Miranda José Patricio, Lardone María Cecilia, Rodríguez Fernando, Cutler Gordon B, Santos José Luis, Corvalán Camila, Pereira Ana, Mericq Verónica
Department of Nutrition, Diabetes, and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
Advanced Center for Chronic Diseases (ACCDiS), Pontificia Universidad Católica de Chile & Universidad de Chile, Santiago, Chile.
J Clin Endocrinol Metab. 2022 Mar 24;107(4):e1727-e1738. doi: 10.1210/clinem/dgab814.
Adrenarche reflects the developmental growth of the adrenal zona reticularis, which produces increasing adrenal androgen secretion (eg, dehydroepiandrosterone [DHEA]/dehydroepiandrosterone sulfate [DHEAS]) from approximately age 5 to 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.
Genome-wide genotyping was performed in participants of the Chilean pediatric Growth and Obesity Chilean Cohort Study (GOCS) cohort (n = 788). We evaluated the genetic determinants of DHEAS levels at the genome-wide level and in targeted genes associated with steroidogenesis. To corroborate our findings, we evaluated a polygenic risk score (PRS) for age at pubarche, based on the discovered variants, in children from the same cohort.
We identified one significant variant at the genome-wide level in the full cohort, close to the GALR1 gene (P = 3.81 × 10-8). In addition, variants suggestive of association (P < 1 × 10-5) 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 PRS for greater DHEAS based on these newly identified variants.
Our results disclose one variant associated with DHEAS concentrations at the level of genome-wide association study significance, and several variants with a suggestive association that may be involved in the genetic regulation of adrenarche.
肾上腺初现反映了肾上腺网状带的发育生长，该区域从大约5岁到15岁会使肾上腺雄激素分泌增加（例如脱氢表雄酮[DHEA]/硫酸脱氢表雄酮[DHEAS]）。
我们假设，对肾上腺初现期间与血清DHEAS变化相关的遗传决定因素进行研究，可能会检测到影响这一过程速率或时间的基因变异。
对智利儿童生长与肥胖队列研究（GOCS）队列（n = 788）的参与者进行全基因组基因分型。我们在全基因组水平以及与类固醇生成相关的目标基因中评估了DHEAS水平的遗传决定因素。为了证实我们的发现，我们基于发现的变异，对同一队列中的儿童评估了阴毛初现年龄的多基因风险评分（PRS）。
在整个队列中，我们在全基因组水平上鉴定出一个与GALR1基因附近相关的显著变异（P = 3.81×10 - 8）。此外，在PRLR、PITX1、PTPRD、NR1H4和BCL11B中观察到了提示性关联的变异（P < 1×10 - 5）。按性别分层后，我们发现男孩在SERBP1和CAMTA1/VAMP3中以及女孩在ZNF98、TRPC6和SULT2A1附近存在提示性关联的变异。基于这些新鉴定的变异，我们还发现，DHEAS水平较高的儿童其PRS较高，阴毛初现年龄显著降低。
我们的结果揭示了一个在全基因组关联研究意义水平上与DHEAS浓度相关的变异，以及几个可能参与肾上腺初现遗传调控的提示性关联变异。
