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 concentrations. Loci near the identified SNPs
included SHBG (rs12150660, 17p13.1, p = 1.8x10(-106)), PRMT6
(rs17496332, 1p13.3, p=1.4x10(-11)), GCKR (rs780093, 2p23.3,
p=2.2x10(-16)), ZBTB10 (rs440837, 8q21.13, p=3.4x10(-09)), JMJD1C
(rs7910927, 10q21.3, p=6.1x10(-35)), SLCO1B1 (rs4149056, 12p12.1,
p=1.9x10(-08)), NR2F2 (rs8023580, 15q26.2, p=8.3x10(-12)), ZNF652
(rs2411984, 17q21.32, p=3.5x10(-14)), TDGF3 (rs1573036, Xq22.3,
p=4.1x10(-14)), LHCGR (rs10454142, 2p16.3, p=1.3x10(-07)), BAIAP2L1
(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 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
similar to 15.6% and similar to 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.