Evidence of statistical epistasis between DISC1, CIT and NDEL1 impacting risk for schizophrenia: biological validation with functional neuroimaging

Abstract

The etiology of schizophrenia likely involves genetic interactions. DISC1, a promising candidate susceptibility gene, encodes a protein which interacts with many other proteins, including CIT, NDEL1, NDE1, FEZ1 and PAFAH1B1, some of which also have been associated with psychosis. We tested for epistasis between these genes in a schizophrenia case-control study using machine learning algorithms (MLAs: random forest, generalized boosted regression andMonteCarlo logic regression). Convergence of MLAs revealed a subset of seven SNPs that were subjected to 2-SNP interaction modeling using likelihood ratio tests for nested unconditional logistic regression models. Of the 7C2 = 21 interactions, four were significant at the α = 0.05 level: DISC1 rs1411771-CIT rs10744743 OR = 3.07 (1.37, 6.98) p = 0.007; CIT rs3847960-CIT rs203332 OR = 2.90 (1.45, 5.79) p = 0.003; CIT rs3847960-CIT rs440299 OR = 2.16 (1.04, 4.46) p = 0.038; one survived Bonferroni correction (NDEL1 rs4791707-CIT rs10744743 OR = 4.44 (2.22, 8.88) p = 0.00013). Three of four interactions were validated via functional magnetic resonance imaging (fMRI) in an independent sample of healthy controls; risk associated alleles at both SNPs predicted prefrontal cortical inefficiency during the N-back task, a schizophrenia-linked intermediate biological phenotype: rs3847960-rs440299; rs1411771-rs10744743, rs4791707-rs10744743 (SPM5 p < 0.05, corrected), although we were unable to statistically replicate the interactions in other clinical samples. Interestingly, the CIT SNPs are proximal to exons that encode theDISC1 interaction domain. In addition, the 3' UTR DISC1 rs1411771 is predicted to be an exonic splicing enhancer and the NDEL1 SNP is ~3,000 bp from the exon encoding the region of NDEL1 that interacts with the DISC1 protein, giving a plausible biological basis for epistasis signals validated by fMRI.

Single-Subject Anxiety Treatment Outcome Prediction using Functional Neuroimaging

“…Because negative scores are due to random variation around zero of the poor predictor variables (Strobl et al, 2009), only variables with an importance score greater than the magnitude of the most negative score were selected for inclusion (Figure 1, Step 3). Following Nicodemus et al (2010), the number of variables retained in the final model was limited to 10 and was based on median permutation importance scores from 500 repetitions of the random forest analysis to ensure stability of importance score estimates. The removal of poor performing variables can increase overall accuracy by increasing the selection of relevant variables for the decision trees and therefore increasing the relevance of included data to outcome prediction.…”

Molecular Characterization of Disrupted in Schizophrenia-1 Risk Variant S704C Reveals the Formation of Altered Oligomeric Assembly

“…Although its impact on disease pathogenesis is debated (10,27), its connection to schizophrenia is credible (28), and its importance in corticogenesis is widely accepted (3,17,29). Likewise, evidence (30,31) associating NDEL1 to schizophrenia biology is debated (32). However, the crucial role of NDEL1, together with DISC1 in cortical layer formation (17,29), is well established.…”

Genome-wide investigation of schizophrenia associated plasma Ndel1 enzyme activity

“…Previous studies investigating Ndel1 in SCZ have largely focused on its interaction with Disc1, with significant results only when haplotypes or interaction with Disc1 was considered (Burdick et al, 2008;Nicodemus et al, 2010). There are mixed results for Ndel1 main effects (Kahler et al, 2008;Tomppo et al, 2009).…”