Biological Effects of COMT Haplotypes and Psychosis Risk in 22q11.2 Deletion Syndrome

Abstract

Background 22q11.2 deletion syndrome (22q11.2DS) is the most common genetic syndrome associated with schizophrenia. The catechol-o-methyltransferase (COMT) gene is located in the obligatory deletion region, and possible associations between COMT variants and neuropsychiatric manifestations in 22q11.2DS have been reported. The purpose of the current study was to evaluate the effect of COMT hemizygosity and molecular haplotypes on gene expression and enzyme activity and its association with psychotic symptoms in 22q11.2DS. Methods Lymphoblast samples were drawn from 53 individuals with 22q11.2DS and 16 typically developing controls. We measured COMT mRNA and protein expression and enzyme activity using standard procedures. The presence of a psychotic disorder and cognitive deficits were also evaluated using structured testing. Results There was a ~50% reduction in COMT mRNA, protein and enzyme activity levels in 22q11.2DS samples. Haplotype analysis revealed clear phenotypic differences between various Val-containing haplotypes on COMT-3′UTR extended mRNA, S-COMT and MB proteins and enzyme activity. The G variant of rs165599, a 3′UTR SNP, was associated with low levels of COMT expression and with the presence of psychosis and lower performance IQ scores in our 22q11.2DS sample. Finally, we demonstrate that the COMT rs74745580 ‘T’ mutation is associated with absent S-COMT expression and very low COMT activity in two 22q11.2DS individuals. Conclusions Our findings confirm a robust effect of COMT hemizygosity on COMT activity and show complex interactions of variants within the COMT gene that influence COMT biology and confound conclusions based on associations with the Val158Met genotype alone.

The dysconnection hypothesis (2016)

“…For example 25–30% of adult patients with 22q11.2 deletion syndrome (DiGeorge Syndrome), a deletion which includes the COMT gene – of relevance for dopamine metabolism (Gothelf et al, 2014) – suffer from schizophrenia (Murphy et al, 1999), making this one of the highest-penetrance genetic changes involved in schizophrenia to date. Other CNVs have also been identified which are significantly associated with schizophrenia (Kirov et al, 2014).…”

22q11.21 Deletion Syndromes: A Review of Proximal, Central, and Distal Deletions and Their Associated Features

“…Additionally, unmasking of other sequence variants throughout the genome and/or in the non-deleted allele that may affect the activities of the gene products has also been hypothesized to contribute to the variability of features for 22q11.2 deletions [Brzustowicz and Bassett, 2012;Zarchi et al, 2013;Carmel et al, 2014;Gothelf et al, 2014;Radoeva et al, 2014]. Other studies have suggested a possible gender effect in proximal deletion subjects, owing to the interaction of estrogen with COMT , but additional studies are needed to clarify whether there is indeed a relationship in DGS patients [Coman et al, 2010;Yu et al, 2012].…”

Catechol-O-Methyltransferase and Genetic Variation Under Hemizygosity

“…The convergence of associations of both psychotic and cognitive phenotypes with this particular SNP might speak to correlations between these dependent variables in VCFS but is particularly interesting, given recent evidence for an enrichment of SNPs associated with diminished cognitive aptitude in schizophrenia (9), and forwards the possibility that, in the context of VCFS, functional common variation in COMT might be an important predictor of neuropsychiatric outcomes. However, as noted by Gothelf et al , (7) their data suggest that the molecular impact of the implicated SNP requires further study to clarify its mechanism of action. For example, the distinguishing effect of this SNP was in the expression of an extended alternate transcript, and its prediction of enzymatic activity was dependent on the status of other COMT markers that were not associated with the clinical variables.…”

“…The new findings of Gothelf et al (7), identifying messenger RNA expression, protein function, and clinical effects of SNPs in the remaining COMT allele in 22q11.2 deletion syndrome, take a step toward answering these questions. By cross-leveraging both multiple common/small effect size and rare/large-effect size variation, the work accomplishes a significant elaboration of COMT biology, demonstrating complex, multi-locus interactions at the cellular level and addressing the important conundrum of incomplete penetrance in VCFS.…”