Bishal Thapaliya ^1,2* Bhaskar Ray ^1,2 Britny Farahdel ^1,2 Pranav Suresh ^1,2 Ram Sapkota ² Bharath Holla ³ Jayant Mahadevan ³ Jiayu Chen ² Nilakshi Vaidya ³ Nora I. Perrone-Bizzozero ⁴ Vivek Benegal ³ Gunter Schumann ⁵ Vince D. Calhoun ^2,6 Jingyu Liu ²

• ¹ Georgia State University, Atlanta, United States
• ² Center for Translational Research in Neuroimaging and Data Science, Georgia State University, Atlanta, Colorado, United States
• ³ Center for Addiction Medicine, National Institute of Mental Health and Neuro Sciences, Bangalore, Karnataka, India
• ⁴ Department of Neurosciences, School of Medicine, University of New Mexico, Albuquerque, New Mexico, United States
• ⁵ Department of Psychiatry and Psychotherapy, Charité University Medicine Berlin, Berlin, Baden-Wurttemberg, Germany
• ⁶ Georgia Institute of Technology, Atlanta, Georgia, United States

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.