The G72/G30 gene complex and cognitive abnormalities in schizophrenia

Terry E. Goldberg, Richard E. Straub, Joseph H. Callicott, Ahmad Hariri, Venkata Mattay, Llewellyn Bigelow, Richard Coppola, Michael F. Egan, Daniel Weinberger

Research output: Contribution to journalArticle

Abstract

A recently discovered gene complex, G72/G30 (hereafter G72, but now termed DAOA), was found to be associated with schizophrenia and with bipolar disorder, possibly because of an indirect effect on NMDA neurotransmission. In principle, if G72 increases risk for psychosis by this mechanism, it might impact with greater penetrance those cortically based cognitive and neurophysiological functions associated with NMDA signaling. We performed two independent family-based association studies (one sample contained more than 200 families and the other more than 65) of multiple SNPs in the G72 region and of multiple SNPs in the gene for D-amino acid oxidase (DAAO), which may be modulated by G72. We examined the relationship between select cognitive measures in attention, working memory, and episodic memory and a restricted set of G72 SNPs in over 600 normal controls, schizophrenic patients, and their nonpsychotic siblings using mixed model ANOVAs. We also determined genotype effects on neurophysiology measures in normal controls using the fMRI BOLD response obtained during activation procedures involving either episodic memory or working memory. There were no significant single G72 SNP associations and clinical diagnosis in either sample, though one approached significance (p = 0.06). Diagnosis by genotype interaction effects for G72 SNP 10 were significant for cognitive variables assessing working memory and attention (p = 0.05), and at the trend level for episodic memory, such that in the schizophrenia group an exaggerated allele load effect in the predicted directions was observed. In the fMRI paradigms, a strong effect of G72 SNP 10 genotype was observed on BOLD activation in the hippocampus during the episodic memory paradigm. Tests of association with DAAO were consistently nonsignificant. We present evidence that SNP variations in the G72 gene region increase risk of cognitive impairment in schizophrenia. SNP variations were not strongly associated with clinical diagnosis in family-based analyses.

Original languageEnglish (US)
Pages (from-to)2022-2032
Number of pages11
JournalNeuropsychopharmacology
Volume31
Issue number9
DOIs
StatePublished - Sep 12 2006
Externally publishedYes

Fingerprint

Single Nucleotide Polymorphism
Schizophrenia
Episodic Memory
Genes
Short-Term Memory
D-Amino-Acid Oxidase
Genotype
N-Methylaspartate
Magnetic Resonance Imaging
Neurophysiology
Penetrance
Bipolar Disorder
Synaptic Transmission
Psychotic Disorders
Cognition
Siblings
Hippocampus
Analysis of Variance
Alleles

Keywords

  • Cognition
  • fMRI
  • G72
  • Gene
  • Glutamate
  • Schizophrenia

ASJC Scopus subject areas

  • Pharmacology

Cite this

The G72/G30 gene complex and cognitive abnormalities in schizophrenia. / Goldberg, Terry E.; Straub, Richard E.; Callicott, Joseph H.; Hariri, Ahmad; Mattay, Venkata; Bigelow, Llewellyn; Coppola, Richard; Egan, Michael F.; Weinberger, Daniel.

In: Neuropsychopharmacology, Vol. 31, No. 9, 12.09.2006, p. 2022-2032.

Research output: Contribution to journalArticle

Goldberg, TE, Straub, RE, Callicott, JH, Hariri, A, Mattay, V, Bigelow, L, Coppola, R, Egan, MF & Weinberger, D 2006, 'The G72/G30 gene complex and cognitive abnormalities in schizophrenia', Neuropsychopharmacology, vol. 31, no. 9, pp. 2022-2032. https://doi.org/10.1038/sj.npp.1301049
Goldberg TE, Straub RE, Callicott JH, Hariri A, Mattay V, Bigelow L et al. The G72/G30 gene complex and cognitive abnormalities in schizophrenia. Neuropsychopharmacology. 2006 Sep 12;31(9):2022-2032. https://doi.org/10.1038/sj.npp.1301049
Goldberg, Terry E. ; Straub, Richard E. ; Callicott, Joseph H. ; Hariri, Ahmad ; Mattay, Venkata ; Bigelow, Llewellyn ; Coppola, Richard ; Egan, Michael F. ; Weinberger, Daniel. / The G72/G30 gene complex and cognitive abnormalities in schizophrenia. In: Neuropsychopharmacology. 2006 ; Vol. 31, No. 9. pp. 2022-2032.
@article{795c21823c334d6f93043ed8c29291a5,
title = "The G72/G30 gene complex and cognitive abnormalities in schizophrenia",
abstract = "A recently discovered gene complex, G72/G30 (hereafter G72, but now termed DAOA), was found to be associated with schizophrenia and with bipolar disorder, possibly because of an indirect effect on NMDA neurotransmission. In principle, if G72 increases risk for psychosis by this mechanism, it might impact with greater penetrance those cortically based cognitive and neurophysiological functions associated with NMDA signaling. We performed two independent family-based association studies (one sample contained more than 200 families and the other more than 65) of multiple SNPs in the G72 region and of multiple SNPs in the gene for D-amino acid oxidase (DAAO), which may be modulated by G72. We examined the relationship between select cognitive measures in attention, working memory, and episodic memory and a restricted set of G72 SNPs in over 600 normal controls, schizophrenic patients, and their nonpsychotic siblings using mixed model ANOVAs. We also determined genotype effects on neurophysiology measures in normal controls using the fMRI BOLD response obtained during activation procedures involving either episodic memory or working memory. There were no significant single G72 SNP associations and clinical diagnosis in either sample, though one approached significance (p = 0.06). Diagnosis by genotype interaction effects for G72 SNP 10 were significant for cognitive variables assessing working memory and attention (p = 0.05), and at the trend level for episodic memory, such that in the schizophrenia group an exaggerated allele load effect in the predicted directions was observed. In the fMRI paradigms, a strong effect of G72 SNP 10 genotype was observed on BOLD activation in the hippocampus during the episodic memory paradigm. Tests of association with DAAO were consistently nonsignificant. We present evidence that SNP variations in the G72 gene region increase risk of cognitive impairment in schizophrenia. SNP variations were not strongly associated with clinical diagnosis in family-based analyses.",
keywords = "Cognition, fMRI, G72, Gene, Glutamate, Schizophrenia",
author = "Goldberg, {Terry E.} and Straub, {Richard E.} and Callicott, {Joseph H.} and Ahmad Hariri and Venkata Mattay and Llewellyn Bigelow and Richard Coppola and Egan, {Michael F.} and Daniel Weinberger",
year = "2006",
month = "9",
day = "12",
doi = "10.1038/sj.npp.1301049",
language = "English (US)",
volume = "31",
pages = "2022--2032",
journal = "Neuropsychopharmacology",
issn = "0893-133X",
publisher = "Nature Publishing Group",
number = "9",

}

TY - JOUR

T1 - The G72/G30 gene complex and cognitive abnormalities in schizophrenia

AU - Goldberg, Terry E.

AU - Straub, Richard E.

AU - Callicott, Joseph H.

AU - Hariri, Ahmad

AU - Mattay, Venkata

AU - Bigelow, Llewellyn

AU - Coppola, Richard

AU - Egan, Michael F.

AU - Weinberger, Daniel

PY - 2006/9/12

Y1 - 2006/9/12

N2 - A recently discovered gene complex, G72/G30 (hereafter G72, but now termed DAOA), was found to be associated with schizophrenia and with bipolar disorder, possibly because of an indirect effect on NMDA neurotransmission. In principle, if G72 increases risk for psychosis by this mechanism, it might impact with greater penetrance those cortically based cognitive and neurophysiological functions associated with NMDA signaling. We performed two independent family-based association studies (one sample contained more than 200 families and the other more than 65) of multiple SNPs in the G72 region and of multiple SNPs in the gene for D-amino acid oxidase (DAAO), which may be modulated by G72. We examined the relationship between select cognitive measures in attention, working memory, and episodic memory and a restricted set of G72 SNPs in over 600 normal controls, schizophrenic patients, and their nonpsychotic siblings using mixed model ANOVAs. We also determined genotype effects on neurophysiology measures in normal controls using the fMRI BOLD response obtained during activation procedures involving either episodic memory or working memory. There were no significant single G72 SNP associations and clinical diagnosis in either sample, though one approached significance (p = 0.06). Diagnosis by genotype interaction effects for G72 SNP 10 were significant for cognitive variables assessing working memory and attention (p = 0.05), and at the trend level for episodic memory, such that in the schizophrenia group an exaggerated allele load effect in the predicted directions was observed. In the fMRI paradigms, a strong effect of G72 SNP 10 genotype was observed on BOLD activation in the hippocampus during the episodic memory paradigm. Tests of association with DAAO were consistently nonsignificant. We present evidence that SNP variations in the G72 gene region increase risk of cognitive impairment in schizophrenia. SNP variations were not strongly associated with clinical diagnosis in family-based analyses.

AB - A recently discovered gene complex, G72/G30 (hereafter G72, but now termed DAOA), was found to be associated with schizophrenia and with bipolar disorder, possibly because of an indirect effect on NMDA neurotransmission. In principle, if G72 increases risk for psychosis by this mechanism, it might impact with greater penetrance those cortically based cognitive and neurophysiological functions associated with NMDA signaling. We performed two independent family-based association studies (one sample contained more than 200 families and the other more than 65) of multiple SNPs in the G72 region and of multiple SNPs in the gene for D-amino acid oxidase (DAAO), which may be modulated by G72. We examined the relationship between select cognitive measures in attention, working memory, and episodic memory and a restricted set of G72 SNPs in over 600 normal controls, schizophrenic patients, and their nonpsychotic siblings using mixed model ANOVAs. We also determined genotype effects on neurophysiology measures in normal controls using the fMRI BOLD response obtained during activation procedures involving either episodic memory or working memory. There were no significant single G72 SNP associations and clinical diagnosis in either sample, though one approached significance (p = 0.06). Diagnosis by genotype interaction effects for G72 SNP 10 were significant for cognitive variables assessing working memory and attention (p = 0.05), and at the trend level for episodic memory, such that in the schizophrenia group an exaggerated allele load effect in the predicted directions was observed. In the fMRI paradigms, a strong effect of G72 SNP 10 genotype was observed on BOLD activation in the hippocampus during the episodic memory paradigm. Tests of association with DAAO were consistently nonsignificant. We present evidence that SNP variations in the G72 gene region increase risk of cognitive impairment in schizophrenia. SNP variations were not strongly associated with clinical diagnosis in family-based analyses.

KW - Cognition

KW - fMRI

KW - G72

KW - Gene

KW - Glutamate

KW - Schizophrenia

UR - http://www.scopus.com/inward/record.url?scp=33745949219&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33745949219&partnerID=8YFLogxK

U2 - 10.1038/sj.npp.1301049

DO - 10.1038/sj.npp.1301049

M3 - Article

C2 - 16554747

AN - SCOPUS:33745949219

VL - 31

SP - 2022

EP - 2032

JO - Neuropsychopharmacology

JF - Neuropsychopharmacology

SN - 0893-133X

IS - 9

ER -