Elsevier

NeuroImage

Volume 53, Issue 3, 15 November 2010, Pages 992-1000
NeuroImage

The COMT Val108/158Met polymorphism and medial temporal lobe volumetry in patients with schizophrenia and healthy adults

https://doi.org/10.1016/j.neuroimage.2009.12.046Get rights and content

Abstract

Abnormalities of the medial temporal lobe have been consistently demonstrated in schizophrenia. A common functional polymorphism, Val108/158Met, in the putative schizophrenia susceptibility gene, catechol-O-methyltransferase (COMT), has been shown to influence medial temporal lobe function. However, the effects of this polymorphism on volumes of medial temporal lobe structures, particularly in patients with schizophrenia, are less clear. Here we measured the effects of COMT Val108/158Met genotype on the volume of two regions within the medial temporal lobe, the amygdala and hippocampus, in patients with schizophrenia and healthy control subjects.

We obtained MRI and genotype data for 98 schizophrenic patients and 114 matched controls. An automated atlas-based segmentation algorithm was used to generate volumetric measures of the amygdala and hippocampus. Regression analyses included COMT met allele load as an additive effect, and also controlled for age, intracranial volume, gender and acquisition site.

Across patients and controls, each copy of the COMT met allele was associated on average 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. There were no effects of COMT genotype on volumes of the whole brain and prefrontal regions.

Thus, the COMT Val108/158Met polymorphism was shown to influence medial temporal lobe volumes in a linear-additive manner, mirroring its effect on dopamine catabolism. Taken together with previous work, our data support a model in which lower COMT activity, and a resulting elevation in extracellular dopamine levels, stimulates growth of medial temporal lobe structures.

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

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