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Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Mol Psychiatry. 2016 Feb;21(2):189-197. doi: 10.1038/mp.2015.37. Epub 2015 Apr 14.
To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32,070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.
为了确定导致认知功能两个特定领域正常变异的常见变异，我们对CHARGE（基因组流行病学心脏与衰老研究队列）联盟中无痴呆的老年人进行了一项关于执行功能和信息处理速度的全基因组关联研究（GWAS）。在发现阶段，来自20个队列的5429 - 32070名45岁及以上欧洲血统的受试者可进行神经心理学测试，这些受试者在认知测试时无痴呆和临床中风。我们分析了连线测验A和B部分、字母数字替换测验（LDST）、数字符号替换任务（DSST）、语义和语音流畅性测验以及斯特鲁普颜色和文字测验的表现。在来自20个独立队列的1311 - 21860名受试者中进行了重复验证。在发现队列中，观察到单核苷酸多态性（SNP）rs17518584存在显著关联（发现阶段P值 = 3.12 × 10⁻⁸），在联合发现和重复验证的荟萃分析中（在对年龄、性别和教育程度进行调整后，P值 = 3.28 × 10⁻⁹），该SNP位于基因细胞黏附分子2（CADM2）的一个内含子中，与LDST/DSST的表现相关。Rs17518584位于CADM2基因主要转录本转录起始位点上游约170 kb处，但在一个包含替代第一外显子的变异转录本的内含子内。该变异与扣带回皮质中CADM2的表达相关（P值 = 4 × 10⁻⁴）。CADM2编码的蛋白质参与谷氨酸信号传导（P值 = 7.22 × 10⁻¹⁵）、γ-氨基丁酸（GABA）转运（P值 = 1.36 × 10⁻¹¹）和神经元细胞间黏附（P值 = 1.48 × 10⁻¹³）。我们的研究结果表明，CADM2基因的遗传变异与信息处理速度的个体差异相关。
