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

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 2106 concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8x10-106 ), PRMT6 (rs17496332, 1p13.3, 211 216 209 p= 1.4x10-11 ), GCKR (rs780093, 2p23.3,p= 2.2x10-16 ), ZBTB10 (rs440837, 8q21.13,p= 3.4x10-09 ), JMJD1C (rs7910927, 10q21.3, 235 208 212 p= 6.1x10-35 ), SLCO1B1 (rs4149056, 12p12.1,p = 1.9x10-08 ), NR2F2 (rs8023580, 15q26.2,p = 8.3x10-12 ), ZNF652 (rs2411984, 214 214 207 17q21.32,p = 3.5610 ), TDGF3 (rs1573036, Xq22.3,p = 4.1x10-14 ), LHCGR (rs10454142, 2p16.3,p = 1.3x10-07 ), BAIAP2L1 208 206 (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 208 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 ~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. [ABSTRACT FROM AUTHOR]