Camerini Laísa, Murray Joseph, de Almeida Júlia Oliveira, Gonzalez Andrea, Santos Iná S, Barros Fernando, Oliveira Isabel O, Matijasevich Alicia, Tovo-Rodrigues Luciana
Postgraduate Program in Epidemiology, Federal University of Pelotas, Rio Grande do Sul, Brazil; ADHD Outpatient Program & Development Psychiatry Program, Hospital de Clínicas de Porto Alegre, Federal University of Rio Grande do Sul, Rio Grande do Sul, Brazil.
Postgraduate Program in Epidemiology, Federal University of Pelotas, Rio Grande do Sul, Brazil; Human Development and Violence Research Centre (DOVE), Federal University of Pelotas, Pelotas, Brazil.
Psychoneuroendocrinology. 2025 Jul;177:107470. doi: 10.1016/j.psyneuen.2025.107470. Epub 2025 Apr 16.
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 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.
遗传学在调节皮质醇方面起着关键作用，这在一项全基因组关联荟萃分析（GWAMA）中，SERPINA6/1基因座与血浆皮质醇浓度的关联中得到了证明。这些基因对于糖皮质激素的运输和调节不可或缺，突显了对皮质醇可用性的直接遗传影响。本研究采用三种不同方法，考察了2004年佩洛塔斯（巴西）出生队列中15岁青少年头发皮质醇浓度（HCC）的遗传贡献：1）多基因评分（PGS），2）基于基因的分析，以及3）候选变异分析。共纳入1667名个体。皮质醇-PGS来自最近的早晨血浆皮质醇GWAMA研究，基于基因的分析使用MAGMA进行。对于SERPINA6/1基因座候选变异的分析，我们从皮质醇GWAMA中选择P值≤5×10的单核苷酸多态性（SNP），并进行了计算机模拟分析以评估潜在的调控功能。共测试了19个SNP。我们的结果显示，经过多重检验校正后，rs11621961与HCC之间存在显著关联。这个基因间SNP位于SERPINA6的3'非翻译区（UTR）1.1 kb处，显示T等位基因与较高的HCC相关（β=0.05，FDR-P=0.038）。计算机模拟功能分析表明，rs11621961可能通过改变基序并作为淋巴母细胞系中的表达数量性状位点（eQTL）来影响基因表达和染色质结构。然而，皮质醇-PGS和基于基因的分析均未显示与HCC有关联。本研究为理解HCC的遗传决定因素做出了重要贡献，推进了对青少年遗传学与皮质醇调节之间关系的认识。
