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 PetersenJennifer 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

    75 Citations (Scopus)

    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

    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

    ASJC Scopus subject areas

    • 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",

    }

    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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    UR - http://www.scopus.com/inward/citedby.url?scp=84864619335&partnerID=8YFLogxK

    U2 - 10.1371/journal.pgen.1002805

    DO - 10.1371/journal.pgen.1002805

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    C2 - 22829776

    AN - SCOPUS:84864619335

    VL - 8

    JO - PLoS Genetics

    JF - PLoS Genetics

    SN - 1553-7390

    IS - 7

    M1 - e1002805

    ER -