Genome-Wide Association Study And Polygenic Risk Scores Of Serum Dheas Levels In A Chilean Children Cohort.

BACKGROUND Adrenarche reflects the developmental growth of the adrenal zona reticularis, which produces increasing adrenal androgen secretion (e.g., DHEA/DHEAS) from ages ~5-15 years. We hypothesized that the study of the genetic determinants associated with variations in serum DHEAS during adrenarche might detect genetic variants influencing the rate or timing of this process. SUBJECTS AND METHODS Genome-wide genotyping was performed in participants of the Chilean pediatric GOCS cohort (n=788). We evaluated the genetic determinants of DHEAS levels at genome-wide level and in targeted genes associated with steroidogenesis. To corroborate our findings, we evaluated a polygenic risk score for age at pubarche, based upon the discovered variants, in children from the same cohort. RESULTS We identified one significant variant at the genome-wide level in the full cohort, close to the GALR1 gene (P = 3.81x10 -8). In addition, variants suggestive of association (P <1x10 -5) were observed in PRLR, PITX1, PTPRD, NR1H4, and BCL11B. Stratifying by sex, we found variants suggestive of association in SERBP1 and CAMTA1/VAMP3 for boys and near ZNF98, TRPC6, and SULT2A1 for girls. We also found significant reductions in age at pubarche in those children with higher polygenic risk scores for greater DHEAS based on these newly identified variants. CONCLUSIONS Our results disclose one variant associated with DHEAS concentrations at the level of GWAS significance, and several variants with suggestive association, which may be involved in the genetic regulation of adrenarche.