Department of Genetics, Stellenbosch University, Private Bag X1, Matieland 7602, South Africa.
Prog Neuropsychopharmacol Biol Psychiatry. 2012 Oct 1;39(1):163-9. doi: 10.1016/j.pnpbp.2012.06.006. Epub 2012 Jun 13.
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.
儿茶酚氧位甲基转移酶（COMT）基因是一个有吸引力的精神分裂症候选基因，编码一种代谢多巴胺的酶。该酶存在两种不同的同工型，其中膜结合酶（即 MB-COMT）主要在大脑中表达。由于非洲人群在遗传/基因组研究中仍然代表性不足，我们进行了一项关联研究，以确定 MB-COMT 遗传变异是否与南非科萨人群的精神分裂症易感性和症状严重程度相关。通过文献检索和计算机分析选择了 14 个候选多态性，并随后在 238 名科萨精神分裂症患者和 240 名健康科萨对照者的队列中进行了基因分型。用精神分裂症易感性和患者组内的症状严重程度来测试遗传关联。还使用功能测定分析了感兴趣的多态性。P2 启动子区域的两个 SNP，rs2020917（OR=0.54，95%CI 0.37-0.79；P=0.0011）和 rs737865（OR=0.52，95%CI 0.36-0.74；P=0.0002），与精神分裂症以及报告基因表达增加（增加=11.2%，95%CI 3.7%-19.2%；P=0.0031）显著相关。这些 SNP 的次要等位基因在精神分裂症队列中代表性不足，表明可能存在保护作用。P2 区域也是与该疾病的阴性症状严重程度相关的单倍型的一部分。本研究产生的数据表明，MB-COMT 的遗传变异可能与科萨人群的精神分裂症和阴性症状严重程度相关，因此可能是导致南非社区该疾病的基因组位点之一。需要在其他非洲精神分裂症人群中进行大规模的未来研究，以进一步阐明这些发现的意义。
