Mapping microRNA expression quantitative trait loci in the prenatal human brain implicates miR-1908-5p expression in bipolar disorder and other brain-related traits

Abstract

Abstract MicroRNA (miRNA) are small non-coding RNA involved in post-transcriptional gene regulation. Given their known involvement in early neurodevelopment processes, we here sought to identify common genetic variants associated with altered miRNA expression in the prenatal human brain. We performed small RNA sequencing on brain tissue from 112 genome-wide genotyped fetuses from the second trimester of gestation, identifying high-confidence (false discovery rate < 0.05) expression quantitative trait loci for 30 mature miRNA. Integrating our findings with genome-wide association study data for brain-related disorders, we implicate increased prenatal expression of miR-1908-5p as a risk mechanism for bipolar disorder and find that predicted mRNA targets of miR-1908-5p that are expressed in the fetal brain are enriched for common variant genetic association with the condition. Extending these analyses to other brain-related traits, we find that common genetic variation associated with increased miR-1908-5p expression in fetal brain is additionally associated with depressive symptoms, irritability, increased right cerebellum exterior volume and increased sleep duration in the general population. Our findings provide support to the view that altered miRNA expression can influence susceptibility to neuropsychiatric illness and suggest an early neurodevelopmental risk mechanism for bipolar disorder.