Association between a common haplotype in the COMT gene region and psychiatric disorders in individuals with 22q11.2DS

Abstract

The 22q11.2 deletion syndrome (22q11.2DS) is the most common hemizygous deletion syndrome in humans. In addition to a wide range of physical abnormalities 22q11.2DS subjects show high prevalence of several psychiatric disorders. In our previous study we showed that the low-activity allele (158Met) of the COMT gene is a risk factor for attention deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD) in 22q11.2DS individuals. In the present study we have genotyped fifty-five 22q11.2DS individuals and 95 of their parents for eight SNPs in and around the COMT gene. A haplotype composed of three SNPs [rs2097603; rs4680 (158Val/Met); rs165599] representing the major linkage disequilibrium blocks in COMT and previously implicated in functional variation, was found to be associated with ADHD and OCD in 22q11.2DS individuals. A common risk haplotype (G-A-A) was significantly associated with both ADHD (OR 3.13, chi2=4.38, p=0.036) and OCD (OR 4.00, chi2=6.41, p=0.011) in 22q11.2DS individuals. Interestingly, the same haplotype was recently found to be associated with efficient prefrontal performance in the general population. The risk haplotype was not found to be associated with IQ scores in our 22q11.2DS sample. Parental origin of the deletion did not affect the susceptibility to ADHD and OCD in the 22q11.2DS subjects. This study demonstrated the association of a particular COMT haplotype with susceptibility to both ADHD and OCD in 22q11.2DS and supports the hypothesis that COMT gene variations contribute to genetic predisposition to psychiatric disorders in the general population.

Association of TMEM132D, COMT, and GABRA6 genotypes with cingulate, frontal cortex and hippocampal emotional processing in panic and major depressive disorder

“…COMT is involved in one of the major catabolic pathways of catecholamine neurotransmitters and is a target in neuropsychiatric genetic studies, including those on MDD, and studies of the mechanism of action of antidepressants (Shifman et al 2002;Hos á k 2007;Michaelovsky et al 2008;Halleland et al 2009). Several studies on COMT SNPs have identifi ed a functional polymorphism (rs4680) that causes a valine to methionine (Val-to-Met) substitution in codon 158 in the membrane-bound form of the enzyme (codon 108 of the soluble form) that generates alleles encoding high-and low-activity forms of the enzyme.…”

Attention Deficit Hyperactivity Disorder and Obsessive-Compulsive Disorder among Former Heroin Addicts Currently in Methadone Maintenance Treatment

“…Those authors reported that OCD and ADHD comorbidity was more frequent among males (21.3%) and earlier-onset OCD patients (20%) and that it was also associated with having tics, bipolar disorder and childhood oppositional defiant disorder. Interestingly, an association of a particular COMT haplotype with susceptibility to both ADHD and OCD was found in velocardiofacial syndrome (22q11.2 deletion syndrome), a genetic disorder caused by a hemizygous microdeletion of chromosome 22q11.2 [22,23,24]. …”

“…Comorbidity of OCD and ADHD has already been reported [for a review, see [21], even from a genetic aspect [22,23,24]. The co-occurrence of the two disorders ADHD and OCD among MMT patients has not yet been reported.…”

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

“…(iv) Two SNPs (rs2073748 and rs2240717) from the ARVCF gene, a gene that is adjacent to COMT and that shares 3′UTR sequence with the long 3′UTR of COMT . These two non-synonymous SNPs cause amino-acid changes in the ARVCF sequence (24) (see Supplement: Table S1). …”