Structural characterization of a complex repeat at the CACNA1C pan-psychiatric locus

Genetic variation within intron 3 of the CACNA1C calcium channel gene is associated with schizophrenia and other neuropsychiatric disorders, but analysis of the causal variants and their effect is complicated by a nearby variable-number tandem repeat (VNTR). Here, we explored the structure and population variability of the CACNA1C intron 3 VNTR using 155 long-read genome assemblies from 78 diverse individuals. Based on sequence differences among repeat units, we clustered individual sequences into 7 VNTR structural alleles called Types. Three Types were related through large duplications, but the other Types diverged much earlier such that only 12 repeat units at the 5' end of the VNTR were shared across most Types. The most diverged Types were rare and present only in individuals with African ancestry, but a multiallelic structural polymorphism was present across populations at different frequencies, consistent with expansion of the VNTR preceding the emergence of early hominins. We demonstrated that this polymorphism was in complete linkage disequilibrium with fine-mapped schizophrenia variants from genomewide association studies (GWAS), and that this risk haplotype was associated with decreased CACNA1C gene expression in the brain. Our work suggests that sequence variation within a human-specific VNTR affects gene expression, and provides a detailed characterization of new alleles at a flagship neuropsychiatric locus. SIGNIFICANCEGenome-wide association studies identify an association between neuropsychiatric disorders and non-coding variants within the gene CACNA1C, which encodes a functionally important Ca2+ channel in neurons. However, the variant(s) responsible for disease risk and their functional consequences are undetermined. These schizophrenia-associated SNPs are near a poorly genotyped repeat, suggesting the repeat might also contribute to disease risk. We use long-read genome assemblies to characterize the genetic diversity of this repeat, its relationship to schizophrenia-associated SNPs, and its evolutionary origins. We find that the schizophrenia risk signal is associated with reduced CACNA1C gene expression, and both are tightly tied to the repeat. Our analysis of repeat variation at CACNA1C will enable targeted investigation of regulatory mechanisms underpinning risk for schizophrenia.