Exploring the genetic influence on hair cortisol concentration: Genetic association of rs11621961 on SERPINA6/1 locus in the 2004 Pelotas Birth Cohort (Brazil)

Genetics plays a critical role in regulating cortisol, as demonstrated by the association of the SERPINA6/1 locus with plasma cortisol concentrations in a genome-wide association meta-analysis (GWAMA). These genes are integral to glucocorticoid transport and regulation, highlighting a direct genetic influence on cortisol availability. This study examines the genetic contribution to hair cortisol concentration (HCC) in adolescents from the 2004 Pelotas (Brazil) Birth Cohort at age 15, employing three distinct approaches: 1) polygenic score (PGS), 2) gene-based analysis, and 3) candidate variations analysis. A total of 1667 individuals were included. The cortisol-PGS was derived from the most recent morning plasma cortisol GWAMA study, and gene-based analyses were performed using MAGMA. For the analysis of candidate variants in the SERPINA6/1 locus, we selected SNPs with P-values ≤ 5 × 10^-8 from the cortisol GWAMA and conducted in silico analyses to assess potential regulatory functions. Nineteen SNPs were tested. Our results revealed a significant association between rs11621961 and HCC after multiple testing correction. This intergenic SNP, located 1.1 kb from the 3'-untranslated region (UTR) of SERPINA6, showed that the T allele was associated with higher HCC (β=0.05, FDR-P = 0.038). Functional in silico analyses suggested that rs11621961 might influence gene expression and chromatin structure by altering motifs and acting as an expression quantitative trait locus (eQTL) in lymphoblastoid cell lines. However, neither the cortisol-PGS nor gene-based analyses showed an association with HCC. This study offers important contributions to the understanding of the genetic determinants of HCC, advancing the knowledge of the relationship between genetics and cortisol regulation in adolescents.