<scp>COMT</scp>rs4680 Met is not always the ‘smart allele’: Val allele is associated with better working memory and larger hippocampal volume in healthy Chinese

Wang, Y.; Li, J.; Chen, C.; Zhu, Bi; Moysis, R. K.; Lei, Xin; Li, H.; Liu, Q.; Xiu, Daiming; Liu, B.; Chen, Wanxu; Xue, Gui; Dong, Qi

doi:10.1111/gbb.12022

Cited by 59 publications

(51 citation statements)

References 62 publications

(97 reference statements)

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“…Possible explanations for this inconsistency may include the different racial backgrounds of the samples and the different cognitive tasks used due to that many other studies have found racial differences in genetic effects (Wang et al, 2013) and that different working memory tasks have shown low inter-correlations (Conway et al, 2005). Future studies should include samples of different racial groups and use a broader range of measures to investigate whether the effect of NOS1 genetic variants is specific to some measures and samples.…”

Section: Discussionmentioning

confidence: 99%

Evidence for the Contribution of NOS1 Gene Polymorphism (rs3782206) to Prefrontal Function in Schizophrenia Patients and Healthy Controls

Zhang¹,

Chen

et al. 2014

Neuropsychopharmacol

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Nitric oxide (NO), a gaseous neurotransmitter, has been implicated in the pathogenesis of schizophrenia. Accordingly, several polymorphisms of the gene that codes for the main NO-producing enzyme, the nitric oxide synthase 1 (NOS1), have been found to convey a risk for schizophrenia. This study examined the role of NOS1 gene polymorphisms in cognitive functions and related neural mechanism. First, with a sample of 580 schizophrenia patients and 720 healthy controls, we found that rs3782206 genotype had main effects on the 1-back task (P ¼ 0.005), the 2-back task (P ¼ 0.049), the AY condition of the dot-pattern expectancy (DPX) task (P ¼ 0.001), and the conflict effect of the attention network (ANT) test (Po0.001 for RT differences and P ¼ 0.002 for RT ratio) and interaction effects with diagnosis on the BX condition of the DPX (P ¼ 0.009), the AY condition of the DPX (Po0.001), and the Stroop conflict effect (P ¼ 0.003 for RT differences and P ¼ 0.038 for RT ratio). Simple effect analyses further showed that the schizophrenia risk allele (T) of rs3782206 was associated with poorer performance in five measures for the patients (1-back, P ¼ 0.025; BX, P ¼ 0.017; AY, Po0.001; ANT conflict effect (RT differences), P ¼ 0.005; Stroop conflict effect (RT differences), P ¼ 0.019) and three measures for the controls ( for the 2-back task, P ¼ 0.042; for the ANT conlict effect (RT differences), P ¼ 0.013; for the ANT conflict effect (RT ratios), P ¼ 0.028). Then, with a separate sample of 78 healthy controls, we examined the association between rs3782206 and brain activation patterns during the N-back task and the Stroop task. Whole brain analyses found that the risk allele carriers showed reduced activation at the right inferior frontal gyrus (IFG) during both tasks. Finally, we examined functional connectivity seeded from the right IFG to the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex under three conditions (the N-back task, the Stroop task, and the resting state). Results showed reduced connectivity with the DLPFC for the risk allele carriers mainly in the Stroop task and the resting state. Taken together, results of this study strongly suggested a link between NOS1 gene polymorphism at rs3782206 and cognitive functions and their neural underpinnings at the IFG. These results have important implications for our understanding of the neural mechanism underlying the association between NOS1 gene polymorphism and schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Evidence for the Contribution of NOS1 Gene Polymorphism (rs3782206) to Prefrontal Function in Schizophrenia Patients and Healthy Controls

Zhang¹,

Chen

et al. 2014

Neuropsychopharmacol

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“…Therefore, genetic association studies between COMT Met/Val and prefrontal cognitive functions were performed. Inconsistent results were reported for the association of the Met allele with either better ( Caldu et al, 2007;Egan et al, 2001) or worse (Buckert et al, 2012;Wang et al, 2013) cognitive performance. Considering enormous genetic heterogeneity of human population, it is not surprising to obtain contradictory results in the association studies.…”

Section: Introductionmentioning

confidence: 96%

Generation and Characterization of Humanized Mice Carrying COMT158 Met/Val Alleles

Risbrough

Hauger

et al. 2014

Neuropsychopharmacol

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The Val158Met polymorphism of human catechol-o-methyltransferase (COMT) is one of the most well-studied single-nucleotide polymorphisms in neuropsychiatry; however, findings are inconsistent due to human genetic heterogeneity. We created the first 'humanized' COMTVal158Met mouse lines, which carry either human COMT Val or Met alleles via gene targeting. The 'humanized' mouse model enables strict comparison of the physiological functions of the two alleles. Consistent with human observation, Met/Met mice exhibited a 30% reduction in enzymatic activity compared with Val/Val mice. On the basis of the reported differences in human Met and Val carriers across working memory, fear processes and sensorimotor gating, we examined these functions between sibling Met/Met and Val/Val mice. Val/Val mice exhibited robust reductions in spatial working memory compared with Met/Met mice in both sexes, with tolcapone treatment significantly reversing the Val/Val alternation deficits. Sex effects were observed in other behaviors, with male Val/ Val mice exhibited lower prepulse inhibition compared with Met/Met mice, whereas female mice exhibited the opposite phenotype. Female but not male Met/Met mice exhibited reduced contextual fear, increased cued fear, and reduced extinction recall. Thus, these mice (1) support the argument that human COMT Val158Met polymorphism modulates behavioral functions and most importantly (2) exhibit the expected treatment effects supporting the 'inverted U shaped' dose response of catecholamine signaling on cognitive function. This model will be invaluable for understanding the effects of human COMT Val158Met polymorphism on cortical development and behavioral functions, and how this polymorphism modulates treatment response.

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“…Much more research is needed to examine both culture-general and culture-specific processes in genetic stratification. Closely related to this point, it should also be noted that there is growing evidence that genetic effects on behaviors may vary by ethnic/ racial groups Kimura 2011;Wang et al 2013). Much more research is needed to ascertain cultural generality or specificity of conclusions on human behaviors and their genetic and neural bases (Chiao and Cheon 2010;Henrich et al 2010).…”

Section: Discussionmentioning

confidence: 94%

Genotypes over-represented among college students are linked to better cognitive abilities and socioemotional adjustment

Chen

Moyzis

et al. 2013

Cult. Brain

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Genotypes over-represented among college students are linked to better cognitive abilities and socioemotional adjustment Genotypes over-represented among college students are linked to better cognitive abilities and socioemotional adjustment Abstract Although much is known about college students as a special sample in terms of their behavioral traits such as intelligence and academic motivation, no studies have examined whether college students represent a ''biased'' sample in terms of their genotype frequencies. The present study investigated this issue by examining the Hardy-Weinberg equilibrium of genotype frequencies of 284 SNPs covering major neurotransmitter genes in a sample of 478 Chinese college students, comparing these frequencies with those of a community sample (the 1000 Genomes dataset), and examining behavioral correlates of the SNPs in Hardy-Weinberg disequilibrium. Results showed that 24 loci showed Hardy-Weinberg disequilibrium among college students, but only two of these were in disequilibrium in the 1000 Genomes sample. These loci were found to be associated with mathematical abilities, executive functions, motivation, and adjustment-related behaviors such as alcohol use and emotion recognition. Generally, genotypes overrepresented in the college sample showed better performance and adjustment than under-represented or non-biased genotypes. This study illustrates a new approach to studying genetic correlates of traits associated with a socially-selected group-college students-and presents the first evidence of genetic stratification in terms of education attainment.

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COMTrs4680 Met is not always the ‘smart allele’: Val allele is associated with better working memory and larger hippocampal volume in healthy Chinese

Cited by 59 publications

References 62 publications

Evidence for the Contribution of NOS1 Gene Polymorphism (rs3782206) to Prefrontal Function in Schizophrenia Patients and Healthy Controls

Evidence for the Contribution of NOS1 Gene Polymorphism (rs3782206) to Prefrontal Function in Schizophrenia Patients and Healthy Controls

Generation and Characterization of Humanized Mice Carrying COMT158 Met/Val Alleles

Genotypes over-represented among college students are linked to better cognitive abilities and socioemotional adjustment

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