Epistasis between catechol-O-methyltransferase and type II metabotropic glutamate receptor 3 genes on working memory brain function

被引：138

作者：

Tan, Hao-Yang ^{[1
]}

Chen, Qiang ^{[1
]}

Sust, Steven ^{[1
]}

Buckholtz, Joshua W. ^{[1
]}

Meyers, John D. ^{[1
]}

Egan, Michael F. ^{[1
]}

Mattay, Venkata S. ^{[1
]}

Meyer-Lindenberg, Andreas ^{[1
]}

Weinberger, Daniel R. ^{[1
]}

Callicott, Joseph H. ^{[1
]}

机构：

[1] NIMH, Inramural Res Program, NIH, Genes Cognit & Psyosis Program,Clin Brain Disorde, Bethesda, MD 20892 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2007年 / 104卷 / 30期

关键词：

dopamine; functional MRI; genetics; schizophrenia;

D O I：

10.1073/pnas.0610125104

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Dopaminergic and glutamatergic systems are critical components responsible for prefrontal signal-to-noise tuning in working memory. Recent functional MRI (fMRl) studies of genetic variation in these systems in catechol-O-methyltransferase (COMT) and in metabotropic glutamate receptor mgluR3 (GRM3), respectively, suggest that these genes influence prefrontal physiological signal-to-noise in humans. Here, using fMRI, we extend these individual gene findings to examine the combined effects of COMT and GRM3 on dissociable components of the frontoparietal working memory network. We observed an apparent epistatic interaction of these two genes on the engagement of prefrontal cortex during working memory. Specifically, the GRM3 genotype putatively associated with suboptimal glutamatergic signaling was significantly associated with inefficient prefrontal engagement and altered prefrontal-parietal coupling on the background of COMT Val-homozygous genotype. Conversely, COMT Met-homozygous background mediated against the effect of GRM3 genotype. These findings extend putative brain dopaminergic and glutamatergic relationships indexed by COMT and GRM3 to a systems-level interaction in human cortical circuits implicated in working memory dysfunction such as in schizophrenia.

引用

页码：12536 / 12541

页数：6

共 69 条

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