Sanders A R, Rusu I, Duan J, Vander Molen J E, Hou C, Schwab S G, Wildenauer D B, Martinez M, Gejman P V
Department of Psychiatry and Behavioral Sciences, Evanston Northwestern Healthcare Research Institute, Center for Psychiatric Genetics, Northwestern University, Evanston, IL 60201, USA.
Mol Psychiatry. 2005 Apr;10(4):353-65. doi: 10.1038/sj.mp.4001586.
Catechol-O-methyltransferase (COMT) has been implicated in schizophrenia by its function through its roles in monoamine neurotransmitter metabolism and its impact on prefrontal cognition, and also by its position through linkage scans and a strong cytogenetic association. Further support comes from association studies, especially family-based ones examining the COMT variant, Val(108/158)Met. We have studied eight markers spanning COMT and including portions of the two immediately adjacent genes, thioredoxin reductase 2 and armadillo repeat deleted in velocardiofacial syndrome (ARVCF), using association testing in 136 schizophrenia families. We found nominal evidence for association of illness to rs165849 (P=0.051) in ARVCF, and a stronger signal (global P=0.0019-0.0036) from three-marker haplotypes spanning the 3' portions of COMT and ARVCF, including Val(108/158)Met with Val(108/158) being the overtransmitted allele, consistent with previous studies. We also find Val(108/158)Met to be in linkage disequilibrium with the markers in ARVCF. These findings support previous association signals of schizophrenia to COMT markers, and suggest that ARVCF might contribute to this signal. ARVCF, a member of the catenin family, besides being a positional candidate, is also one due to its function, that is, its potential role in neurodevelopment, which is implicated in schizophrenia pathogenesis by several lines of evidence.
儿茶酚-O-甲基转移酶（COMT）因其在单胺神经递质代谢中的作用及其对前额叶认知的影响所发挥的功能，以及通过连锁扫描和强大的细胞遗传学关联所确定的位置，而与精神分裂症存在关联。关联研究进一步提供了支持，尤其是基于家系的研究对COMT变体Val（108/158）Met进行了检测。我们在136个精神分裂症家系中进行关联测试，研究了跨越COMT的8个标记，包括紧邻的两个基因硫氧还蛋白还原酶2和腭心面综合征（VCFS）缺失的犰狳重复序列（ARVCF）的部分区域。我们发现疾病与ARVCF中的rs165849存在名义上的关联证据（P = 0.051），并且从跨越COMT和ARVCF 3'部分的三标记单倍型中得到了更强的信号（全局P = 0.0019 - 0.0036），其中包括Val（108/158）Met，Val（108/158）为过度传递的等位基因，这与先前的研究一致。我们还发现Val（108/158）Met与ARVCF中的标记处于连锁不平衡状态。这些发现支持了先前精神分裂症与COMT标记的关联信号，并表明ARVCF可能对该信号有贡献。ARVCF是连环蛋白家族的成员，除了是一个定位候选基因外，因其功能，即其在神经发育中的潜在作用，也成为一个候选基因，多条证据表明神经发育与精神分裂症发病机制有关。
