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 = 1.86102106), PRMT6 (rs17496332, 1p13.3,
p = 1.4610211), GCKR (rs780093, 2p23.3,p= 2.2610216), ZBTB10 (rs440837, 8q21.13,p= 3.4610209), JMJD1C (rs7910927, 10q21.3,
p = 6.1610235), SLCO1B1 (rs4149056, 12p12.1, p= 1.9610208), NR2F2 (rs8023580, 15q26.2, p= 8.3610212), ZNF652 (rs2411984,
17q21.32, p= 3.5610214), TDGF3 (rs1573036, Xq22.3, p= 4.1610214), LHCGR (rs10454142, 2p16.3, p= 1.3610207), BAIAP2L1
(rs3779195, 7q21.3, p= 2.7610208), and UGT2B15 (rs293428, 4q13.2, p= 5.5610206). 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 = 2.5610208, 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 sexdifferentiated
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.