Parsing the Functional Impact of Non-Coding Genetic Variants in the Brain Epigenome

Abstract The heritability of common psychiatric disorders has motivated global efforts to identify risk-associated genetic variants and elucidate molecular pathways connecting DNA sequence to disease-associated brain dysfunction. The over-representation of risk variants among gene-regulatory instead of protein-coding loci, however, poses a unique challenge in discerning which among the many thousands of variants identified contribute functionally to disease etiology. Defined broadly, psychiatric epigenomics seeks to understand the effects of disease-associated genetic variation on functional readouts of chromatin in an effort to prioritize variants in terms of their impact on gene expression in the brain. Here, we provide an overview of epigenomic mapping in the human brain and highlight findings of particular relevance to psychiatric genetics. Computational methods, including convolutional neuronal networks (CNNs) and other machine learning approaches hold great promise for elucidating the functional impact of both common and rare genetic variants, thereby refining the epigenomic architecture of psychiatric disorders and enabling integrative analyses of regulatory non-coding variants in the context of large population-level ‘genome and phenome’ databases.