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1] Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK [2] Department of Psychology, University of Edinburgh, Edinburgh, UK.
School of Mathematics and Statistics, University of Sydney, Sydney, NSW, Australia.
Mol Psychiatry. 2015 Feb;20(2):183-92. doi: 10.1038/mp.2014.188. Epub 2015 Feb 3.
General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53,949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10(-9), MIR2113; rs17522122, P=2.55 × 10(-8), AKAP6; rs10119, P=5.67 × 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.
从青春期到老年，一般认知功能在整个人类生命历程中都具有显著的遗传性。我们研究了中年及老年人群中这种与健康和幸福相关的重要性状变异的遗传贡献。我们对31个队列（N = 53,949）的全基因组关联研究进行了荟萃分析，这些队列中的参与者进行了多种不同的认知测试。通过主成分分析在每个队列中检测并创建了一个一般认知功能表型。我们在三个基因组区域6q16.1、14q12和19q13.32中报告了13个全基因组显著的单核苷酸多态性（SNP）关联（最佳SNP和最接近的基因分别为：rs10457441，P = 3.93×10^(-9)，MIR2113；rs17522122，P = 2.55×10^(-8)，AKAP6；rs10119，P = 5.67×10^(-9)，APOE/TOMM40）。我们报告了一个基于基因的与位于21号染色体上的HMGN1基因的显著关联（P = 1×10^(-6)）。这些基因先前已与神经精神表型相关联。荟萃分析结果与多基因遗传模型一致。为了估计基于SNP的遗传力，将全基因组复杂性状分析程序应用于两个大型队列，即社区动脉粥样硬化风险研究（N = 6617）和健康与退休研究（N = 5976）。所有基因分型的常见SNP所解释的表型变异比例分别为29%（标准误 = 5%）和28%（标准误 = 7%）。使用多基因预测分析，在苏格兰一代队列（N = 5487；P = 1.5×10^(-17)）中预测了一般认知功能中约1.2%的变异。在假设驱动的测试中，一般认知功能与先前与阿尔茨海默病相关的四个基因TOMM40、APOE、ABCG1和MEF2C之间存在显著关联。
