A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple loci implicated in sex steroid hormone regulation

Coviello, AD and Haring, R and Wellons, M and Vaidya, D and Lehtimäki, T and Keildson, S and Lunetta, KL and He, C and Fornage, M and Lagou, V and Mangino, M and Onland-Moret, NC and Chen, B and Eriksson, J and Garcia, M and Liu, YM and Koster, A and Lohman, K and Lyytikäinen, LP and Petersen, AK and Prescott, J and Stolk, L and Vandenput, L and Wood, AR and Zhuang, WV and Ruokonen, A and Hartikainen, AL and Pouta, A and Bandinelli, S and Biffar, R and Brabant, G and Cox, DG and Chen, Y and Cummings, S and Ferrucci, L and Gunter, MJ and Hankinson, SE and Martikainen, H and Hofman, A and Homuth, G and Illig, T and Jansson, JO and Johnson, AD and Karasik, D and Karlsson, M and Kettunen, J and Kiel, DP and Kraft, P and Liu, J and Ljunggren, O and Lorentzon, M and Maggio, M and Markus, MRP and Mellström, D and Miljkovic, I and Mirel, D and Nelson, S and Morin Papunen, L and Peeters, PHM and Prokopenko, I and Raffel, L and Reincke, M and Reiner, AP and Rexrode, K and Rivadeneira, F and Schwartz, SM and Siscovick, D and Soranzo, N and Stöckl, D and Tworoger, S and Uitterlinden, AG and van Gils, CH and Vasan, RS and Wichmann, HE and Zhai, G and Bhasin, S and Bidlingmaier, M and Chanock, SJ and de Vivo, I and Harris, TB and Hunter, DJ and Kähönen, M and Liu, S and Ouyang, P and Spector, TD and van der Schouw, YT and Viikari, J and Wallaschofski, H and McCarthy, MI and Frayling, TM and Murray, A and Franks, S and Järvelin, MR and de Jong, FH and Raitakari, O and Teumer, A and Ohlsson, C and Murabito, JM and 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, 8 (7). ISSN 1553-7390

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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.

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Item Type:	Article
Status:	Published
Creators/Authors:	Creators Email Pitt Username ORCID 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, O Lorentzon, M Maggio, M Markus, MRP Mellström, D Miljkovic, I MiljkovicI@edc.pitt.edu IVM1 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
Contributors:	Contribution Contributors Name Email Pitt Username ORCID Editor Gibson, Greg UNSPECIFIED UNSPECIFIED UNSPECIFIED
Date:	1 July 2012
Date Type:	Publication
Journal or Publication Title:	PLoS Genetics
Volume:	8
Number:	7
DOI or Unique Handle:	10.1371/journal.pgen.1002805
Schools and Programs:	School of Public Health > Epidemiology
Refereed:	Yes
ISSN:	1553-7390
Date Deposited:	25 Jun 2014 22:31
Last Modified:	22 Jun 2021 13:56
URI:	http://d-scholarship.pitt.edu/id/eprint/22116

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