Lack of association of the COMT (Val158/108 Met) gene and schizophrenia: a meta-analysis of case–control studies

Abstract

There is strong evidence for a genetic contribution to schizophrenia, but the contribution of individual candidate genes remains uncertain. We attempted to replicate a recent metaanalysis that reported an association of the catechol O-methyltransferase (COMT) Val allele with schizophrenia, and suggested that this effect may be moderated by ancestry. We included reports published subsequent to the original meta-analysis, and included a formal test of the moderating effect of ancestry in order to test whether the association operates differently in populations of European ancestry compared to populations of Asian ancestry. A corrected Pvalue for the 5% significance threshold was employed where appropriate, using Bonferroni's method, and studies that demonstrated departure from Hardy-Weinberg equilibrium among controls were excluded. When all studies were included in a meta-regression, there was evidence for a significant association of COMT Val allele frequency with schizophrenia case status and a significant main effect of ancestry. The interaction of COMT Val allele frequency and ancestry was also significant. However, when only studies that reported allele frequencies that did not depart significantly from Hardy-Weinberg equilibrium among controls were included, these effects were no longer significant. The results of our meta-analysis do not support an association between the COMT Val allele and schizophrenia case status, and do not support recent claims that this association may be moderated by ancestry. Twin studies provide convincing evidence that susceptibility to schizophrenia is attributable largely to genetic factors, 1,2 but progress in identifying the specific genetic variants responsible has been slow. One approach is to look at genes involved in the metabolism of dopamine, on the hypothesis that schizophrenia is primarily caused by dysregulation of dopaminergic neurotransmission in corticostriatal circuits. 3 This is one reason why the gene coding for catechol O-methyltransferase (COMT) has attracted considerable attention as a potential candidate, as it inactivates catechols at postsynaptic sites in the human brain. COMT contains a functional polymorphism, a single-nucleotide polymorphism at position 108/158 that results in a change from valine (val) to methionine (met). The amino-acid change affects function of the enzyme: val-COMT has significantly lower enzyme activity than met-COMT. 4,5 An association between the functional Val 158/108 Met polymorphism of the COMT gene and schizophrenia has been investigated in a number of studies, but with equivocal results. The small effect sizes of putative candidate genes such as COMT may, however, result in the absence of significant association in individual studies with modest sample sizes. This may explain the conflicting findings that have been reported in repeated studies of this association.A recent meta-analysis 6 of case-control and familybased studies of the association between the COMT gene Val 158/108 Met polymorphism and schizophrenia concluded...

Catechol-O-methyl Transferase and Expression of Schizophrenia in 73 Adults with 22q11 Deletion Syndrome

“…The results suggest that the COMT functional allele is not a major factor in expression of schizophrenia in 22q11DS, similar to findings for schizophrenia in the general population (Glatt et al 2003;Munafo et al 2005). We must look elsewhere for major risk factors for schizophrenia.…”

“…Several studies have found the COMT Met allele to be more common than the Val allele in severe forms of schizophrenia (Bilder et al 2004), yet there is an overall trend for association of the COMT Val allele with schizophrenia (Glatt et al 2003). The disparate results may be partly due to the etiologic heterogeneity of schizophrenia (Strous et al 2006), which could also account for the small effect sizes observed in association studies (Glatt et al 2003;Munafo et al 2005). …”

Clinical involvement of catechol-O-methyltransferase polymorphisms in schizophrenia spectrum disorders: influence on the severity of psychotic symptoms and on the response to neuroleptic treatment

“…Nevertheless, two other studies did not report a significant contribution of the Val 158 Met polymorphism of the COMT gene to schizophrenia and concluded that either the Val allele is in linkage disequilibrium (LD) with a nearby causal marker or the results differ when ethnically different populations are considered or the risk conferred by the Val allele is extremely low. 12,13 Results have also been obtained that suggest an eventual influence of this polymorphism in the response of schizophrenic patients to typical 14 and atypical 15 neuroleptics.…”

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

“…4 However, recent meta-analyses have questioned the association between schizophrenia and the COMT Val 158 Met polymorphism. [15][16][17] Impaired performance on the WCST has long been of interest in schizophrenia because WCST failure is associated with 'hypofrontality', that is a failure to activate the PFC. 6 More recently, WCST performance has attracted considerable interest as a potential endophenotype of schizophrenia, because it shows considerable heritability 18 and is impaired in the healthy relatives of patients with schizophrenia compared with unrelated controls.…”