title: 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.
authors.affiliation: Genes, Cognition and Psychosis Program, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA. kristin.nicodemus@well.ox.ac.uk
authors.forename: Kristin K
authors.initials: KK
authors.lastname: Nicodemus
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Callicott
authors.forename: Rachel G
authors.initials: RG
authors.lastname: Higier
authors.forename: Augustin
authors.initials: A
authors.lastname: Luna
authors.forename: Devon C
authors.initials: DC
authors.lastname: Nixon
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Lipska
authors.forename: Radhakrishna
authors.initials: R
authors.lastname: Vakkalanka
authors.forename: Ina
authors.initials: I
authors.lastname: Giegling
authors.forename: Dan
authors.initials: D
authors.lastname: Rujescu
authors.forename: David
authors.initials: D
authors.lastname: St Clair
authors.forename: Pierandrea
authors.initials: P
authors.lastname: Muglia
authors.forename: Yin Yao
authors.initials: YY
authors.lastname: Shugart
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Weinberger
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000465:Algorithms; D000483:Alleles; D001185:Artificial Intelligence; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D004843:Epistasis, Genetic; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D016013:Likelihood Functions; D016015:Logistic Models; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D009010:Monte Carlo Method; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; C412476:DISC1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C421108:NDEL1 protein, human; D009419:Nerve Tissue Proteins; C115635:citron-kinase; D017346:Protein Serine-Threonine Kinases