Relationship of Catechol-O-Methyltransferase Variants to Brain Structure and Function in a Population at High Risk of Psychosis

McIntosh, Andrew M.; Baig, Benjamin; Hall, Jérémy; Job, Dominic; Whalley, Heather C.; Lymer, G. Katherine S.; Moorhead, T. William J.; Owens, David C.; Miller, Patrick; Porteous, David J.; Lawrie, Stephen M.; Johnstone, Eve C.

doi:10.1016/j.biopsych.2006.05.020

Cited by 109 publications

(70 citation statements)

References 47 publications

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“…To test this hypothesis, future studies might use tasks that enable more precise segregation of cognitive processes. However, positive associations with COMT genotype have now been reported across a very broad range of cognitive phenotypes 13,30,31,[38][39][40] as well as with structural 41,42 and functional 34,[43][44][45] brain measures. These wide-ranging reports suggest that COMT's effects on cognition may be relatively widespread.…”

Section: Discussionmentioning

confidence: 99%

Effects of the catechol-O-methyltransferase Val158Met polymorphism on executive function: a meta-analysis of the Wisconsin Card Sort Test in schizophrenia and healthy controls

et al. 2007

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The catechol-O-methyltransferase (COMT) Val 158 Met polymorphism is hypothesized to affect executive function in patient and control populations. Studies inconsistently report better performance on the Wisconsin Card Sort Test (WCST) in individuals with one or more Met alleles. We conducted a meta-analysis of studies published until August 2006 that reported WCST perseverative errors from healthy volunteers or patients with schizophrenia-spectrum disorders. Twelve studies met inclusion criteria (total n = 1910) providing 10 samples each of patients and controls. In healthy controls, individuals with the Met/Met genotype performed better than those with the Val/Val genotype (d = 0.29; 95% confidence interval (CI) 0.02-0.55; P = 0.03), but this was not supported in the patient sample (d = À0.07; 95% CI À0.40 to 0.26; P = 0.68). Post hoc analyses suggested that Val and Met alleles are codominant in their effects on cognition. Effect size was greater in studies published at an earlier date and may also be larger in non-Caucasian samples. Gender did not affect the results. There was no evidence of publication bias. We conclude that there is small but significant relationship between Val 158 Met genotype and executive function in healthy individuals but not in schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Effects of the catechol-O-methyltransferase Val158Met polymorphism on executive function: a meta-analysis of the Wisconsin Card Sort Test in schizophrenia and healthy controls

et al. 2007

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“…However, little is known about the associations between such polymorphisms and structural abnormalities in schizophrenia. Valine substituted polymorphisms at the gene for catechol-O-methyltransferase (COMT), which degrades extracellular dopamine, have been related to smaller anterior cingulate gray matter in high-risk relatives of schizophrenia subjects (75). Distinct patterns of shape abnormality may serve as potential endophenotypes by fulfilling at least some criteria proposed by Gottesman & Gould, 2003 (60).…”

Section: Discussionmentioning

confidence: 99%

Basal Ganglia Shape Abnormalities in the Unaffected Siblings of Schizophrenia Patients

Mamah¹,

Harms²,

Wang³

et al. 2008

Biological Psychiatry

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Objective-Abnormalities of basal ganglia structure in schizophrenia have been attributed to the effects of antipsychotic drugs. Our aim was to test the hypothesis that abnormalities of basal ganglia structure are intrinsic features of schizophrenia, by assessing basal ganglia volume and shape in the unaffected siblings of schizophrenia subjects.Method-The study involved 25 pairs of schizophrenia subjects and their unaffected siblings and 40 pairs of healthy controls and their siblings. Large deformation, high-dimensional brain mapping was used to obtain surface representations of the caudate, putamen, and globus pallidus. Surfaces were derived from transformations of anatomical templates and shapes were analyzed using reduceddimensional measures of surface variability (i.e. principal components and canonical analysis). Canonical functions were derived using schizophrenia and control groups, and were then used to compare shapes in the sibling groups. To visualize shape differences, maps of the estimated surface displacement between groups were created.Results-In the caudate, putamen and globus pallidus, the degree of shape abnormality observed in the siblings of the schizophrenia subjects was intermediate between the schizophrenia subjects and the controls. In the schizophrenia subjects, significant correlations were observed between measures of caudate, putamen and globus pallidus structure and the selected measures of lifetime psychopathology.Conclusions-Attenuated abnormalities of basal ganglia structure are present in the unaffected siblings of schizophrenia subjects. This finding implies that basal ganglia structural abnormalities observed in subjects with schizophrenia are at least in part an intrinsic feature of the illness. KeywordsSchizophrenia; Siblings; Basal Ganglia; Caudate; Putamen; Globus Pallidus Corresponding Author: Daniel Mamah, M.D., M.P.E. Department of Psychiatry (Box 8134), Washington University School of Medicine, 660 S. Euclid, St. Louis, MO 63110, (314) 747-2160, Fax: (314) 747-2182, E-mail: mamahd@psychiatry.wustl.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Evidence from family, twin and adoption studies suggest that genetic factors play an important role in the pathogenesis of schizophrenia (1,2). Consistent with the involvement of genetic factors in schizophrenia, cognitive (3,4), neurologic (5,6) and neurobiological (7,8) abnormalities have been found in the unaffected relatives of schizophrenia subjects, generally in attenuated form. NIH Public AccessA number of lines of research suggest that basal ganglia abnormalities mi...

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“…In line with the prevailing concept of schizophrenia as a neurodevelopmental disorder (Murray and Lewis 1987;Weinberger 1987), it has been further postulated that aberrant synaptic pruning, programmed cell death and/or synaptic plasticity affecting schizophrenia patients (Feinberg 1982) may also have similar but less severe effects on reducing fronto-temporal brain volumes in nonpsychotic relatives (Keshavan et al 1997). With recent advances in the complex genetics of schizophrenia (Harrison and Weinberger 2005) and the current interest in genotype-phenotype association studies (Ho et al 2005b), this hypothetical relationship between schizophrenia susceptibility genes and brain structural and functional abnormalities in nonpsychotic relatives are now beginning to be tested more directly (Hall et al 2006;McIntosh et al 2007). Of particular interest would be genes whose products mediate neurobiological processes involved in late maturational events of synaptic remodeling and myelination.…”

Section: Discussionmentioning

confidence: 99%

MRI brain volume abnormalities in young, nonpsychotic relatives of schizophrenia probands are associated with subsequent prodromal symptoms

2007

Schizophrenia Research

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Schizophrenia is characterized by subtle but well-replicated total and regional (frontal and temporal) brain tissue volume deficits. Studies of individuals at-risk for developing schizophrenia suggest that the onset of brain volume decrement may closely pre-date overt manifestations of schizophrenia, making brain volume abnormalities potential predictors for early identification. In an ongoing longitudinal morphometric MRI study of young, nonpsychotic first-or second-degree relatives of schizophrenia probands, we compared brain volumes in 46 relatives who are still within age range for developing schizophrenia against comparison groups of 46 schizophrenia patients and 46 healthy volunteers without family history of schizophrenia. Relatives had similar brain volume abnormalities as schizophrenia patients albeit less severe. Relatives had significantly larger whole brain, frontal, temporal and parietal gray matter (GM) volumes than patients. Relatives also had significantly smaller frontal GM volumes than healthy volunteers. Both relatives and patients had significantly larger whole brain WM (specifically parietal WM) volumes compared to healthy volunteers. Abnormally greater WM volumes in relatives and patients are suggestive of genetically-mediated dysmaturation of the age-expected myelination during adolescence through mid adulthood. On prodromal symptoms assessed in relatives one year after MRI brain scans, initial GM deficits as well as larger WM volumes correlated significantly with greater severity of subsequent prodromal symptoms. Together with previous genetic high-risk studies of adolescent or young adult relatives, these findings indicate that premorbid MRI brain abnormalities may be of predictive value for the early identification of schizophrenia.

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Relationship of Catechol-O-Methyltransferase Variants to Brain Structure and Function in a Population at High Risk of Psychosis

Cited by 109 publications

References 47 publications

Effects of the catechol-O-methyltransferase Val158Met polymorphism on executive function: a meta-analysis of the Wisconsin Card Sort Test in schizophrenia and healthy controls

Effects of the catechol-O-methyltransferase Val158Met polymorphism on executive function: a meta-analysis of the Wisconsin Card Sort Test in schizophrenia and healthy controls

Basal Ganglia Shape Abnormalities in the Unaffected Siblings of Schizophrenia Patients

MRI brain volume abnormalities in young, nonpsychotic relatives of schizophrenia probands are associated with subsequent prodromal symptoms

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