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

View/ Open
Author
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
Eriksson, Joel
Garcia, Melissa
Liu, Yong Mei
Koster, Annemarie
Lohman, Kurt
Lyytikäinen, Leo-Pekka
Petersen, Ann-Kristin
Stolk, Lisette
Vandenput, Liesbeth
Wood, Andrew R.
Zhuang, Wei Vivian
Ruokonen, Aimo
Hartikainen, Anna-Liisa
Pouta, Anneli
Bandinelli, Stefania
Biffar, Reiner
Brabant, Georg
Chen, Yuhui
Cummings, Steven
Ferrucci, Luigi
Gunter, Marc J.
Martikainen, Hannu
Homuth, Georg
Illig, Thomas
Jansson, John-Olov
Karlsson, Magnus
Kettunen, Johannes
Liu, Jingmin
Ljunggren, Östen
Lorentzon, Mattias
Maggio, Marcello
Markus, Marcello R. P.
Mellström, Dan
Miljkovic, Iva
Mirel, Daniel
Morin Papunen, Laure
Peeters, Petra H. M.
Prokopenko, Inga
Raffel, Leslie
Reincke, Martin
Reiner, Alex P.
Rivadeneira, Fernando
Schwartz, Stephen M.
Siscovick, David
Soranzo, Nicole
Stöckl, Doris
Uitterlinden, André G.
van Gils, Carla H.
Vasan, Ramachandran S.
Wichmann, H.-Erich
Zhai, Guangju
Bhasin, Shalender
Bidlingmaier, Martin
Chanock, Stephen J.
Harris, Tamara B.
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.
Chen, Brian
Cox, David G.
Johnson, Andrew D.
Nelson, Sarah
Kraft, Peter
Note: Order does not necessarily reflect citation order of authors.
Published Version
https://doi.org/10.1371/journal.pgen.1002805Metadata
Show full item recordCitation
Coviello, Andrea D., Robin Haring, Melissa Wellons, Dhananjay Vaidya, Terho Lehtimäki, Sarah Keildson, Kathryn L. Lunetta, 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): e1002805.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×\(10^{−9}\)), 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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3400553/pdf/Terms of Use
This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAACitable link to this page
http://nrs.harvard.edu/urn-3:HUL.InstRepos:10465991
Collections
- HMS Scholarly Articles [17714]
- SPH Scholarly Articles [6329]
Contact administrator regarding this item (to report mistakes or request changes)