Obsessive–compulsive disorder and a novel polymorphism adjacent to the oestrogen response element (ERE 6) upstream from the COMT gene

Abstract

Family and twin studies have consistently provided evidence for involvement of genetic mechanisms in obsessive-compulsive disorder (OCD). This has given rise to association studies involving several candidate genes in an endeavour to identify susceptibility factors. One of the more promising candidate genes appears to be the catecol-O-methyltransferase (COMT) gene. Recent association studies in North American and Afrikaner populations have reported a likely association between a functional polymorphism of COMT (linked with COMT enzyme activity levels) and OCD. COMT expression has been demonstrated to be regulated by oestrogen through the oestrogen-response elements (EREs) in the promoter region of the gene. In the light of this association, the authors tested for an association between a novel polymorphism (C --> T transition) adjacent to ERE 6 in the promoter area of COMT and OCD in 48 Afrikaners and 48 ethnically matched controls. The C --> T transition was not significantly associated with OCD (P = 0.93) or gender (P = 0.67). These findings, although limited by a small sample size, suggest that the novel polymorphism adjacent to ERE 6 in the promoter area of COMT does not play a major role in the genetic predisposition to OCD.

Gender differences in obsessive-compulsive disorder: a literature review

“…Kinnear et al 64 -The C-T transition adjacent to ERE 6 in the promoter area of COMT and OCD was not significantly associated with OCD (p = 0.93) or gender (p = 0.67) (males n = 45) (females n = 51)…”

“…63 The main controversial point of this study is that plasma levels of COMT do not necessarily reflect what occurs in the CNS, leaving the interpretation of the present results for future studies. Kinnear et al 64 failed to detect statistical significance in their sample stratified by gender when studying the association between a new polymorphism (Cà T transition) in the COMT gene, its levels of enzymatic activity, and the regulation by estrogen through the estrogen responsive elements in the promoter region of this gene in OCD patients. 64 The positive findings are biologically plausible: compared to val-COMT, met-COMT individuals performed less well on tests of task shifting, had an electrophysiological profile indicative of decreased flexibility of prefrontal neural processing, and showed greater amygdala-orbitofrontal connectivity in response to negative emotional stimuli suggestive of inflexible emotional processing.…”

“…Kinnear et al 64 failed to detect statistical significance in their sample stratified by gender when studying the association between a new polymorphism (Cà T transition) in the COMT gene, its levels of enzymatic activity, and the regulation by estrogen through the estrogen responsive elements in the promoter region of this gene in OCD patients. 64 The positive findings are biologically plausible: compared to val-COMT, met-COMT individuals performed less well on tests of task shifting, had an electrophysiological profile indicative of decreased flexibility of prefrontal neural processing, and showed greater amygdala-orbitofrontal connectivity in response to negative emotional stimuli suggestive of inflexible emotional processing. It may be speculated that the stability and relative inflexibility of neural processing associated with met-COMT may become excessive, and thereby render the individual vulnerable to obsessions and compulsions.…”

Psychiatric genetics in South Africa: cutting a rough diamond

“…In line with international research, these studies have predominantly focussed on genes involved in serotoninergic and dopaminergic function. [47][48][49][50][51][52][53][54][55][56][57][58] A summary of genes that have been significantly associated on occasion with OCD and related traits in South African populations can be found in Table III. The serotoninergic genes are believed to be involved in OCD pathogenesis as selective serotonin reuptake inhibitors BD, bipolar disorder; SA, South Africa; SCZ, schizophrenia (SSRIs) effectively treat OCD and form the first-line of pharmacotherapy for the disorder. 59 Genes that have been investigated with regards to OCD in South African populations due to their functional relevance in the serotoninergic system include the serotonin transporter (5-HTT) gene (SLC6A4), two serotonin receptor genes, 5-HT1Db (also known as HTR1B) and 5-HT2A (also known as HTR2A), and the monoamine oxidase A gene (MAO-A).…”

“…number of OCD patients genotyped ranged from 48 to 250). 49,56 Furthermore, some of the significant findings reported in Tables II and III may have been caused by type I error due to multiple testing. …”