Abstract
BACKGROUND: MicroRNAs (miRNAs) are key regulators of gene expression in the human genome and may contribute to risk for neuropsychiatric disorders. miRNAs play an acknowledged role in the strongest of genetic risk factors for schizophrenia, 22q11.2 deletions. We hypothesized that in schizophrenia there would be an enrichment of other rare copy number variants (CNVs) that overlap miRNAs. METHODS: Using high-resolution genome-wide microarrays and rigorous methods, we compared the miRNA content of rare CNVs in well-characterized cohorts of schizophrenia cases (n = 420) and comparison subjects, excluding 22q11.2 CNVs. We also performed a gene-set enrichment analysis of the predicted miRNA target genes. RESULTS: The schizophrenia group was enriched for the proportion of individuals with a rare CNV overlapping a miRNA (3.29-fold increase over comparison subjects, p < .0001). The presence of a rare CNV overlapping a miRNA remained a significant predictor of schizophrenia case status (p = .0072) in a multivariate logistic regression model correcting for total CNV size. In contrast, comparable analyses correcting for CNV size showed no enrichment of rare CNVs overlapping protein-coding genes. A gene-set enrichment analysis indicated that predicted target genes of recurrent CNV-overlapped miRNAs in schizophrenia may be functionally enriched for neurodevelopmental processes, including axonogenesis and neuron projection development. Predicted gene targets driving these results included CAPRIN1, NEDD4, NTRK2, PAK2, RHOA, and SYNGAP1. CONCLUSIONS: These data are the first to demonstrate a genome-wide role for CNVs overlapping miRNAs in the genetic risk for schizophrenia. The results provide support for an expanded multihit model of causation, with potential implications for miRNA-based therapeutics.