A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple loci implicated in sex steroid hormone regulation
Journal article
Coviello, A.D., Haring, Robin, Wellons, Melissa, Vaidya, Dhananjay, Lehtimaki, Terho, Keildson, S., Lunetta, Kathryn, He, Chunyan, Fornage, Myriam, Lagou, Vasiliki, Mangino, Massimo, Onland-Moret, N. Charlotte, Vandenput, Liesbeth, Lorentzon, Karl Mattias and et. al.. (2012). A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple loci implicated in sex steroid hormone regulation. PLoS Genetics. 8(7), pp. 1-12. https://doi.org/10.1371/journal.pgen.1002805
Authors | Coviello, A.D., Haring, Robin, Wellons, Melissa, Vaidya, Dhananjay, Lehtimaki, Terho, Keildson, S., Lunetta, Kathryn, He, Chunyan, Fornage, Myriam, Lagou, Vasiliki, Mangino, Massimo, Onland-Moret, N. Charlotte, Vandenput, Liesbeth, Lorentzon, Karl Mattias and et. al. |
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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. |
Keywords | Sex hormone-binding globulin; sex steroid hormone; genome-wide association study; trait variance; breast cancer; prostate cancer; type 2 diabetes |
Year | 01 Jan 2012 |
Journal | PLoS Genetics |
Journal citation | 8 (7), pp. 1-12 |
Publisher | Public Library of Science |
ISSN | 1553-7390 |
Digital Object Identifier (DOI) | https://doi.org/10.1371/journal.pgen.1002805 |
Web address (URL) | https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1002805#s5 |
Open access | Published as ‘gold’ (paid) open access |
Research or scholarly | Research |
Page range | 1-12 |
Publisher's version | License File Access Level Open |
Output status | Published |
Publication dates | |
Online | 19 Jul 2012 |
Publication process dates | |
Accepted | 19 May 2012 |
Deposited | 08 May 2024 |
Additional information | This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. |
Copyright of PLoS Genetics is the property of Public Library of Science and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. | |
Place of publication | United States |
https://acuresearchbank.acu.edu.au/item/906z3/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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License: CC0 | |
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