Evidence of association of the DISC1 interactome gene set with schizophrenia from GWAS

Abstract

DISC1 was discovered as a gene disrupted by a balanced translocation in a large pedigree that segregated with major mental disorders, including schizophrenia. Further attempts to find genetic association with schizophrenia were inconclusive. Most of the biology of DISC1 was inferred from the functionality of its protein partners. Recently, a gene set constituted by DISC1 and several of its partners has been associated with cognitive performance during development, a well-known schizophrenia endophenotype, by means of burden test of rare disruptive variants. Here, we performed a gene set analysis using common variants from the largest schizophrenia genome-wide association study of the Psychiatric Genomics Consortium to test if this gene set is associated with schizophrenia. The main test was based on the MAGMA software. Several additional tests were performed to analyze the robustness of the main findings. The DISC1 interactome gene set was associated with schizophrenia (P = .0056), confirmed by an additional method (INRICH). This association was robust to removal of the major histocompatibility complex region, different definitions of gene boundaries, or different statistical gene models. Conditional analysis revealed that the association was not solely explained by higher expression in brain. Three genes from the gene set, CLIC1, DST, and PDE4B, were associated with schizophrenia at the gene level. Consideration of other DISC1 interactome gene sets revealed the importance of gene set definition. Therefore, we present the first evidence from genome-wide association studies of the role of DISC1 and interacting partners in schizophrenia susceptibility, reconciling genetic and molecular biology data.