[Show abstract][Hide abstract] ABSTRACT: Existing data suggest a genetic association between the met(158) allele of catechol-O-methyltransferase (COMT) and obsessive-compulsive disorder (OCD). However, the results are inconclusive and complicated by possible gender differences. We sought to resolve the question in two ways. First, we carried out a new case-control study in 87 adults with OCD and 327 healthy comparison subjects. The study replicated reports of an increased met(158) allele frequency in men with OCD (odds ratio (OR)=1.91, 95% confidence interval (CI) 1.07-3.40, P=0.026), with no effect in women (OR=1.13, 95% CI 0.74-1.72, P=0.56). Second, we performed a meta-analysis of all published case-control data (n=1908 subjects). This revealed an association of COMT met(158) with OCD (OR=1.23, 95% CI 1.06-1.42, P=0.005) and an interaction with gender (z=4.27, P<0.0001). The association between COMT met(158) and OCD was present in men (OR=1.88, 95% CI 1.45-2.44, P<0.001) but not in women (OR=0.98, 95% CI 0.78-1.22, P=0.83). We conclude that COMT may play a role in the genetic aetiology of OCD in men. The biological plausibility of the association is increased by the functionality of the val(158)met polymorphism in terms of its effect on COMT enzyme activity, and by the role of COMT in cortical dopamine signalling and information processing. The finding also extends the evidence for sexual dimorphism in COMT and in OCD.
Preview · Article · Jun 2007 · Molecular Psychiatry
[Show abstract][Hide abstract] ABSTRACT: The serotonin 5-HT(2C) receptor (HTR2C) helps regulate appetite and body weight. An HTR2C promoter polymorphism (-759C/T) has been associated with obesity and with weight gain in response to antipsychotic (neuroleptic) drugs. We studied this polymorphism in 120 obese women (BMI > or = 30) and 104 non-obese (BMI < or = 25) women. The C allele was commoner in the obese group (OR = 1.72 [95% CI, 1.13-2.64], P = 0.008). Ninety-five of the obese women participated in a randomized trial of psychological treatments for weight loss. Among these women, heterozygotes lost less weight during the trial than did homozygotes (6.8 vs. 9.7 kg; P = 0.047) and weighed more 6 months (90.1 vs. 83.6 kg; P = 0.006) and 12 months (91.8 vs. 84.6 kg; P = 0.009) later. Heterozygotes also had higher triglyceride levels than homozygotes. C/C subjects in the obesity trial did not differ from T/T subjects in terms of weight loss or triglycerides. In a separate RT-PCR study of 43 subjects, we found that HTR2C mRNA abundance in frontal cortex was unaffected by -759C/T status. Our data extend the evidence that HTR2C promoter variation may be a risk factor for obesity and, perhaps through heterosis, influences weight loss by obese women. Pharmacogenetic testing of HTR2C promoter variants may be valuable when evaluating anti-obesity drugs which act directly or indirectly on the receptor.
Full-text · Article · Apr 2004 · American Journal of Medical Genetics Part B Neuropsychiatric Genetics
[Show abstract][Hide abstract] ABSTRACT: There is a heritable component to suicidal behaviour, encouraging the search for the associated risk alleles. Given the putative role of the 5-HT (5-hydroxytryptamine; serotonin) system in suicidal behaviour, serotonergic genes are leading candidates. In particular, several studies have reported an association with variants in the tryptophan hydroxylase (TPH) gene.
We studied six serotonergic gene polymorphisms in a well-characterized sample of 129 deliberate self-harm subjects and 329 comparison subjects. The polymorphisms were TPH (A779C), 5-HT transporter (5-HTT, LPR S/L), monoamine oxidase A (MAOA G941T), 5-HT1B receptor (HTR1B G861C), 5-HT2A receptor (HTR2A T102C), and 5-HT2C receptor (HTR2C Cys23Ser). Genotyping was done using polymerase chain reaction (PCR)-based assays. The primary analyses compared allele and genotype frequencies between cases and controls. There were a limited number of planned secondary analyses within the deliberate self-harm group.
The TPH A779 allele was more common in deliberate self-harm subjects than in controls (OR 1.38, 95% CI 1.02-1.88; P = 0.03). None of the other polymorphisms was associated with deliberate self-harm. Within the deliberate self-harm group there were no associations with impulsivity, suicide risk, lifetime history of depression, or family history of deliberate self-harm.
Our data extend the evidence that allelic variation in the TPH gene is a risk factor for deliberate self-harm. No evidence was found to implicate the other polymorphisms.
No preview · Article · Aug 2003 · Psychological Medicine
[Show abstract][Hide abstract] ABSTRACT: Disruption of the serotonergic system is suggested to be involved in suicidal behaviour and depression. Results from polymorphism studies have been equivocal in their appraisal of a genetic contribution to this involvement. In the current investigation, the frequencies of the 5-HT2A receptor (T102C) and 5-HT2C receptor (Cys23Ser) polymorphisms were examined in a well-characterised sample of deliberate self-harm (DSH) patients and in healthy controls. DSH patients (n= 144) were recruited from the general hospital in Oxford (UK) as part of the WHO/EURO multicentre study on parasuicide. Interviews were conducted using the European Parasuicide Interview Schedule. Additional psychiatric and personality assessments were carried out using structured interview schedules. Controls (currently n = 265; matched for age, gender and ethnicity) were recruited from local blood donation clinics. Genotyping was performed using PCR-based methods (Marshall et al., 1999. Am J Med Genet. 88; 621-7). Allele frequencies were in Hardy-Weinberg equilibrium. Preliminary Chi-squared (cs) analysis of the 5-HT2A (T102 vs. C102: cs = 0.0) and 5-HT2C (Cys23 vs. Ser23: males-cs = 0.38; females-cs = 0.64) revealed no association between allele frequencies and DSH. Within the DSH group there was no association of allele frequencies with either history of major depression or with a composite score for high suicide risk. These results indicate a lack of association between these polymorphisms and suicidal behaviour.