Howard David M, Adams Mark J, Clarke Toni-Kim, Wigmore Eleanor M, Zeng Yanni, Hagenaars Saskia P, Lyall Donald M, Thomson Pippa A, Evans Kathryn L, Porteous David J, Nagy Reka, Hayward Caroline, Haley Chris S, Smith Blair H, Murray Alison D, Batty G David, Deary Ian J, McIntosh Andrew M
Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK.
Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
Wellcome Open Res. 2017 Aug 10;2:61. doi: 10.12688/wellcomeopenres.12171.1. eCollection 2017.
Cognitive ability is a heritable trait with a polygenic architecture, for which several associated variants have been identified using genotype-based and candidate gene approaches. Haplotype-based analyses are a complementary technique that take phased genotype data into account, and potentially provide greater statistical power to detect lower frequency variants.
In the present analysis, three cohort studies (n = 48,002) were utilised: Generation Scotland: Scottish Family Health Study (GS:SFHS), the English Longitudinal Study of Ageing (ELSA), and the UK Biobank. A genome-wide haplotype-based meta-analysis of cognitive ability was performed, as well as a targeted meta-analysis of several gene coding regions.
None of the assessed haplotypes provided evidence of a statistically significant association with cognitive ability in either the individual cohorts or the meta-analysis. Within the meta-analysis, the haplotype with the lowest observed -value overlapped with the D-amino acid oxidase activator ( ) gene coding region. This coding region has previously been associated with bipolar disorder, schizophrenia and Alzheimer's disease, which have all been shown to impact upon cognitive ability. Another potentially interesting region highlighted within the current genome-wide association analysis (GS:SFHS: = 4.09 x 10 ), was the butyrylcholinesterase ( ) gene coding region. The protein encoded by has been shown to influence the progression of Alzheimer's disease and its role in cognitive ability merits further investigation.
Although no evidence was found for any haplotypes with a statistically significant association with cognitive ability, our results did provide further evidence that the genetic variants contributing to the variance of cognitive ability are likely to be of small effect.
认知能力是一种具有多基因结构的可遗传性状，已经使用基于基因型和候选基因的方法鉴定出了几种与之相关的变异。基于单倍型的分析是一种补充技术，它考虑了分阶段的基因型数据，并有可能提供更大的统计能力来检测低频变异。
在本分析中，使用了三项队列研究（n = 48,002）：苏格兰世代研究：苏格兰家庭健康研究（GS:SFHS）、英国老龄化纵向研究（ELSA）和英国生物银行。对认知能力进行了全基因组基于单倍型的荟萃分析，以及对几个基因编码区域的靶向荟萃分析。
在个体队列或荟萃分析中，所评估的单倍型均未提供与认知能力有统计学显著关联的证据。在荟萃分析中，观察到的P值最低的单倍型与D-氨基酸氧化酶激活剂（DAAO）基因编码区域重叠。该编码区域先前已与双相情感障碍、精神分裂症和阿尔茨海默病相关，这些疾病均已显示会影响认知能力。在当前全基因组关联分析中突出显示的另一个潜在有趣区域（GS:SFHS：P = 4.09 x 10⁻⁵）是丁酰胆碱酯酶（BCHE）基因编码区域。已证明由BCHE编码的蛋白质会影响阿尔茨海默病的进展，其在认知能力中的作用值得进一步研究。
尽管未发现任何单倍型与认知能力有统计学显著关联的证据，但我们的结果确实提供了进一步的证据，表明导致认知能力差异的遗传变异可能影响较小。
