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Circulating androgen levels are often used as indicators of physiological or pathological conditions. More than half of the variance for circulating androgen levels is thought to be genetically influenced. A genome-wide association study (GWAS) has identified two loci,  SHBG  at 17p13 and  FAM9B  at Xp22, for serum testosterone (T) levels; however, these explain only a small fraction of inter-individual variability. To identify additional genetic determinants of androgen levels, a GWAS of baseline serum T and dihydrotestosterone (DHT) levels was conducted in 3225 men of European ancestry from the REduction by DUtasteride of Prostate Cancer Events (REDUCE) study. Cross-validation was used to confirm the observed associations between the drug ( n  = 1581) and placebo ( n  = 1644) groups of REDUCE. In addition to confirming the associations of two known loci with serum T levels (rs727428 in  SHBG :  P  = 1.26 × 10 −12 ; rs5934505 in  FAM9B :  P  = 1.61 × 10 −8 ), we identified a new locus,  JMJD1C  at 10q21 that was associated with serum T levels at a genome-wide significance level (rs10822184:  P  = 1.12 × 10 −8 ). We also observed that the  SHBG  locus was associated with serum DHT levels (rs727428:  P  = 1.47 × 10 −11 ). Moreover, two additional variants in  SHBG  [rs72829446, in strong linkage equilibrium with the missense variant D356N (rs6259), and rs1799941] were also independently associated with circulating androgen levels in a statistical scale. These three loci ( JMJD1C ,  SHBG  and  FAM9B ) were estimated to account for ∼5.3 and 4.1% of the variance of serum T and DHT levels. Our findings may provide new insights into the regulation of circulating androgens and potential targets for androgen-based therapy.

Genome-wide association study identifies a new locus JMJD1C at 10q21 that may influence serum androgen levels in men