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Interacting haplotypes at the NPAS3 locus alter risk of schizophrenia and bipolar disorder

Pickard, B.S. and Christoforou, A. and Thomson, P.A. and Fawkes, A. and Evans, K.L. and Morris, S.W. and Porteous, D.J. and Blackwood, D.H.R. and Muir, W.J. (2009) Interacting haplotypes at the NPAS3 locus alter risk of schizophrenia and bipolar disorder. Molecular Psychiatry, 14 (9). pp. 874-884. ISSN 1359-4184

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The neuronal PAS domain 3 (NPAS3) gene encodes a neuronal transcription factor that is implicated in psychiatric disorders by the identification of a human chromosomal translocation associated with schizophrenia and a mouse knockout model with behavioural and hippocampal neurogenesis defects. To determine its contribution to the risk of psychiatric illness in the general population, we genotyped 70 single-nucleotide polymorphisms across the NPAS3 gene in 368 individuals with bipolar disorder, 386 individuals with schizophrenia and 455 controls. Modestly significant single-marker and global and individual haplotypes were identified in four discrete regions of the gene. The presence of both risk and protective haplotypes at each of these four regions indicated locus and allelic heterogeneity within NPAS3 and suggested a model whereby interactions between variants across the gene might contribute to susceptibility to illness. This was supported by predicting the most likely haplotype for each individual at each associated region and then calculating an NPAS3-mediated 'net genetic load' value. This value differed significantly from controls for both bipolar disorder (P = 0.0000010) and schizophrenia (P = 0.0000012). Logistic regression analysis also confirmed the combinatorial action of the four associated regions on disease risk. In addition, sensitivity/specificity plots showed that the extremes of the genetic loading distribution possess the greatest predictive power-a feature suggesting multiplicative allele interaction. These data add to recent evidence that the combinatorial analysis of a number of relatively small effect size haplotypes may have significant power to predict an individual's risk of a complex genetic disorder such as psychiatric illness.

Item type: Article
ID code: 25913
Notes: Strathprints' policy is to record up to 8 authors per publication, plus any additional authors based at the University of Strathclyde. More authors may be listed on the official publication than appear in the Strathprints' record.
Keywords: schizophrenia, bipolar disorder, association, haplotype, psychiatric genetics, Other systems of medicine, Cellular and Molecular Neuroscience, Molecular Biology, Psychiatry and Mental health
Subjects: Medicine > Other systems of medicine
Department: Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
Depositing user: Strathprints Administrator
Date Deposited: 20 Aug 2010 12:46
Last modified: 05 Sep 2014 04:31

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