Genome-wide association studies (GWAS) identify heritable blocks of genomic sequence that are associated with a variety of phenotypes. In recent years, GWAS have implicated hundreds of loci in psychiatric illnesses, providing an unprecedented opportunity to explore the underlying biology. Well-powered GWAS can result in hundreds of putative targets, only some of which have a true biological effect, which makes pursuing each one individually costly and time consuming. Here, we built a novel, data-driven method to prioritize 350 GWAS targets for schizophrenia and predict their underlying biological mechanisms. We focused on exon inclusion with publicly available gene expression data, with an emphasis on genes previously implicated by psychiatry GWAS. We aimed to prioritize genes in GWAS peak regions that show either tissue specificity to the tissue of interest or differential splicing patterns across genotypes previously associated with schizophrenia. Association analyses were used to determine if exon inclusion can be reliably predicted from tissue or nearby genotypes. Data were provided by the Genotype-Tissue Expression (GTEx) project (53 tissue and cell types, 175 donors, and 1,659 samples). Splice junction events were used to determine an exon’s presence or absence in the transcript. These junction reads were normalized using a percent-spliced-in methodology. We identified eight genes that were undergoing differential splicing in the cortex and influenced by the GWAS loci. These genes may play an important role in the etiology of schizophrenia, however, functional studies are needed to validate this hypothesis. In the future, we anticipate this prioritization methodology may allow researchers to further articulate therapeutic targets in a time- and cost-effective manner.
PROJECT: Predicting Exon Inclusion for Genome-Wide Association Study Target Prioritization
Spending the summer at the Broad has been a powerful, transformative process for me. Not only were my notions about being a scientist and working in a scientific community fundamentally challenged, but I was also able to conduct research at the forefront of cutting-edge technologies and see first-hand how our science impacts humankind.