Cognitive effects of genetic variation in monoamine neurotransmitter systems: A population-based study of COMT, MAOA, and 5HTTLPR

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Abstract

Individual differences in cognitive function are highly heritable and most likely driven by multiple genes of small effect. Well-characterized common functional polymorphisms in the genes MAOA, COMT, and 5HTTLPR each have predictable effects on the availability of the monoamine neurotransmitters dopamine, noradrenaline, and serotonin. We hypothesized that 5HTTLPR genotype would show little association with prefrontal cognitive performance, but that COMT and MAOA would have interacting effects on cognition through their shared influence on prefrontal catecholamine availability. We assessed the individual and epistatic effects of functional polymorphisms in COMT, MAOA, and 5HTTLPR on children's prefrontal cognitive function in nearly 6,000 children from the population-based Avon Longitudinal Study of Parents and Children (ALSPAC). Neither MAOA nor 5HTTLPR polymorphisms showed significant effects on cognitive function. In boys but not girls, there was a modest but statistically significant interaction between MAOA and COMT genotypes such that increased prefrontal catecholamine availability was associated with better working memory. These results suggest that assessment of multiple genes within functionally related systems may improve our understanding of the genetic basis of cognition. © 2010 Wiley-Liss, Inc.

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Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region.

S Sabol, K-P Lesch, Russell D Hamer … (1996)

Transporter-facilitated uptake of serotonin (5-hydroxytryptamine or 5-HT) has been implicated in anxiety in humans and animal models and is the site of action of widely used uptake-inhibiting antidepressant and antianxiety drugs. Human 5-HT transporter (5-HTT) gene transcription is modulated by a common polymorphism in its upstream regulatory region. The short variant of the polymorphism reduces the transcriptional efficiency of the 5-HTT gene promoter, resulting in decreased 5-HTT expression and 5-HT uptake in lymphoblasts. Association studies in two independent samples totaling 505 individuals revealed that the 5-HTT polymorphism accounts for 3 to 4 percent of total variation and 7 to 9 percent of inherited variance in anxiety-related personality traits in individuals as well as sibships.

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Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain.

Jingshan Chen, Barbara K. Lipska, Nader Halim … (2004)

Catechol-O-methyltransferase (COMT) is a key enzyme in the elimination of dopamine in the prefrontal cortex of the human brain. Genetic variation in the COMT gene (MIM 116790) has been associated with altered prefrontal cortex function and higher risk for schizophrenia, but the specific alleles and their functional implications have been controversial. We analyzed the effects of several single-nucleotide polymorphisms (SNPs) within COMT on mRNA expression levels (using reverse-transcriptase polymerase chain reaction analysis), protein levels (using Western blot analysis), and enzyme activity (using catechol methylation) in a large sample (n = 108) of postmortem human prefrontal cortex tissue, which predominantly expresses the -membrane-bound isoform. A common coding SNP, Val158Met (rs4680), significantly affected protein abundance and enzyme activity but not mRNA expression levels, suggesting that differences in protein integrity account for the difference in enzyme activity between alleles. A SNP in intron 1 (rs737865) and a SNP in the 3' flanking region (rs165599)--both of which have been reported to contribute to allelic expression differences and to be associated with schizophrenia as part of a haplotype with Val--had no effect on mRNA expression levels, protein immunoreactivity, or enzyme activity. In lymphocytes from 47 subjects, we confirmed a similar effect on enzyme activity in samples with the Val/Met genotype but no effect in samples with the intron 1 or 3' SNPs. Separate analyses revealed that the subject's sex, as well as the presence of a SNP in the P2 promoter region (rs2097603), had small effects on COMT enzyme activity. Using site-directed mutagenesis of mouse COMT cDNA, followed by in vitro translation, we found that the conversion of Leu at the homologous position into Met or Val progressively and significantly diminished enzyme activity. Thus, although we cannot exclude a more complex genetic basis for functional effects of COMT, Val is a predominant factor that determines higher COMT activity in the prefrontal cortex, which presumably leads to lower synaptic dopamine levels and relatively deleterious prefrontal function.

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Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia.

M Egan, T Goldberg, B. S. Kolachana … (2001)

Abnormalities of prefrontal cortical function are prominent features of schizophrenia and have been associated with genetic risk, suggesting that susceptibility genes for schizophrenia may impact on the molecular mechanisms of prefrontal function. A potential susceptibility mechanism involves regulation of prefrontal dopamine, which modulates the response of prefrontal neurons during working memory. We examined the relationship of a common functional polymorphism (Val(108/158) Met) in the catechol-O-methyltransferase (COMT) gene, which accounts for a 4-fold variation in enzyme activity and dopamine catabolism, with both prefrontally mediated cognition and prefrontal cortical physiology. In 175 patients with schizophrenia, 219 unaffected siblings, and 55 controls, COMT genotype was related in allele dosage fashion to performance on the Wisconsin Card Sorting Test of executive cognition and explained 4% of variance (P = 0.001) in frequency of perseverative errors. Consistent with other evidence that dopamine enhances prefrontal neuronal function, the load of the low-activity Met allele predicted enhanced cognitive performance. We then examined the effect of COMT genotype on prefrontal physiology during a working memory task in three separate subgroups (n = 11-16) assayed with functional MRI. Met allele load consistently predicted a more efficient physiological response in prefrontal cortex. Finally, in a family-based association analysis of 104 trios, we found a significant increase in transmission of the Val allele to the schizophrenic offspring. These data suggest that the COMT Val allele, because it increases prefrontal dopamine catabolism, impairs prefrontal cognition and physiology, and by this mechanism slightly increases risk for schizophrenia.

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Author and article information

Journal

Journal ID (nlm-ta): Am J Med Genet B Neuropsychiatr Genet

Journal ID (iso-abbrev): Am. J. Med. Genet. B Neuropsychiatr. Genet

Journal ID (publisher-id): ajmg

Title: American Journal of Medical Genetics

Publisher: Wiley Subscription Services, Inc., A Wiley Company (Hoboken )

ISSN (Print): 1552-4841

ISSN (Electronic): 1552-485X

Publication date (Print): March 2011

Publication date (Electronic): 16 December 2010

Volume: 156

Issue: 2

Pages: 158-167

Affiliations

[1 ]Department of Psychiatry, University of Cambridge Cambridge, UK

[2 ]Cambridge Cognition Ltd Cambridge, UK

[3 ]Department of Psychiatry, Yale University New Haven, Connecticut

[4 ]Department of Social Medicine, Bristol University Bristol, UK

[5 ]Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism Rockville, Maryland

[6 ]MRC/Wellcome Trust Behavioural & Clinical Neurosciences Institute (BCNI) Cambridge, UK

Author notes

*Correspondence to: Jennifer H. Barnett, Ph.D., Department of Psychiatry, Box 189 Addenbrooke's Hospital, Cambridge CB2 2QQ, UK. E-mail: jhb32@ 123456cam.ac.uk

Grant sponsor: Wellcome Trust; Grant Number: 074296/Z/04/Z; Grant sponsor: NIHR CLAHRC for Cambridgeshire & Peterborough.

How to Cite this Article: Barnett JH, Xu K, Heron J, Goldman D, Jones PB. 2011. Cognitive Effects of Genetic Variation in Monoamine Neurotransmitter Systems: A Population-Based Study of COMT, MAOA, and 5HTTLPR. Am J Med Genet Part B 156:158–167.

Article

DOI: 10.1002/ajmg.b.31150

PMC ID: 3494973

PubMed ID: 21302344

SO-VID: e5c62ec0-eeb5-4020-bba6-27b888adbf2b

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Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

Cognitive effects of genetic variation in monoamine neurotransmitter systems: A population-based study of COMT, MAOA, and 5HTTLPR

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Serotonin and BEYOND

Most cited references 72

Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region.

Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain.

Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia.

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