London Calling 2023: Discovery of novel neuropsychiatric disorder risk-gene transcripts in the human brain

Disruptions to alternative RNA splicing are associated with human diseases, including neuropsychiatric disorders. Genome-wide association studies have recently identified hundreds of risk loci for these disorders. However, how these genes contribute to disease risk through altered gene expression and RNA splicing remains poorly understood. We reveal the precise RNA isoform profiles of 32 neuropsychiatric risk genes using post-mortem brain samples from healthy individuals. We reveal highly expressed novel isoforms in the schizophrenia risk gene ATG13, and two isoforms including novel exons in the depression gene NEGR1. Overall, we identified 765 novel isoforms and 22 novel exons, of which most (16/22) appear to be “poison exons”. Our results show that current gene transcript annotations are incomplete and  supports the use of long-read sequencing to identify novel RNA isoforms. Uncovering the splicing repertoire for neuropsychiatric risk genes will inform future analyses of the functional impact these isoforms have on neuropsychiatric disorder development.