Original Investigation

Human Genetics

, Volume 127, Issue 4, pp 441-452

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

  • Kristin K. NicodemusAffiliated withGenes, Cognition and Psychosis Program, Intramural Research Program, National Institute of Mental Health, National Institutes of HealthWellcome Trust Centre for Human Genetics, University of OxfordDepartment of Clinical Pharmacology, Old Road Campus Research Building, University of Oxford
  • , Joseph H. CallicottAffiliated withGenes, Cognition and Psychosis Program, Intramural Research Program, National Institute of Mental Health, National Institutes of Health
  • , Rachel G. HigierAffiliated withGenes, Cognition and Psychosis Program, Intramural Research Program, National Institute of Mental Health, National Institutes of Health
  • , Augustin LunaAffiliated withGenes, Cognition and Psychosis Program, Intramural Research Program, National Institute of Mental Health, National Institutes of Health
  • , Devon C. NixonAffiliated withGenes, Cognition and Psychosis Program, Intramural Research Program, National Institute of Mental Health, National Institutes of Health
  • , Barbara K. LipskaAffiliated withGenes, Cognition and Psychosis Program, Intramural Research Program, National Institute of Mental Health, National Institutes of Health
  • , Radhakrishna VakkalankaAffiliated withGenes, Cognition and Psychosis Program, Intramural Research Program, National Institute of Mental Health, National Institutes of Health
  • , Ina GieglingAffiliated withSection of Molecular and Clinical Neurobiology, Department of Psychiatry, Ludwig Maximilians University
  • , Dan RujescuAffiliated withSection of Molecular and Clinical Neurobiology, Department of Psychiatry, Ludwig Maximilians University
    • , David St. ClairAffiliated withInstitute of Medical Sciences, University of Aberdeen
    • , Pierandrea MugliaAffiliated withGlaxoSmithKline
    • , Yin Yao ShugartAffiliated withDepartment of Epidemiology, Johns Hopkins Bloomberg School of Public HealthGenomic Research Branch, Division of Neuroscience Center, National Institute of Mental Health, National Institutes of Health
    • , Daniel R. WeinbergerAffiliated withGenes, Cognition and Psychosis Program, Intramural Research Program, National Institute of Mental Health, National Institutes of Health Email author 

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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 and Monte Carlo 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 the DISC1 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.