MicroRNA-eQTLs in the developing human neocortex link miR-4707-3p expression to brain size

Expression quantitative trait loci (eQTL) data have proven important for linking non-coding loci to protein-coding genes. But eQTL studies rarely measure microRNAs (miRNAs), small noncoding RNA known to play a role in human brain development and neurogenesis. Here, we perform small-RNA sequencing across 212 mid-gestation human neocortical tissue samples, profiled 907 miRNAs, discovering 111 novel early brain-expressed miRNAs, and identified 85 local-miRNA-eQTLs. Colocalization of miRNA-eQTLs with GWAS summary statistics yielded one robust colocalization of miR-4707-3p expression with educational attainment and head size phenotypes, where the miRNA expression increasing allele was associated with decreased head size. Exogenous expression of miR-4707-3p in primary human neural progenitor cells led to increased proliferative and neurogenic gene markers, indicating miR-4707-3p modulates progenitor proliferation. Integrating miRNA-eQTLs with existing GWAS yielded discovery of a miRNA modulating developmental fate decisions that alter human brain size.