Genetic control of non-coding RNAs in the human brain and their implications for complex traits

Non-coding RNAs (ncRNAs) play crucial roles in the regulation of gene expression, but their genetic underpinnings and roles in human traits and diseases remain largely elusive. Here, we identified 38,441 long non-coding RNAs (lncRNAs) and 23,548 circular RNAs (circRNAs) from RNA sequencing (RNA-seq) data of 2,865 human cortex samples, of which 27,453 lncRNAs and all circRNAs were not reported in GENCODE. Expression quantitative trait locus (eQTL) analyses identified cis-eQTLs for 15,362 lncRNAs and 1,312 circRNAs. We showed that lncRNA- or circRNA-eQTLs were largely independent of, and had larger effects on average than, eQTLs of their adjacent or parental protein-coding genes (PCGs). The circRNA-eQTLs were highly enriched in canonical splice sites, highlighting the crucial role of back-splicing in circRNA biogenesis. LncRNA-eQTLs were enriched for heritability of brain-related complex traits and associated with 72 (11.2%) of the colocalized genome-wide association study (GWAS) signals that showed no evidence of colocalization with PCG-eQTLs or splicing quantitative trait loci (QTLs) identified in the same dataset. We showcased lncRNAs (e.g., those near VPS45, MAPT, and RGS6) and circRNAs (e.g., that for GRIN2A) that may be implicated in complex traits through genetic regulation of ncRNAs. Our study provides insights into the genetic regulation of ncRNAs and their implications in brain-related complex traits.