Association of MB-COMT polymorphisms with schizophrenia-susceptibility and symptom severity in an African cohort

• Published in: Progress in neuro-psychopharmacology & biological psychiatry Vol. 39; no. 1; pp. 163 - 169
• Main Authors: Wright, Galen E.B., Niehaus, Dana J.H., van der Merwe, Lize, Koen, Liezl, Korkie, Lundi J., Kinnear, Craig J., Drögemöller, Britt I., Warnich, Louise
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.10.2012; Elsevier
• Subjects: Adult; Adult and adolescent clinical studies; African Continental Ancestry Group - genetics; African population; Alleles; Biological and medical sciences; Brain; Case-Control Studies; Catechol O-methyltransferase; Catechol O-Methyltransferase - genetics; Cell Line; Dopamine; Enzymes; Female; Genetic Association Studies - methods; Genetic Association Studies - statistics & numerical data; Genetic Predisposition to Disease - genetics; genomics; Genotype; Haplotypes; Humans; Isoenzymes - genetics; Male; MB-COMT; Medical sciences; Membrane Proteins - genetics; Mental disorders; Negative symptoms; Neuropharmacology; Pharmacology. Drug treatments; Polymorphism, Single Nucleotide - genetics; Promoter Regions, Genetic - genetics; Psychiatric Status Rating Scales - statistics & numerical data; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychoses; Schizophrenia; Schizophrenia - diagnosis; Schizophrenia - genetics; Symptom Assessment - methods; Symptom Assessment - statistics & numerical data; Xhosa; Val; A; DSM-IV; C; LQ; G; Schizophrenia; COMT; bp; SNP; T; HWE; kb; 22qDS; UQ; gDNA; OR; Xhosa; CI; n; OCD; S-COMT; MB-COMT; Negative symptoms; SANS; DNA; SAPS; LD; African population; Met; PCR; Enzyme; Transferases; Catechol O-methyltransferase; African; Psychosis; Symptomatology; Sensitivity; Methyltransferases; Negative symptom; Severity score; Public health; Polymorphism
• ISSN: 0278-5846; 1878-4216
• DOI: 10.1016/j.pnpbp.2012.06.006

The catechol-O-methyltransferase (COMT) gene is an attractive schizophrenia candidate gene, encoding a catabolic dopamine enzyme. The enzyme exists as two distinct isoforms, with the membrane bound enzyme (i.e. MB-COMT) being predominantly expressed in the brain. Since African populations remain underrepresented in genetic/genomic research, we performed an association study to determine whether MB-COMT genetic variants are associated with schizophrenia-susceptibility and symptom severity in the South African Xhosa population. Fourteen candidate polymorphisms were selected by means of a literature search and in silico analyses and were subsequently genotyped in a cohort of 238 Xhosa schizophrenia patients and 240 healthy Xhosa controls. Genetic association was tested with schizophrenia-susceptibility as well as symptom severity within the patient group. Polymorphisms of interest were also analysed using functional assays. Two SNPs, rs2020917 (OR=0.54, 95% CI 0.37–0.79; P=0.0011) and rs737865 (OR=0.52, 95% CI 0.36–0.74; P=0.0002), in the P2 promoter region were significantly associated with schizophrenia as well as an increase (increase=11.2%, 95% CI 3.7%–19.2%; P=0.0031) in reporter gene expression. The minor alleles of these SNPs were underrepresented in the schizophrenia cohort, indicating a possible protective effect. The P2 region also formed part of a haplotype found to be associated with the severity of the negative symptoms of the disorder. The data generated by this study indicate that genetic variation of MB-COMT could be associated with schizophrenia and negative symptom severity in the Xhosa population and may therefore be one of the genomic loci contributing towards the disorder in the South African community. Future large-scale studies in other African schizophrenia populations are required to further elucidate the significance of these findings. ► Two MB-COMT SNPs were associated with schizophrenia in an African cohort. ► Functional assays indicate that this variation effects P2 mediated gene expression. ► Exploratory analyses revealed associations of MB-COMT with the negative symptoms. ► African patients should be adequately represented in psychiatric genetic studies.