Eight Common Genetic Variants Associated with Serum DHEAS Levels Suggest a Key Role in Ageing Mechanisms
Guangju Zhai, Alexander Teumer, Lisette Stolk, John R. B. Perry, Liesbeth Vandenput, Andrea D. Coviello, Annemarie Koster, Jordana T. Bell, Shalender Bhasin, Joel Eriksson, et al.
PLoS Genetics2011
Summary (paraphrased)
DHEA sulfate is the most abundant circulating adrenal steroid and declines markedly with age, prompting speculation that relative deficiency contributes to age-related disease. A meta-analysis of genome-wide association data in 14,846 individuals identified eight independent common SNPs associated with serum DHEAS. The implicated loci include SULT2A1 (rs2637125, p = 2.61e-19), CYP2C9 (rs2185570, p = 2.29e-8), ZKSCAN5, ARPC1A, TRIM4, BMF, HHEX, and BCL2L11. Several SNPs tracked with gene-expression changes, and the genes connect to pathways linking DHEAS with ageing. The authors present this as the first robust genetic map of DHEAS regulation.
Why it’s in the systems review
DHEA/DHEAS sits at the top of the neurosteroid cascade that the Melcangi group places at the center of PFS pathophysiology, and this GWAS pins two corpus-relevant genes — SULT2A1 (Powers-named) and CYP2C9 (a drug/xenobiotic-metabolizing CYP) — to circulating DHEAS in humans at genome-wide significance. It gives the corpus its first genome-wide (hypothesis-free) anchor for the sulfation axis and adds CYP2C9, relevant to retinoid and drug metabolism, to the marker list.
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In healthy volunteers given exogenous testosterone, the authors tested whether copy-number variation in sulfotransferase genes predicted urinary excretion of steroid sulfates. SULT2A1 copy number was significantly associated with excretion rates of sulfate…
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