Dorval K M, Wigg K G, Crosbie J, Tannock R, Kennedy J L, Ickowicz A, Pathare T, Malone M, Schachar R, Barr C L
Cell and Molecular Biology Division, Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada.
Genes Brain Behav. 2007 Jul;6(5):444-52. doi: 10.1111/j.1601-183X.2006.00273.x. Epub 2006 Sep 8.
The glutamatergic signaling pathway represents an ideal candidate susceptibility system for attention-deficit/hyperactivity disorder (ADHD). Disruption of specific N-methyl-D-aspartate-type glutamate receptor subunit genes (GRIN1, 2A-D) in mice leads to significant alterations in cognitive and/or locomotor behavior including impairments in latent learning, spatial memory tasks and hyperactivity. Here, we tested for association of GRIN2B variants with ADHD, by genotyping nine single nucleotide polymorphisms (SNPs) in 205 nuclear families identified through probands with ADHD. Transmission of alleles from heterozygous parents to affected offspring was examined using the transmission/disequilibrium test. Quantitative trait analyses for the ADHD symptom dimensions [inattentive (IA) and hyperactive/impulsive (HI)] and cognitive measures of verbal working memory and verbal short-term memory were performed using the fbat program. Three SNPs showed significantly biased transmission (P < 0.05), with the strongest evidence of association found for rs2,284,411 (chi(2)= 7.903, 1 degree of freedom, P= 0.005). Quantitative trait analyses showed associations of these markers with both the IA and the HI symptom dimensions of ADHD but not with the cognitive measures of verbal short-term memory or verbal working memory. Our data suggest an association between variations in the GRIN2B subunit gene and ADHD as measured categorically or as a quantitatively distributed trait.
谷氨酸能信号通路是注意缺陷多动障碍（ADHD）理想的候选易感性系统。小鼠中特定的N-甲基-D-天冬氨酸型谷氨酸受体亚基基因（GRIN1、2A-D）的破坏会导致认知和/或运动行为的显著改变，包括潜在学习、空间记忆任务受损和多动。在此，我们通过对205个通过ADHD先证者确定的核心家庭中的9个单核苷酸多态性（SNP）进行基因分型，来检测GRIN2B变异与ADHD的关联。使用传递/不平衡检验来检查等位基因从杂合子父母向受影响后代的传递。使用fbat程序对ADHD症状维度[注意力不集中（IA）和多动/冲动（HI）]以及言语工作记忆和言语短期记忆的认知指标进行数量性状分析。三个SNP显示出显著的偏向性传递（P < 0.05），其中rs2,284,411的关联证据最强（卡方 = 7.903，1个自由度，P = 0.005）。数量性状分析表明，这些标记与ADHD的IA和HI症状维度均相关，但与言语短期记忆或言语工作记忆的认知指标无关。我们的数据表明，GRIN2B亚基基因的变异与ADHD之间存在关联，ADHD可按分类或作为定量分布性状来衡量。
