Elsevier

Biological Psychiatry

Volume 75, Issue 5, 1 March 2014, Pages 406-413
Biological Psychiatry

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

https://doi.org/10.1016/j.biopsych.2013.07.021Get rights and content

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 control subjects. We measured COMT messenger (m)RNA 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 an approximately 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′ untranslated region extended mRNA, soluble COMT and membrane-bound proteins, and enzyme activity. The G variant of rs165599, a 3′ untranslated region single nucleotide polymorphism, 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 soluble 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.

Section snippets

Human Study Samples

Individuals with 22q11.2DS were recruited from the Behavioral Neurogenetics Center at a large tertiary referral center in Israel, and control subjects were taken from samples of European ancestry at the National Institute of Mental Health (see Methods in Supplement 1) (10). The study protocol was approved by the Institutional Review Board of Rabin Medical Center and the National Institute of Mental Health Institutional Review Board, and informed consent was obtained from all participants or

22q11.2DS Versus Normal Control Subjects

To compare main effects of hemizygosity, we selected a subset of 20 adult individuals with 22q11.2DS who were age and sex matched to 16 healthy adult comparison subjects (28.8 ± 6.4 years vs. 31.4 ± 8.4 years, p = .32 and male/female ratio of 10/10 vs. 7/9, p = .49, respectively). As expected, there were significant, robust differences between 22q11.2DS and control subjects in all COMT products including COMT-extended and COMT-common mRNAs, S-COMT and MB-COMT protein levels and COMT enzyme

Discussion

The principal findings of this study are as follows: 1) 22q11.2DS is associated with reduced expression of COMT gene products in peripheral cells, with individuals having approximately 50% less COMT mRNA, COMT protein expression, and enzyme activity compared with normal comparison subjects; 2) the Val158Met genotype had predicted but weak effects on COMT biology in 22q11.2DS, as previously reported in nonhemizygous individuals (14); 3) identification of haplotypes consisting of previously

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    Authors DG and AJL contributed equally to the work.

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    Authors DG and AJL contributed equally to the work.

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