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

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.

Figure 1

Freesurfer subcortical segmentation of the hippocampus and amygdala (white arrow in C) and cortical parcellations with the DLPFC (green arrow in D). Models are displayed overlaid on one randomly chosen female patient. Images A and B constructed using Slicer 3.0 (www.slicer.org), C using tkmedit and D using tksurfer (http://surfer.nmr.mgh.harvard.edu/). The DLPFC parcellations were generated by: (A) Merging the standard Freesurfer parcellation labels of the superior frontal gyrus, the rostral middle frontal gyrus and caudal middle frontal gyrus. (B) Making a cut along the vertex on the inflated cortical surface to divide medial and lateral components and (C) Introducing a coronal cut of the lateral component at Talairach coordinate y=26 to separate DLPFC from premotor cortex.

Figure 2

Boxplots of the raw volumes of the four brain regions of interest and the control regions in mm³ for 98 schizophrenic patients (SCZ) and 114 healthy controls (HC). The differences between patients and controls (while controlling for the effect of COMT, gender, age and ICV) were significant for all regions (*p<0.03; **p<0.001).

Figure 3

Barcharts showing mean and standard errors of the standardized residuals for the effects of COMT on amygdala and hippocampus volumes in healthy controls (HC) and patients with schizophrenia (SCZ) controlled for intracranial volume, age and gender. The additive effect of COMT is significant for right and left amygdala as well as right hippocampus.