Hum Mutat. 2022 Oct 11. doi: 10.1002/humu.24481. Online ahead of print.
ABSTRACT
Psychiatric disorders have a polygenic architecture, often associated with dozens or hundreds of independent genomic loci. Most associated loci impact non-coding regions of the genome, suggesting that the majority of disease heritability originates from the disruption of regulatory sequences. While most research has focused on variants that modify regulatory DNA elements, those affecting cis-acting RNA sequences, such as miRNA binding sites, are also likely to have a significant impact. We intersected genome-wide association study (GWAS) summary statistics with the dbMTS database of predictions for miRNA binding site variants (MBSVs). We compared the distributions of MBSV association statistics to non-MBSVs within brain-expressed 3’UTR regions. We aggregated GWAS p-values at the gene, pathway, and miRNA family levels to investigate cellular functions and miRNA families strongly associated with each trait. We performed these analyses in several psychiatric disorders as well as non-psychiatric traits for comparison. We observed significant enrichment of MBSVs in schizophrenia, depression, bipolar disorder, and anorexia nervosa, particularly in genes targeted by several miRNA families, including miR-335-5p, miR-21-5p/590-5p, miR-361-5p, and miR-557, and a nominally significant association between miR-323b-3p MBSVs and schizophrenia risk. We identified evidence for association between MBSVs in synaptic gene sets in schizophrenia and bipolar disorder. We also observed significant association of MBSVs in other complex traits including type 2 diabetes. These observations support the role of miRNA in the pathophysiology of psychiatric disorders and suggest that MBSVs are an important class of regulatory variants that have functional implications for many disorders, as well as other complex human traits. This article is protected by copyright. All rights reserved.
PMID:36217923 | DOI:10.1002/humu.24481
