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; Muir, W J

doi:10.1038/mp.2008.24

Cited by 101Schizophrenia research and treatmentGenetic Associations and EpidemiologyBipolar Disorder and Treatment

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 +1 more·2009·Molecular Psychiatry

DOI 10.1038/mp.2008.24

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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.

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Several single-nucleotide variants of NPAS3 confer higher susceptibility and/or protection to the development of schizophrenia and bipolar disorder.
“Interestingly, several single-nucleotide variants of NPAS3 confer higher susceptibility and/or protection to the development of schizophrenia and bipolar disorder (Pickard et al. 2009).”
From The Human Accelerated Region HAR202 Controls NPAS3 Expression in the Developing Forebrain Displaying Differential Enhancer Activity Between Modern and Archaic Human Sequences (2024) · cites this paper as Pickard et al. 2009
Subsequent studies have linked NPAS3 to multiple human psychiatric and neurodevelopmental disorders, including bipolar disorder, schizophrenia, attention-deficit/hyperactivity disorder, major depression, and intellectual disability.
“Subsequent studies have further linked NPAS3 to multiple human psychiatric and neurodevelopmental disorders, including bipolar disorder (Pickard et al. 2009; Huang et al. 2010; Nurnberger et al. 2014), schizophrenia (Pickard et al. 2005, 2006, 2009; Huang et al. 2010; Macintyre et al. 2010; Yu et al. 2014)”
From The Human Accelerated Region HAR202 Controls NPAS3 Expression in the Developing Forebrain Displaying Differential Enhancer Activity Between Modern and Archaic Human Sequences (2024) · cites this paper as Pickard et al. 2009
Most case-control studies including NPAS3 had been performed using European or European descent population data and did not include the East Asian polymorphism analyzed in this study.
“Regretfully, most case-control studies including NPAS3 had been performed using European or European descent population data and did not include the East Asian polymorphism analyzed in our study (Pickard et al. 2009).”
From The Human Accelerated Region HAR202 Controls NPAS3 Expression in the Developing Forebrain Displaying Differential Enhancer Activity Between Modern and Archaic Human Sequences (2024) · cites this paper as Pickard et al. 2009

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Authors: Pickard, B. S., Christoforou, A., Thomson, P. A., Fawkes, A., Evans, K. L., Morris, S. W., Porteous, D. J., Blackwood, D. H., & Muir, W. J.
Affiliations: University of Strathclyde (GB)
Western General Hospital (GB)
Royal Edinburgh Hospital (GB)
Corresponding author: Pickard, B S
ORCID: Pickard, B S
Thomson, P A
Fawkes, A
Evans, K L
Morris, S W
Porteous, D J
Blackwood, D H
Venue: Molecular Psychiatry
Publisher: Springer Science and Business Media LLC
Published: 2008-03-04
Volume: 14
Issue: 9
Pages: 874-884
ISSN: 1359-4184 (ISSN-L)
1476-5578
DOI: 10.1038/mp.2008.24
OpenAlex: W1984808953
Cited by: 101
References: 34
Citations by year: 2026: 3 · 2025: 2 · 2024: 1 · 2023: 3 · 2022: 2 · 2021: 3 · 2020: 3 · 2019: 4 · 2018: 6 · 2017: 6 · 2016: 9 · 2015: 7 · 2014: 4 · 2013: 6 · 2012: 9
FWCI: 7.49
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Molecular Psychiatry (publishedVersion)
PubMed (publishedVersion)
Funders: Wellcome Trust
Topics: Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
Keywords: NPAS3, schizophrenia, bipolar disorder, haplotype association, genetic susceptibility, single nucleotide polymorphisms, allelic heterogeneity, locus heterogeneity, psychiatric genetics
MeSH terms: Bipolar Disorder, Female, Haplotypes, Humans, Male, Nerve Tissue Proteins, Risk Factors, Schizophrenia, Sensitivity and Specificity, Transcription Factors, Linkage Disequilibrium, Logistic Models, Odds Ratio, Case-Control Studies, Polymorphism, Single Nucleotide, Basic Helix-Loop-Helix Proteins, Genome-Wide Association Study

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

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