Human Genetics

, Volume 127, Issue 4, pp 441–452 | Cite as

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

  • Kristin K. Nicodemus
  • Joseph H. Callicott
  • Rachel G. Higier
  • Augustin Luna
  • Devon C. Nixon
  • Barbara K. Lipska
  • Radhakrishna Vakkalanka
  • Ina Giegling
  • Dan Rujescu
  • David St. Clair
  • Pierandrea Muglia
  • Yin Yao Shugart
  • Daniel R. WeinbergerEmail author
Original Investigation


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.


Schizophrenia Random Forest Exonic Splice Enhancer Allele Homozygote Variable Importance Measure 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This study utilized the high performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD ( We thank Michael Dean, Bert Gold and Kate McGee for assistance with GAIN genotyping data. The authors declare the following competing interest: Pierandrea Muglia is a full-time employee of the pharmaceutical company GlaxoSmithKline who have filed patent applications for SNPs associated with schizophrenia (United States Patent Applications 20080176239 and 20080176240 and International Application Number PCT/EP2008/050477).

Supplementary material

439_2009_782_MOESM1_ESM.doc (180 kb)
Supplementary material 1 (DOC 179 kb)


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Copyright information

© US Government 2010

Authors and Affiliations

  • Kristin K. Nicodemus
    • 1
    • 2
    • 3
  • Joseph H. Callicott
    • 1
  • Rachel G. Higier
    • 1
  • Augustin Luna
    • 1
  • Devon C. Nixon
    • 1
  • Barbara K. Lipska
    • 1
  • Radhakrishna Vakkalanka
    • 1
  • Ina Giegling
    • 4
  • Dan Rujescu
    • 4
  • David St. Clair
    • 5
  • Pierandrea Muglia
    • 6
  • Yin Yao Shugart
    • 7
    • 8
  • Daniel R. Weinberger
    • 1
    Email author
  1. 1.Genes, Cognition and Psychosis Program, Intramural Research Program, National Institute of Mental HealthNational Institutes of HealthBethesdaUSA
  2. 2.Wellcome Trust Centre for Human GeneticsUniversity of OxfordOxfordUK
  3. 3.Department of Clinical Pharmacology, Old Road Campus Research BuildingUniversity of OxfordOxfordUK
  4. 4.Section of Molecular and Clinical Neurobiology, Department of PsychiatryLudwig Maximilians UniversityMunichGermany
  5. 5.Institute of Medical SciencesUniversity of AberdeenAberdeenUK
  6. 6.GlaxoSmithKlineVeronaItaly
  7. 7.Department of EpidemiologyJohns Hopkins Bloomberg School of Public HealthBaltimoreUSA
  8. 8.Genomic Research Branch, Division of Neuroscience CenterNational Institute of Mental Health, National Institutes of HealthBethesdaUSA

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