MCGA: a multi-strategy conditional gene-based association framework integrating with isoform-level expression profiles reveals new susceptible and druggable candidate genes of schizophrenia

Abstract

Linkage disequilibrium and disease-associated variants in non-coding regions make it difficult to distinguish truly associated genes from redundantly associated genes for complex diseases. In this study, we proposed a new conditional gene-based framework called MCGA that leveraged an improved effective chi-squared statistic to control the type I error rates and remove the redundant associations. MCGA initially integrated two conventional strategies to map genetic variants to genes, i.e., mapping a variant to its physically nearby gene and mapping a variant to a gene if the variant is a gene-level expression quantitative trait locus (eQTL) of the gene. We further performed a simulation study and demonstrated that the isoform-level eQTL was more powerful than the gene-level eQTL in the association analysis. Then the third strategy, i.e., mapping a variant to a gene if the variant is an isoform-level eQTL of the gene, was also integrated with MCGA. We applied MCGA to predict the potential susceptibility genes of schizophrenia and found that the potential susceptibility genes identified by MCGA were enriched with many neuronal or synaptic signaling-related terms in the Gene Ontology knowledgebase and antipsychotics-gene interaction terms in the drug-gene interaction database (DGIdb). More importantly, nine susceptibility genes were the target genes of multiple approved antipsychotics in DrugBank. Comparing the susceptibility genes identified by the above three strategies implied that strategy based on isoform-level eQTL could be an important supplement for the other two strategies and help predict more candidate susceptibility isoforms and genes for complex diseases in a multi-tissue context.