The COMT Val108/158Met polymorphism and medial temporal lobe volumetry in patients with schizophrenia and healthy adults
Introduction
Catechol-O-methyltransferase (COMT) is an enzyme found throughout the mammalian central nervous system which degrades the catecholamine neurotransmitters dopamine, epinephrine, and norepinephrine. A common G-to-A transition in exon 4 of the COMT gene, resulting in a valine (val)-to-methionine (met) substitution at amino acid position 108 or 158 (depending on the splice variant), leads to a four-fold decrease in enzyme activity in met homozygotes, while heterozygotes demonstrate intermediate activity (Lachman et al., 1996). Because schizophrenia is associated with dysregulation of dopaminergic neurotransmission, the relationship between the COMT Val108/158Met polymorphism and schizophrenia has been studied intensively. A small association between the val allele and schizophrenia has been found in family-based studies, but not in overall meta-analyses (Glatt et al., 2003, Munafo et al., 2005). However, one recent study found that the risk contributed by COMT genotype may be more evident when evaluated within a high risk sample (McIntosh et al., 2007), in which other schizophrenia susceptibility genes are presumably also playing a role.
The low-activity COMT met allele has been associated with higher extracellular dopamine levels (Lotta et al., 1995) and more efficient activation of the dorsolateral prefrontal cortex (DLPFC) in tests of executive functioning and working memory (Bertolino et al., 2006, Egan et al., 2001, Ho et al., 2005). In addition, the Val108/158Met polymorphism has been found to influence the physiology of regions within the medial temporal lobe, including the amygdala (Smolka et al., 2005) and hippocampus (Drabant et al., 2006).
The effect of COMT Val108/158Met genotype on brain structure is less clear. Several studies have found no direct effect of this polymorphism on measures of brain structural integrity, including total frontal gray matter volume (Ho et al., 2005) and regional gray matter density (Zinkstok et al., 2006). However, a recent large study of healthy subjects which used voxel-based morphometry found that participants with higher numbers of met alleles had increased hippocampal gray matter intensity (Honea et al., 2009). Also, a study of patients with velocardiofacial syndrome, who have only one copy of the COMT gene, found that these patients have larger amygdala volumes compared to healthy control subjects (Kates et al., 2006). Taken together, these studies suggest that less COMT activity and higher extracellular dopamine levels may be associated with elevated responsiveness and larger volumes of medial temporal lobe structures.
Morphometric investigations have consistently found a small reduction in medial temporal lobe volume in schizophrenia, with approximately 4–6% reductions in the volume of the hippocampus and a 6% reduction in the volume of the amygdala (Honea et al., 2005, Wright et al., 2000). Abnormalities of the structure and function of the amygdala and hippocampus in schizophrenia have been associated with deficits in memory and executive function (Antonova et al., 2004) and emotional processing (Exner et al., 2004, Holt and Phillips, 2009, Namiki et al., 2007), suggesting that these structural changes could reflect a central pathophysiological process associated with the illness (Heckers, 2001).
Given the evidence for an effect of COMT Val108/158Met genotype on the function and structure of the medial temporal lobe and its putative contribution to risk for schizophrenia, in the current study we sought to measure the influence of this polymorphism on amygdala and hippocampus volumes in patients with schizophrenia and healthy control subjects. An automated atlas-based segmentation technique, which estimates volumes objectively in the original (untransformed) MR images (Fischl et al., 2002), was used to measure amygdala and hippocampal volumes. We tested the prediction that COMT Val108/158Met genotype influences amygdala and hippocampal volumes in a linear-additive manner, i.e. each copy of the met allele is associated with a proportionate increase in amygdala and hippocampal volume. Measurement of total brain volume served as a control in this analysis. Because of evidence for effects of COMT genotype on frontal lobe function (Bertolino et al., 2006, Egan et al., 2001, Ho et al., 2005), exploratory analyses of the effect of this genotype on volumes of frontal lobe regions were also conducted.
Section snippets
Participants
The Mind Clinical Imaging Consortium (MCIC) study of schizophrenia (Roffman et al., 2008a) obtained baseline structural MRI scans on a total of 328 subjects (160 individuals with schizophrenia, 168 healthy controls) from four participating sites: Universities of Iowa (UI), Minnesota (UMN), and New Mexico (UNM) and Massachusetts General Hospital in Boston (MGH). The schizophrenic patient group (SCZ) consisted of individuals with a DSM-IV diagnosis of schizophrenia, established using structured
Sample characteristics
Patients and healthy control subjects did not differ in age, parental SES or handedness score. Patients had a significantly lower premorbid IQ than controls, and there were slightly more male and more non-white participants in the patient group as compared to the control group (Table 1). COMT genotype frequency was in Hardy–Weinberg equilibrium and there was no significant association between genotype and diagnosis (Armitage's trend test χ2 = 0.09, p = 0.770). A series of linear or logistic
Discussion
Using an automated segmentation procedure to measure regional brain volumes in a large number of healthy and schizophrenic subjects, we detected a significant effect of the COMT Val108/158Met polymorphism on medial temporal lobe volumes. Across patients and controls, each copy of the COMT met allele was associated with a 2.6% increase in right amygdala volume, a 3.8% increase in left amygdala volume and a 2.2% increase in right hippocampus volume. These dose-dependent effects are consistent
Financial disclosures
During the preceding 5 years, Dr. Ho has received research funding from Janssen-Cilag, and consulting fees from Solvay Pharmaceuticals. All other authors declare no biomedical financial interests or potential conflicts of interest.
Acknowledgments
This work was supported by NIH/NCRR P41RR14075, Department of Energy, Mental Illness and Neuroscience Discovery (MIND) Research Network, Morphometry Biomedical Informatics Research Network (mBIRN) 1U24, RR021382A, Function BIRN U24RR021992, NIMH K23 MH076054 (D.J.H.), NIMH K23 MH080954 (E.M.M.), National Alliance for Research in Schizophrenia and Depression (D.J.H., B.C.H., E.M.M.) with the Sidney R. Baer, Jr Foundation (D.J.H.), Burroughs Wellcome Fund (E.M.M.), the Nellie Ball Research Trust
References (62)
- et al.
The relationship between brain structure and neurocognition in schizophrenia: a selective review
Schizophr. Res.
(2004) - et al.
Prefrontal dysfunction in schizophrenia controlling for COMT Val158Met genotype and working memory performance
Psychiatry Res.
(2006) - et al.
A unified approach for morphometric and functional data analysis in young, old, and demented adults using automated atlas-based head size normalization: reliability and validation against manual measurement of total intracranial volume
Neuroimage
(2004) - et al.
Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene × environment interaction
Biol. Psychiatry
(2005) - et al.
An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest
Neuroimage
(2006) - et al.
Impaired emotional learning and reduced amygdala size in schizophrenia: a 3-month follow-up
Schizophr. Res.
(2004) - et al.
Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain
Neuron
(2002) - et al.
Heritability of brain morphology related to schizophrenia: a large-scale automated magnetic resonance imaging segmentation study
Biol. Psychiatry
(2008) - et al.
Impact of interacting functional variants in COMT on regional gray matter volume in human brain
Neuroimage
(2009) - et al.
Grey matter changes over time in high risk subjects developing schizophrenia
Neuroimage
(2005)