Strong evidence that GNB1L is associated with schizophrenia

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

Research output: Contribution to journalArticle

46 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)555-566
Number of pages12
JournalHuman Molecular Genetics
Volume17
Issue number4
DOIs
StatePublished - Feb 14 2008
Externally publishedYes

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Schizophrenia
22q11 Deletion Syndrome
Psychotic Disorders
Sensory Gating
Chromosomes, Human, Pair 22
Bulgaria
Genetic Linkage
Genes
Single Nucleotide Polymorphism
Meta-Analysis
Case-Control Studies
Alleles
Gene Expression
Incidence

ASJC Scopus subject areas

  • Genetics

Cite this

Williams, N. M., Glaser, B., Norton, N., Williams, H., Pierce, T., Moskvina, V., ... Owen, M. J. (2008). Strong evidence that GNB1L is associated with schizophrenia. Human Molecular Genetics, 17(4), 555-566. https://doi.org/10.1093/hmg/ddm330

Strong evidence that GNB1L is associated with schizophrenia. / Williams, Nigel M.; Glaser, Beate; Norton, Nadine; Williams, Hywel; Pierce, Timothy; Moskvina, Valentina; Monks, Stephen; Del Favero, Jurgen; Goossens, Dirk; Rujescu, Dan; Giegling, Ina; Kirov, George; Craddock, Nicholas; Murphy, Kieran C.; O'Donovan, Michael C.; Owen, Michael J.

In: Human Molecular Genetics, Vol. 17, No. 4, 14.02.2008, p. 555-566.

Research output: Contribution to journalArticle

Williams, NM, Glaser, B, Norton, N, Williams, H, Pierce, T, Moskvina, V, Monks, S, Del Favero, J, Goossens, D, Rujescu, D, Giegling, I, Kirov, G, Craddock, N, Murphy, KC, O'Donovan, MC & Owen, MJ 2008, 'Strong evidence that GNB1L is associated with schizophrenia', Human Molecular Genetics, vol. 17, no. 4, pp. 555-566. https://doi.org/10.1093/hmg/ddm330
Williams NM, Glaser B, Norton N, Williams H, Pierce T, Moskvina V et al. Strong evidence that GNB1L is associated with schizophrenia. Human Molecular Genetics. 2008 Feb 14;17(4):555-566. https://doi.org/10.1093/hmg/ddm330
Williams, Nigel M. ; Glaser, Beate ; Norton, Nadine ; Williams, Hywel ; Pierce, Timothy ; Moskvina, Valentina ; Monks, Stephen ; Del Favero, Jurgen ; Goossens, Dirk ; Rujescu, Dan ; Giegling, Ina ; Kirov, George ; Craddock, Nicholas ; Murphy, Kieran C. ; O'Donovan, Michael C. ; Owen, Michael J. / Strong evidence that GNB1L is associated with schizophrenia. In: Human Molecular Genetics. 2008 ; Vol. 17, No. 4. pp. 555-566.
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AU - Williams, Nigel M.

AU - Glaser, Beate

AU - Norton, Nadine

AU - Williams, Hywel

AU - Pierce, Timothy

AU - Moskvina, Valentina

AU - Monks, Stephen

AU - Del Favero, Jurgen

AU - Goossens, Dirk

AU - Rujescu, Dan

AU - Giegling, Ina

AU - Kirov, George

AU - Craddock, Nicholas

AU - Murphy, Kieran C.

AU - O'Donovan, Michael C.

AU - Owen, Michael J.

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N2 - 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.

AB - 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.

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