Elucidating the expression and splicing patterns of neuropsychiatric disease genes in human brain
The Schizophrenia and Bipolar disorder risk gene CACNA1C is one of the most promising targets for future psychiatric therapeutics, with both a known function and established 'druggability'. However, its extreme length (>13kb), number of exons (>50) and high level of alternative splicing means CACNA1C isoform structure and expression is poorly understood, making it difficult to identify which gene isoforms confer disease risk and where they are expressed. We have investigated CACNA1C expression in six regions of post-mortem human brain by Nanopore sequencing of the complete coding sequence from expressed transcripts. The ability of Nanopore sequencing to define the complete exonic structure of CACNA1C allows us to identify known and novel gene isoforms, including novel exons and multi-exonic skipping events and their expression across multiple brain regions. These results are the first step in evaluating CACNA1C as a potential therapeutic target and demonstrate the power of long-read Nanopore sequencing to elucidate the true nature of expressed genes.