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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; Lehtimaki, Terho; Keildson, Sarah; Lunetta, Kathryn L.; He, Chunyan; Fornage, Myriam and Lagou, Vasiliki, et al. (2012) In PLoS Genetics 8(7).
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... (More)
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. (Less)
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PLoS Genetics
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1553-7404
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10.1371/journal.pgen.1002805
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@article{609e539b-1012-40ad-b9c6-35ecbfa9f16c,
  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 Haring, Robin and Wellons, Melissa and Vaidya, Dhananjay and Lehtimaki, Terho and Keildson, Sarah and Lunetta, Kathryn L. and He, Chunyan and Fornage, Myriam and Lagou, Vasiliki and Mangino, Massimo and Onland-Moret, N. Charlotte and Chen, Brian and Eriksson, Joel and Garcia, Melissa and Mei, Yong and Koster, Annemarie and Lohman, Kurt and Lyytikainen, Leo-Pekka and Petersen, Ann-Kristin and Prescott, Jennifer and Stolk, Lisette and Vandenput, Liesbeth and Wood, Andrew R. and Zhuang, Wei Vivian and Ruokonen, Aimo and Hartikainen, Anna-Liisa and Pouta, Anneli and Bandinelli, Stefania and Biffar, Reiner and Brabant, Georg and Cox, David G. and Chen, Yuhui and Cummings, Steven and Ferrucci, Luigi and Gunter, Marc J. and Hankinson, Susan E. and Martikainen, Hannu and Hofman, Albert and Homuth, Georg and Illig, Thomas and Jansson, John-Olov and Johnson, Andrew D. and Karasik, David and Karlsson, Magnus and Kettunen, Johannes and Kiel, Douglas P. and Kraft, Peter and Liu, Jingmin and Ljunggren, Osten and Lorentzon, Mattias and Maggio, Marcello and Markus, Marcello R. P. and Mellstrom, Dan and Miljkovic, Iva and Mirel, Daniel and Nelson, Sarah and Papunen, Laure Morin and Peeters, Petra H. M. and Prokopenko, Inga and Raffel, Leslie and Reincke, Martin and Reiner, Alex P. and Rexrode, Kathryn and Rivadeneira, Fernando and Schwartz, Stephen M. and Siscovick, David and Soranzo, Nicole and Stockl, Doris and Tworoger, Shelley and Uitterlinden, Andre G. and van Gils, Carla H. and Vasan, Ramachandran S. and Wichmann, H. -Erich and Zhai, Guangju and Bhasin, Shalender and Bidlingmaier, Martin and Chanock, Stephen J. and De Vivo, Immaculata and Harris, Tamara B. and Hunter, David J. and Kahonen, Mika and Liu, Simin and Ouyang, Pamela and Spector, Tim D. and van der Schouw, Yvonne T. and Viikari, Jorma and Wallaschofski, Henri and McCarthy, Mark I. and Frayling, Timothy M. and Murray, Anna and Franks, Steve and Jarvelin, Marjo-Riitta and de Jong, Frank H. and Raitakari, Olli and Teumer, Alexander and Ohlsson, Claes and Murabito, Joanne M. and Perry, John R. B.},
  issn         = {1553-7404},
  language     = {eng},
  number       = {7},
  publisher    = {Public Library of Science},
  series       = {PLoS Genetics},
  title        = {A Genome-Wide Association Meta-Analysis of Circulating Sex Hormone-Binding Globulin Reveals Multiple Loci Implicated in Sex Steroid Hormone Regulation},
  url          = {http://dx.doi.org/10.1371/journal.pgen.1002805},
  volume       = {8},
  year         = {2012},
}