Cross-continental environmental and genome-wide association study on children and adolescent anxiety and depression.

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.

Replication and Refinement of Brain Age Model for adolescent development.

The discrepancy between chronological age and estimated brain age, known as the brain age gap, may serve as a biomarker to reveal brain development and neuropsychiatric problems. This has motivated many studies focusing on the accurate estimation of brain age using different features and models, of which the generalizability is yet to be tested. Our recent study has demonstrated that conventional machine learning models can achieve high accuracy on brain age prediction during development using only a small set of selected features from multimodal brain imaging data. In the current study, we tested the replicability of various brain age models on the Adolescent Brain Cognitive Development (ABCD) cohort. We proposed a new refined model to improve the robustness of brain age prediction. The direct replication test for existing brain age models derived from the age range of 8-22 years onto the ABCD participants at baseline (9 to 10 years old) and year-two follow-up (11 to 12 years old) indicate that pre-trained models could capture the overall mean age failed precisely estimating brain age variation within a narrow range. The refined model, which combined broad prediction of the pre-trained model and granular information with the narrow age range, achieved the best performance with a mean absolute error of 0.49 and 0.48 years on the baseline and year-two data, respectively. The brain age gap yielded by the refined model showed significant associations with the participants' information processing speed and verbal comprehension ability on baseline data.

Cross-continental environmental and genome-wide association study on children and adolescent anxiety and depression.

Anxiety and depression in children and adolescents warrant special attention as a public health issue 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 investigated the impact of environmental factors and genomics on anxiety and depression in children and adolescents across three cohorts: the Adolescent Brain and Cognitive Development Study (US), the Consortium on Vulnerability to Externalizing Disorders and Addictions (India), and IMAGEN (Europe). Linear mixed-effect models, recursive feature elimination regression, and LASSO regression models were used to identify the environmental impact on anxiety/depression. Genome-wide association analyses were then performed for all three cohorts with consideration of significant environmental effects. The most significant and consistent environmental factors were early life stress and school risk. A novel SNP, rs79878474 in chr11p15, was identified as the most promising SNP associated with anxiety and depression. Gene set analysis found significant enrichment in regions of chr11p15 and chr3q26, in the function of potassium channels and insulin secretion, particularly 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. The study highlights the consistent impact of early life stress and school risk on anxiety and depression during development and suggests the potential role of mutations in potassium channels and the cerebellum region. Further investigation is needed to better understand these findings.

Cross-continental environmental and genome-wide association study on children and adolescent anxiety and depression.

Anxiety and depression in children and adolescents warrant special attention as a public health issue 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), Consortium on Vulnerability to Externalizing Disorders and Addictions (INDIA, age of 6-17) and IMAGEN (EUROPE, age of 14). 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 risk had the most significant and consistent impact across all three cohorts. Both meta and mega-analysis identified a novel SNP rs79878474 in chr11p15 to be the most promising SNP associated with anxiety and depression. 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 evidence of consistent environmental impact from early life stress and school risks on anxiety and depression during development and also highlight the genetic association between mutations in potassium channels along with the potential role of the cerebellum region, which are worthy of further investigation.