PDF(Pubmed)
Abstract：
Anxiety and depression in children and adolescents warrant special attention as a public health concern given their devastating and long-term effects on development and mental health. Multiple factors, ranging from genetic vulnerabilities to environmental stressors, influence the risk for the disorders. This study aimed to understand how environmental factors and genomics affect children and adolescents anxiety and depression across three cohorts: Adolescent Brain and Cognitive Development Study (US, age of 9-10; N=11,875), Consortium on Vulnerability to Externalizing Disorders and Addictions (INDIA, age of 6-17; N=4,326) and IMAGEN (EUROPE, age of 14; N=1888). We performed data harmonization and identified the environmental impact on anxiety/depression using a linear mixed-effect model, recursive feature elimination regression, and the LASSO regression model. Subsequently, genome-wide association analyses with consideration of significant environmental factors were performed for all three cohorts by mega-analysis and meta-analysis, followed by functional annotations. The results showed that multiple environmental factors contributed to the risk of anxiety and depression during development, where early life stress and school support index had the most significant and consistent impact across all three cohorts. In both meta, and mega-analysis, SNP rs79878474 in chr11p15 emerged as a particularly promising candidate associated with anxiety and depression, despite not reaching genomic significance. Gene set analysis on the common genes mapped from top promising SNPs of both meta and mega analyses found significant enrichment in regions of chr11p15 and chr3q26, in the function of potassium channels and insulin secretion, in particular Kv3, Kir-6.2, SUR potassium channels encoded by the KCNC1, KCNJ11, and ABCCC8 genes respectively, in chr11p15. Tissue enrichment analysis showed significant enrichment in the small intestine, and a trend of enrichment in the cerebellum. Our findings provide evidences of consistent environmental impact from early life stress and school support index on anxiety and depression during development and also highlight the genetic association between mutations in potassium channels, which support the stress-depression connection via hypothalamic-pituitary-adrenal axis, along with the potential modulating role of potassium channels.
摘要：
儿童和青少年的焦虑和抑郁值得特别关注，因为它们对发展和心理健康具有破坏性和长期影响。多重因素,从遗传脆弱性到环境压力，影响疾病的风险。这项研究旨在了解环境因素和基因组学如何影响儿童和青少年的焦虑和抑郁，包括三个队列：青少年大脑和认知发展研究（美国，9-10岁；N=11,875)，对外部化障碍和成瘾的脆弱性联盟(印度，6-17岁；N=4,326)和IMAGEN(欧洲，14岁；N=1888)。我们进行了数据协调，并使用线性混合效应模型确定了环境对焦虑/抑郁的影响，递归特征消除回归，和LASSO回归模型。随后，通过大型分析和荟萃分析对所有三个队列进行了考虑重要环境因素的全基因组关联分析，其次是功能注释。结果表明,多种环境因素对发育过程中的焦虑和抑郁风险有贡献,在所有三个队列中，早期生活压力和学校支持指数的影响最为显著和一致。在这两个元，和大型分析，chr11p15中的SNPrs79878474成为与焦虑和抑郁相关的特别有前途的候选人，尽管没有达到基因组意义。对来自meta和mega分析的最有希望的SNP的常见基因进行的基因集分析发现，在chr11p15和chr3q26区域中，钾通道和胰岛素分泌的功能显着富集，特别是Kv3，Kir-6.2，分别由KCNC1，KCNJ11和ABCCC8基因编码的SUR钾通道，在chr11p15。组织富集分析显示在小肠中显著富集,和小脑富集的趋势。我们的研究结果为早期生活压力和学校支持指数对发育过程中的焦虑和抑郁产生一致的环境影响提供了证据，同时也突出了钾通道突变之间的遗传关联。通过下丘脑-垂体-肾上腺轴支持压力-抑制连接，以及钾通道的潜在调节作用。
