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

B.S. Pickard, A. Christoforou, P.A. Thomson, A. Fawkes, K.L. Evans, S.W. Morris, D.J. Porteous, D.H.R. Blackwood, W.J. Muir

Research output: Contribution to journalArticle

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Abstract

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.
LanguageEnglish
Pages874-884
Number of pages11
JournalMolecular Psychiatry
Volume14
Issue number9
DOIs
Publication statusPublished - Sep 2009

Fingerprint

Bipolar Disorder
Haplotypes
Schizophrenia
Psychiatry
Genes
Genetic Load
Forensic Anthropology
Genetic Translocation
Inborn Genetic Diseases
Neurogenesis
Knockout Mice
Single Nucleotide Polymorphism
Transcription Factors
Logistic Models
Alleles
Regression Analysis
Sensitivity and Specificity
Population

Keywords

  • schizophrenia
  • bipolar disorder
  • association
  • haplotype
  • psychiatric genetics

Cite this

Pickard, B. S., Christoforou, A., Thomson, P. A., Fawkes, A., Evans, K. L., Morris, S. W., ... Muir, W. J. (2009). Interacting haplotypes at the NPAS3 locus alter risk of schizophrenia and bipolar disorder. Molecular Psychiatry, 14(9), 874-884. https://doi.org/10.1038/mp.2008.24
Pickard, B.S. ; Christoforou, A. ; Thomson, P.A. ; Fawkes, A. ; Evans, K.L. ; Morris, S.W. ; Porteous, D.J. ; Blackwood, D.H.R. ; Muir, W.J. / Interacting haplotypes at the NPAS3 locus alter risk of schizophrenia and bipolar disorder. In: Molecular Psychiatry. 2009 ; Vol. 14, No. 9. pp. 874-884.
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Pickard, BS, Christoforou, A, Thomson, PA, Fawkes, A, Evans, KL, Morris, SW, Porteous, DJ, Blackwood, DHR & Muir, WJ 2009, 'Interacting haplotypes at the NPAS3 locus alter risk of schizophrenia and bipolar disorder' Molecular Psychiatry, vol. 14, no. 9, pp. 874-884. https://doi.org/10.1038/mp.2008.24

Interacting haplotypes at the NPAS3 locus alter risk of schizophrenia and bipolar disorder. / Pickard, B.S.; Christoforou, A.; Thomson, P.A.; Fawkes, A.; Evans, K.L.; Morris, S.W.; Porteous, D.J.; Blackwood, D.H.R.; Muir, W.J.

In: Molecular Psychiatry, Vol. 14, No. 9, 09.2009, p. 874-884.

Research output: Contribution to journalArticle

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AU - Pickard, B.S.

AU - Christoforou, A.

AU - Thomson, P.A.

AU - Fawkes, A.

AU - Evans, K.L.

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AB - 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.

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