A Genome-Wide Association Meta-Analysis of Circulating Sex Hormone-Binding Globulin Reveals Multiple Loci Implicated in Sex Steroid Hormone Regulation

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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 = 1.8x10(-106)), PRMT6 (rs17496332, 1p13.3, p=1.4x10(-11)), GCKR (rs780093, 2p23.3, p=2.2x10(-16)), ZBTB10 (rs440837, 8q21.13, p=3.4x10(-09)), JMJD1C (rs7910927, 10q21.3, p=6.1x10(-35)), SLCO1B1 (rs4149056, 12p12.1, p=1.9x10(-08)), NR2F2 (rs8023580, 15q26.2, p=8.3x10(-12)), ZNF652 (rs2411984, 17q21.32, p=3.5x10(-14)), TDGF3 (rs1573036, Xq22.3, p=4.1x10(-14)), LHCGR (rs10454142, 2p16.3, p=1.3x10(-07)), BAIAP2L1 (rs3779195, 7q21.3, p=2.7x10(-08)), and UGT2B15 (rs293428, 4q13.2, p=5.5x10(-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 = 2.5x10(-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 similar to 15.6{\%} and similar to 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 Lehtimaki 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 Yong Mei and Annemarie Koster and Kurt Lohman and Leo-Pekka Lyytikainen and Ann-Kristin Petersen and Jennifer Prescott and Lisette Stolk and Liesbeth Vandenput and Wood, {Andrew R.} and Zhuang, {Wei Vivian} and Aimo Ruokonen and Anna-Liisa Hartikainen 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 John-Olov Jansson and Johnson, {Andrew D.} and David Karasik and Magnus Karlsson and Johannes Kettunen and Kiel, {Douglas P.} and Peter Kraft and Jingmin Liu and Osten Ljunggren and Mattias Lorentzon and Marcello Maggio and Markus, {Marcello R. P.} and Dan Mellstrom and Iva Miljkovic and Daniel Mirel and Sarah Nelson and Papunen, {Laure Morin} 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 Stockl and Shelley Tworoger and Uitterlinden, {Andre 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 Kahonen 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 Marjo-Riitta Jarvelin 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",
doi = "10.1371/journal.pgen.1002805",
language = "English",
volume = "8",
journal = "PLoS Genetics",
issn = "1553-7404",
publisher = "Public Library of Science",
number = "7",