Strong evidence that GNB1L is associated with schizophrenia (original) (raw)

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1

Department of Psychological Medicine, Wales School of Medicine

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Cardiff University

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Heath Park, Cardiff CF14 4XN

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UK

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Department of Psychological Medicine, Wales School of Medicine

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Cardiff University

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Heath Park, Cardiff CF14 4XN

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UK

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Department of Psychological Medicine, Wales School of Medicine

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Cardiff University

,

Heath Park, Cardiff CF14 4XN

,

UK

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Department of Psychological Medicine, Wales School of Medicine

,

Cardiff University

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Heath Park, Cardiff CF14 4XN

,

UK

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Department of Psychological Medicine, Wales School of Medicine

,

Cardiff University

,

Heath Park, Cardiff CF14 4XN

,

UK

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Department of Psychological Medicine, Wales School of Medicine

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Cardiff University

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Heath Park, Cardiff CF14 4XN

,

UK

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The Department of Psychiatry, Royal College of Surgeons in Ireland

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Education and Research Centre, Beaumont Hospital

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Dublin

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Ireland

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The Applied Molecular Genomics Group, Department of Molecular Genetics

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VIB and University of Antwerp

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Antwerpen

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Belgium

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The Applied Molecular Genomics Group, Department of Molecular Genetics

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VIB and University of Antwerp

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Antwerpen

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Belgium

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Division of Molecular and Clinical Neurobiology

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Ludwig Maximilians University

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Nußbaumstr. 7, 80336 Munich

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Germany

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Received:

28 September 2007

Accepted:

09 November 2007

Published:

13 November 2007

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Nigel M. Williams, Beate Glaser, Nadine Norton, Hywel Williams, Timothy Pierce, Valentina Moskvina, Stephen Monks, Jurgen Del Favero, Dirk Goossens, Dan Rujescu, Ina Giegling, George Kirov, Nicholas Craddock, Kieran C. Murphy, Michael C. O'Donovan, Michael J. Owen, Strong evidence that GNB1L is associated with schizophrenia , Human Molecular Genetics, Volume 17, Issue 4, 14 February 2008, Pages 555–566, https://doi.org/10.1093/hmg/ddm330
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Abstract

Evidence that a gene or genes on chromosome 22 is involved in susceptibility to schizophrenia comes from two sources: the increased incidence of schizophrenia in individuals with 22q11 deletion syndrome (22q11DS) and genetic linkage studies. In mice, hemizygous deletion of either Tbx1 or Gnb1l can cause deficits in pre-pulse inhibition, a sensory motor gating defect which is associated with schizophrenia. We tested the hypothesis that variation at this locus confers risk of schizophrenia and related disorders in a series of case–control association studies. First, we found evidence for a male-specific genotypic association ( P = 0.00017) TBX1/GNB1L in 662 schizophrenia cases and 1416 controls from the UK. Moreover, we replicated this finding in two independent case–control samples (additional 746 cases and 1330 controls) (meta analysis P = 1.8×10 −5 ) and also observed significant evidence for genotypic association in an independent sample of 480 schizophrenia parent-proband trios from Bulgaria with markers at this locus, which was again strongest in the male probands ( P = 0.004). Genotyping the most significant SNPs in a sample of 83 subjects with 22q11DS with and without psychosis again revealed a significant allelic association with psychosis in males with 22q11DS ( P = 0.01). Finally, using allele specific expression analysis, we have shown that the markers associated with psychosis are also correlated with alterations in GNB1L expression, raising the hypothesis that the risk to develop psychosis at this locus could be mediated in a dose sensitive manner via gene expression. However, other explanations are possible, and further analyses will be required to clarify the correct functional mechanism.

© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Topic:

• alleles
• genes
• genotype
• single nucleotide polymorphism
• psychotic disorders
• schizophrenia
• genotype determination
• 22q11 deletion syndrome

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