Functional Genomics Analysis to Disentangle the Role of Genetic Variants in Major Depression

Abstract

Understanding the molecular basis of major depression is critical for identifying new potential biomarkers and drug targets to alleviate its burden on society. Leveraging available GWAS data and functional genomic tools to assess regulatory variation could help explain the role of major depression-associated genetic variants in disease pathogenesis. We have conducted a fine-mapping analysis of genetic variants associated with major depression and applied a pipeline focused on gene expression regulation by using two complementary approaches: cis-eQTL colocalization analysis and alteration of transcription factor binding sites. The fine-mapping process uncovered putative causally associated variants whose proximal genes were linked with major depression pathophysiology. Four colocalizing genetic variants altered the expression of five genes, highlighting the role of SLC12A5 in neuronal chlorine homeostasis and MYRF in nervous system myelination and oligodendrocyte differentiation. The transcription factor binding analysis revealed the potential role of rs62259947 in modulating P4HTM expression by altering the YY1 binding site, altogether regulating hypoxia response. Overall, our pipeline could prioritize putative causal genetic variants in major depression. More importantly, it can be applied when only index genetic variants are available. Finally, the presented approach enabled the proposal of mechanistic hypotheses of these genetic variants and their role in disease pathogenesis.