Susan E. ; Martikainen, Hannu ; Hofman, Albert ; Homuth, Georg ; Illig, Thomas ; Jansson, John Olov ; Johnson, Andrew D. ; Karasik, David ; Karlsson, Magnus ; Kettunen, Johannes ; Kiel, Douglas P. ; Kraft, Peter ; Liu, Jingmin ; Ljunggren, Östen ; Lorentzon, Mattias ; Maggio, Marcello ; Markus, Marcello R P ; Mellström, Dan ; Miljkovic, Iva ; Mirel, Daniel ; Nelson, Sarah ; Morin Papunen, Laure ; Peeters, Petra H M ; Prokopenko, Inga ; Raffel, Leslie ; Reincke, Martin ; Reiner, Alex P. ; Rexrode, Kathryn ; Rivadeneira, Fernando ; Schwartz, Stephen M. ; Siscovick, David ; Soranzo, Nicole ; Stöckl, Doris ; Tworoger, Shelley ; Uitterlinden, André G. ; van Gils, Carla H. ; Vasan, Ramachandran S. ; Wichmann, H. Erich ; Zhai, Guangju ; Bhasin, Shalender ; Bidlingmaier, Martin ; Chanock, Stephen J. ; de Vivo, Immaculata ; Harris, Tamara B. ; Hunter, David J. ; Kähönen, Mika ; Liu, Simin ; Ouyang, Pamela ; Spector, Tim D. ; van der Schouw, Yvonne T. ; Viikari, Jorma ; Wallaschofski, Henri ; McCarthy, Mark I. ; Frayling, Timothy M. ; Murray, Anna ; Franks, Steve ; Järvelin, Marjo Riitta ; de Jong, Frank H. ; Raitakari, Olli ; Teumer, Alexander ; Ohlsson, Claes ; Murabito, Joanne M. ; Perry, John R B. / A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple loci implicated in sex steroid hormone regulation. In: PLoS Genetics. 2012 ; Vol. 8, No. 7.
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title = "A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple loci implicated in sex steroid hormone regulation",
abstract = "Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8×10-106), PRMT6 (rs17496332, 1p13.3, p = 1.4×10-11), GCKR (rs780093, 2p23.3, p = 2.2×10-16), ZBTB10 (rs440837, 8q21.13, p = 3.4×10-09), JMJD1C (rs7910927, 10q21.3, p = 6.1×10-35), SLCO1B1 (rs4149056, 12p12.1, p = 1.9×10-08), NR2F2 (rs8023580, 15q26.2, p = 8.3×10-12), ZNF652 (rs2411984, 17q21.32, p = 3.5×10-14), TDGF3 (rs1573036, Xq22.3, p = 4.1×10-14), LHCGR (rs10454142, 2p16.3, p = 1.3×10-07), BAIAP2L1 (rs3779195, 7q21.3, p = 2.7×10-08), and UGT2B15 (rs293428, 4q13.2, p = 5.5×10-06). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5×10-08, women p = 0.66, heterogeneity p = 0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained ~15.6{\%} and ~8.4{\%} of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance.",
author = "Coviello, {Andrea D.} and Robin Haring and Melissa Wellons and Dhananjay Vaidya and Terho Lehtim{\"a}ki and Sarah Keildson and Lunetta, {Kathryn L.} and Chunyan He and Myriam Fornage and Vasiliki Lagou and Massimo Mangino and Onland-Moret, {N. Charlotte} and Brian Chen and Joel Eriksson and Melissa Garcia and Liu, {Yong Mei} and Annemarie Koster and Kurt Lohman and Lyytik{\"a}inen, {Leo Pekka} and Petersen, {Ann Kristin} and Jennifer Prescott and Lisette Stolk and Liesbeth Vandenput and Wood, {Andrew R.} and Zhuang, {Wei Vivian} and Aimo Ruokonen and Hartikainen, {Anna Liisa} and Anneli Pouta and Stefania Bandinelli and Reiner Biffar and Georg Brabant and Cox, {David G.} and Yuhui Chen and Steven Cummings and Luigi Ferrucci and Gunter, {Marc J.} and Hankinson, {Susan E.} and Hannu Martikainen and Albert Hofman and Georg Homuth and Thomas Illig and Jansson, {John Olov} and Johnson, {Andrew D.} and David Karasik and Magnus Karlsson and Johannes Kettunen and Kiel, {Douglas P.} and Peter Kraft and Jingmin Liu and {\"O}sten Ljunggren and Mattias Lorentzon and Marcello Maggio and Markus, {Marcello R P} and Dan Mellstr{\"o}m and Iva Miljkovic and Daniel Mirel and Sarah Nelson and {Morin Papunen}, Laure and Peeters, {Petra H M} and Inga Prokopenko and Leslie Raffel and Martin Reincke and Reiner, {Alex P.} and Kathryn Rexrode and Fernando Rivadeneira and Schwartz, {Stephen M.} and David Siscovick and Nicole Soranzo and Doris St{\"o}ckl and Shelley Tworoger and Uitterlinden, {Andr{\'e} G.} and {van Gils}, {Carla H.} and Vasan, {Ramachandran S.} and Wichmann, {H. Erich} and Guangju Zhai and Shalender Bhasin and Martin Bidlingmaier and Chanock, {Stephen J.} and {de Vivo}, Immaculata and Harris, {Tamara B.} and Hunter, {David J.} and Mika K{\"a}h{\"o}nen and Simin Liu and Pamela Ouyang and Spector, {Tim D.} and {van der Schouw}, {Yvonne T.} and Jorma Viikari and Henri Wallaschofski and McCarthy, {Mark I.} and Frayling, {Timothy M.} and Anna Murray and Steve Franks and J{\"a}rvelin, {Marjo Riitta} and {de Jong}, {Frank H.} and Olli Raitakari and Alexander Teumer and Claes Ohlsson and Murabito, {Joanne M.} and Perry, {John R B}",
year = "2012",
month = "7",
doi = "10.1371/journal.pgen.1002805",
language = "English",
volume = "8",
journal = "PLoS Genetics",
issn = "1553-7390",
publisher = "Public Library of Science",
number = "7",

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TY - JOUR

T1 - A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple loci implicated in sex steroid hormone regulation

AU - Coviello, Andrea D.

AU - Haring, Robin

AU - Wellons, Melissa

AU - Vaidya, Dhananjay

AU - Lehtimäki, Terho

AU - Keildson, Sarah

AU - Lunetta, Kathryn L.

AU - He, Chunyan

AU - Fornage, Myriam

AU - Lagou, Vasiliki

AU - Mangino, Massimo

AU - Onland-Moret, N. Charlotte

AU - Chen, Brian

AU - Eriksson, Joel

AU - Garcia, Melissa

AU - Liu, Yong Mei

AU - Koster, Annemarie

AU - Lohman, Kurt

AU - Lyytikäinen, Leo Pekka

AU - Petersen, Ann Kristin

AU - Prescott, Jennifer

AU - Stolk, Lisette

AU - Vandenput, Liesbeth

AU - Wood, Andrew R.

AU - Zhuang, Wei Vivian

AU - Ruokonen, Aimo

AU - Hartikainen, Anna Liisa

AU - Pouta, Anneli

AU - Bandinelli, Stefania

AU - Biffar, Reiner

AU - Brabant, Georg

AU - Cox, David G.

AU - Chen, Yuhui

AU - Cummings, Steven

AU - Ferrucci, Luigi

AU - Gunter, Marc J.

AU - Hankinson, Susan E.

AU - Martikainen, Hannu

AU - Hofman, Albert

AU - Homuth, Georg

AU - Illig, Thomas

AU - Jansson, John Olov

AU - Johnson, Andrew D.

AU - Karasik, David

AU - Karlsson, Magnus

AU - Kettunen, Johannes

AU - Kiel, Douglas P.

AU - Kraft, Peter

AU - Liu, Jingmin

AU - Ljunggren, Östen

AU - Lorentzon, Mattias

AU - Maggio, Marcello

AU - Markus, Marcello R P

AU - Mellström, Dan

AU - Miljkovic, Iva

AU - Mirel, Daniel

AU - Nelson, Sarah

AU - Morin Papunen, Laure

AU - Peeters, Petra H M

AU - Prokopenko, Inga

AU - Raffel, Leslie

AU - Reincke, Martin

AU - Reiner, Alex P.

AU - Rexrode, Kathryn

AU - Rivadeneira, Fernando

AU - Schwartz, Stephen M.

AU - Siscovick, David

AU - Soranzo, Nicole

AU - Stöckl, Doris

AU - Tworoger, Shelley

AU - Uitterlinden, André G.

AU - van Gils, Carla H.

AU - Vasan, Ramachandran S.

AU - Wichmann, H. Erich

AU - Zhai, Guangju

AU - Bhasin, Shalender

AU - Bidlingmaier, Martin

AU - Chanock, Stephen J.

AU - de Vivo, Immaculata

AU - Harris, Tamara B.

AU - Hunter, David J.

AU - Kähönen, Mika

AU - Liu, Simin

AU - Ouyang, Pamela

AU - Spector, Tim D.

AU - van der Schouw, Yvonne T.

AU - Viikari, Jorma

AU - Wallaschofski, Henri

AU - McCarthy, Mark I.

AU - Frayling, Timothy M.

AU - Murray, Anna

AU - Franks, Steve

AU - Järvelin, Marjo Riitta

AU - de Jong, Frank H.

AU - Raitakari, Olli

AU - Teumer, Alexander

AU - Ohlsson, Claes

AU - Murabito, Joanne M.

AU - Perry, John R B

PY - 2012/7

Y1 - 2012/7

N2 - Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8×10-106), PRMT6 (rs17496332, 1p13.3, p = 1.4×10-11), GCKR (rs780093, 2p23.3, p = 2.2×10-16), ZBTB10 (rs440837, 8q21.13, p = 3.4×10-09), JMJD1C (rs7910927, 10q21.3, p = 6.1×10-35), SLCO1B1 (rs4149056, 12p12.1, p = 1.9×10-08), NR2F2 (rs8023580, 15q26.2, p = 8.3×10-12), ZNF652 (rs2411984, 17q21.32, p = 3.5×10-14), TDGF3 (rs1573036, Xq22.3, p = 4.1×10-14), LHCGR (rs10454142, 2p16.3, p = 1.3×10-07), BAIAP2L1 (rs3779195, 7q21.3, p = 2.7×10-08), and UGT2B15 (rs293428, 4q13.2, p = 5.5×10-06). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5×10-08, women p = 0.66, heterogeneity p = 0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained ~15.6% and ~8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance.

AB - Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8×10-106), PRMT6 (rs17496332, 1p13.3, p = 1.4×10-11), GCKR (rs780093, 2p23.3, p = 2.2×10-16), ZBTB10 (rs440837, 8q21.13, p = 3.4×10-09), JMJD1C (rs7910927, 10q21.3, p = 6.1×10-35), SLCO1B1 (rs4149056, 12p12.1, p = 1.9×10-08), NR2F2 (rs8023580, 15q26.2, p = 8.3×10-12), ZNF652 (rs2411984, 17q21.32, p = 3.5×10-14), TDGF3 (rs1573036, Xq22.3, p = 4.1×10-14), LHCGR (rs10454142, 2p16.3, p = 1.3×10-07), BAIAP2L1 (rs3779195, 7q21.3, p = 2.7×10-08), and UGT2B15 (rs293428, 4q13.2, p = 5.5×10-06). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5×10-08, women p = 0.66, heterogeneity p = 0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained ~15.6% and ~8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance.

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U2 - 10.1371/journal.pgen.1002805

DO - 10.1371/journal.pgen.1002805

M3 - Article

VL - 8

JO - PLoS Genetics

JF - PLoS Genetics

SN - 1553-7390

IS - 7

M1 - e1002805

ER -