Eight common genetic variants associated with serum DHEAS levels suggest a key role in ageing mechanisms

Abstract

Dehydroepiandrosterone sulphate (DHEAS) is the most abundant circulating steroid secreted by adrenal glands--yet its function is unknown. Its serum concentration declines significantly with increasing age, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. We conducted a meta-analysis of genome-wide association data with 14,846 individuals and identified eight independent common SNPs associated with serum DHEAS concentrations. Genes at or near the identified loci include ZKSCAN5 (rs11761528; p = 3.15 × 10(-36)), SULT2A1 (rs2637125; p = 2.61 × 10(-19)), ARPC1A (rs740160; p = 1.56 × 10(-16)), TRIM4 (rs17277546; p = 4.50 × 10(-11)), BMF (rs7181230; p = 5.44 × 10(-11)), HHEX (rs2497306; p = 4.64 × 10(-9)), BCL2L11 (rs6738028; p = 1.72 × 10(-8)), and CYP2C9 (rs2185570; p = 2.29 × 10(-8)). These genes are associated with type 2 diabetes, lymphoma, actin filament assembly, drug and xenobiotic metabolism, and zinc finger proteins. Several SNPs were associated with changes in gene expression levels, and the related genes are connected to biological pathways linking DHEAS with ageing. This study provides much needed insight into the function of DHEAS.

Figure 1. Manhattan plots for the genome-wide meta-analysis results.

Green dots indicate the SNPs with p<5×10⁻⁸.

Figure 2. Regional linkage disequilibrium plots.

For rs6738028 (A), rs740160 (B), rs11761528 (C), rs17277546 (D), rs2497306 (E), rs2185570 (F), rs7181230 (G), and rs2637125 (H). Note: p values from the conditional analysis were used for (a) and (b), both of them became genome-wide significant in the conditional analysis. Annotation key: ▴ - framestop or splice; ▾ - NonSynonymous; ▪ - Synonymous or UTR; •- nothing; *- TFBScons; -MCS44 Placental.