M90 - FUNCTIONAL CHARACTERIZATION OF PSYCHIATRIC DISEASE-ASSOCIATED CACNA1C VARIANTS THROUGH GENETIC, MOLECULAR AND CELLULAR APPROACHES

Abstract

Background Despite recent advancements in human genomics and identifying hundreds of risk loci for psychiatric disorders, drug development in psychiatry remains a challenge. While Genome-Wide Association Studies (GWAS) provide us with a great starting point by highlighting risk regions of the genome, translating disease-associated DNA variants to physiological function has been quite sluggish. This is mostly due to polygenic and multifactorial nature of psychiatric diseases which in turn have made development of relevant cellular and in vivo models particularly difficult. One recent GWAS identified over hundred genes that are strongly associated with schizophrenia but contribution of each gene to the disease seems to be small. Each risk gene is identified with tens of SNPs, most of which are common SNPs residing in the intronic regions of DNA. Methods Therefore, establishing cellular models to understand the directionality (loss or gain) and functional defect caused by each risk SNP within each gene can be an enormous undertaking. On the other hand, rare exon variants found in the disease population can serve as a more reliable starting point to understand how the function of a risk gene is affected in the disease. Results Here we examined effects of rare variants reported for CACNA1C, a top schizophrenia GWAS hit, in cellular models. CACNA1C is also linked to bipolar disorder, ADHD, depression and autism where schizophrenia GWAS identified over 160 risk SNPs for this gene. We used linkage disequilibrium information to identify a small number of risk SNPs that have the highest chance of affecting the overall function of CACNA1C gene. We have combined these two approaches, built neuronal functional assays and identified several important disease related phenotypes. Discussion These studies show a proof of concept in the context of the CACNA1C gene but this approach can be used as a platform to characterize other GWAS hits several other disease areas.