Zinkstok J, Schmitz N, van Amelsvoort T, Moeton M, Baas F, Linszen D
Department of Psychiatry, Academic Medical Center, University of Amsterdam, The Netherlands.
Genes Brain Behav. 2008 Feb;7(1):61-9. doi: 10.1111/j.1601-183X.2007.00326.x. Epub 2007 May 14.
Haploinsufficiency of 22q11 genes including catechol-O-methyltransferase (COMT) and proline dehydrogenase (PRODH) may result in structural and functional brain abnormalities and increased vulnerability to schizophrenia as observed in patients with microdeletions of 22q11. Thus, COMT and PRODH could be modifier genes for schizophrenia. We examined association of polymorphisms in COMT and PRODH with brain anatomy in young patients with schizophrenia and schizoaffective disorder. We acquired structural magnetic resonance imaging data from 51 male patients and genotyped two single nucleotide polymorphisms (SNPs) in the COMT gene and three in the PRODH gene. Statistical Parametric Mapping software and optimized voxel-based morphometry were used to determine regional gray matter (GM) and white matter (WM) density differences, and total GM and WM volume differences between genotype groups. Two nonsynonymous SNPs in the PRODH gene were associated with bilateral frontal WM density reductions and an SNP in the P2 promoter region of COMT (rs2097603) was associated with GM increase in the right superior temporal gyrus. Furthermore, we found evidence for COMT and PRODH epistasis: in patients with a COMT Val allele (rs4680) and with one or two mutated PRODH alleles, we observed increased WM density in the left inferior frontal lobe. Our results suggest that genetic variation in COMT and PRODH has significant effects on brain regions known to be affected in schizophrenia. Further research is needed to investigate the role of 22q11 genes on brain structure and function and their role in vulnerability for schizophrenia.
包括儿茶酚-O-甲基转移酶（COMT）和脯氨酸脱氢酶（PRODH）在内的22q11基因单倍剂量不足，可能会导致大脑结构和功能异常，并增加患精神分裂症的易感性，正如在22q11微缺失患者中所观察到的那样。因此，COMT和PRODH可能是精神分裂症的修饰基因。我们研究了精神分裂症和分裂情感性障碍年轻患者中COMT和PRODH基因多态性与脑解剖结构的关联。我们获取了51名男性患者的结构磁共振成像数据，并对COMT基因中的两个单核苷酸多态性（SNP）和PRODH基因中的三个SNP进行了基因分型。使用统计参数映射软件和优化的基于体素的形态测量法，来确定基因型组之间的区域灰质（GM）和白质（WM）密度差异，以及总GM和WM体积差异。PRODH基因中的两个非同义SNP与双侧额叶WM密度降低相关，而COMT基因P2启动子区域的一个SNP（rs2097603）与右侧颞上回GM增加相关。此外，我们发现了COMT和PRODH基因上位性的证据：在携带COMT Val等位基因（rs4680）且有一个或两个PRODH突变等位基因的患者中，我们观察到左下额叶WM密度增加。我们的结果表明，COMT和PRODH的基因变异对已知在精神分裂症中受影响的脑区有显著影响。需要进一步研究来调查22q11基因在脑结构和功能上的作用，以及它们在精神分裂症易感性中的作用。
