title: Genome-wide association study identifies a new locus JMJD1C at 10q21 that may influence serum androgen levels in men.
abstract: 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.
authors.affiliation: Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Guangfu
authors.initials: G
authors.lastname: Jin
authors.forename: Jielin
authors.initials: J
authors.lastname: Sun
authors.forename: Seong-Tae
authors.initials: ST
authors.lastname: Kim
authors.forename: Junjie
authors.initials: J
authors.lastname: Feng
authors.forename: Zhong
authors.initials: Z
authors.lastname: Wang
authors.forename: Sha
authors.initials: S
authors.lastname: Tao
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Chen
authors.forename: Lina
authors.initials: L
authors.lastname: Purcell
authors.forename: Shelly
authors.initials: S
authors.lastname: Smith
authors.forename: William B
authors.initials: WB
authors.lastname: Isaacs
authors.forename: Roger S
authors.initials: RS
authors.lastname: Rittmaster
authors.forename: S Lilly
authors.initials: SL
authors.lastname: Zheng
authors.forename: Lynn D
authors.initials: LD
authors.lastname: Condreay
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Xu
mesh_terms: D000368:Aged; D000728:Androgens / Q000097:blood*; D002879:Chromosomes, Human, Pair 10; D002886:Chromosomes, Human, Pair 17; D041321:Chromosomes, Human, X; D013196:Dihydrotestosterone / Q000097:blood; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D013739:Testosterone / Q000097:blood
chemical_list: D000728:Androgens; D013196:Dihydrotestosterone; D013739:Testosterone; C520448:JMJD1C protein, human; D056484:Jumonji Domain-Containing Histone Demethylases; D010089:Oxidoreductases, N-Demethylating