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 ¼ 0.06). Diagnosis by genotype interaction effects for G72 SNP 10 were significant for cognitive variables assessing working memory and attention (p ¼ 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.

Allelic association of G72/G30 with schizophrenia and bipolar disorder: A comprehensive meta-analysis

“…Several studies were excluded because of sample duplication with another study (Yue et al, 2006), lack of sufficient data even after requesting informative data from the authors (Fallin et al, 2005;Goldberg et al, 2006;Hall et al, 2004;Nicodemus et al, 2007). M12, M15, M23 and M24 were excluded for BP because they were analyzed in only one or two studies (Schulze et al, 2005).…”

“…An association has been reported in multiple independent studies (Addington et al, 2004;Chen et al, 2004;Fallin et al, 2005;Hall et al, 2004;Hong et al, 2006;Korostishevsky et al, 2004;Korostishevsky et al, 2006;Ma et al, 2006;Schulze et al, 2005;Schumacher et al, 2004;Wang et al, 2004;Williams et al, 2006;Yue et al, 2006;Yue et al, 2007;Zou et al, 2005). However, several studies did not find association with traditional BP or SCZ phenotype (Bakker et al, 2007;Goldberg et al, 2006;Liu et al, 2006;Mulle et al, 2005;Vilella et al, 2007;Wood et al, 2006). In addition, an obvious inconsistency of allelic association(s) has been observed.…”

“…Since then, 13 more G72/G30 association studies in SCZ and three more in BP have been published (Bakker et al, 2007;Fallin et al, 2005;Goldberg et al, 2006;Hong et al, 2006;Korostishevsky et al, 2006;Liu et al, 2006;Ma et al, 2006;Nicodemus et al, 2007;Schulze et al, 2005;Vilella et al, 2007;Williams et al, 2006;Wood et al, 2006;Yue et al, 2006;Yue et al, 2007), with inconsistent associated alleles or haplotypes. Here we report an updated meta-analysis to re-evaluate the relationship between variants in the G72/G30 gene region and these two major psychiatric disorders.…”

Genetic variation in the DAOA gene complex: Impact on susceptibility for schizophrenia and on cognitive performance

“…Goldberg et al (2006) demonstrated a significant effect of several SNPs on cognitive measures, which are putatively dependent on NMDA signaling in a cohort of 600 subjects, including patients with schizophrenia, their unaffected siblings, and healthy controls. Further, these associations were also related to neurophysiological response parameters during those tasks, as measured by functional magnetic resonance imaging (fMRI).…”

Physiogenomic Analysis of Localized fMRI Brain Activity in Schizophrenia

“…For example, the association of the G72/G30 locus with schizophrenia and bipolar disorder has been reported in several studies. 22,36 Other genes and polymorphisms studied in schizophrenia include a brain-derived neurotrophic factor (BDNF) prodomain polymorphism, 2,41,72 Catechol-Omethyl-transferase (COMT), 42,71,75 gamma aminobutyric acid (GABA), 38,55,59,112 histidine triad nucleotide-binding protein (HINT1) and cytosolic malate dehydrogenase (MDH1). 3,16,109 Some researchers have presented data derived from multimodal imaging or combined data from both imaging and other modalities, including genomic imaging).…”