Warrier Varun, Chee Vivienne, Smith Paula, Chakrabarti Bhismadev, Baron-Cohen Simon
Autism Research Centre, Department of Psychiatry, University of Cambridge, Douglas House, 18B Trumpington Road, Cambridge, CB2 8AH UK.
Centre for Integrative Neuroscience and Neurodynamics, School of Psychology and Clinical Language Sciences, University of Reading, Reading, UK.
Mol Autism. 2015 Aug 28;6:49. doi: 10.1186/s13229-015-0041-0. eCollection 2015.
Autism spectrum conditions (ASC) are a group of neurodevelopmental conditions characterized by difficulties in social interaction and communication alongside repetitive and stereotyped behaviours. ASC are heritable, and common genetic variants contribute substantial phenotypic variability. More than 600 genes have been implicated in ASC to date. However, a comprehensive investigation of candidate gene association studies in ASC is lacking.
In this study, we systematically reviewed the literature for association studies for 552 genes associated with ASC. We identified 58 common genetic variants in 27 genes that have been investigated in three or more independent cohorts and conducted a meta-analysis for 55 of these variants. We investigated publication bias and sensitivity and performed stratified analyses for a subset of these variants.
We identified 15 variants nominally significant for the mean effect size, 8 of which had P values below a threshold of significance of 0.01. Of these 15 variants, 11 were re-investigated for effect sizes and significance in the larger Psychiatric Genomics Consortium dataset, and none of them were significant. Effect direction for 8 of the 11 variants were concordant between both the datasets, although the correlation between the effect sizes from the two datasets was poor and non-significant.
This is the first study to comprehensively examine common variants in candidate genes for ASC through meta-analysis. While for majority of the variants, the total sample size was above 500 cases and 500 controls, the total sample size was not large enough to accurately identify common variants that contribute to the aetiology of ASC.
自闭症谱系障碍（ASC）是一组神经发育障碍，其特征是社交互动和沟通困难，同时伴有重复和刻板行为。ASC具有遗传性，常见的基因变异会导致显著的表型变异。迄今为止，已有600多个基因与ASC有关。然而，目前缺乏对ASC候选基因关联研究的全面调查。
在本研究中，我们系统地回顾了与ASC相关的552个基因的关联研究文献。我们在27个基因中鉴定出58个常见的基因变异，这些基因已在三个或更多独立队列中进行了研究，并对其中5个变异进行了荟萃分析。我们调查了发表偏倚和敏感性，并对这些变异的一个子集进行了分层分析。
我们鉴定出15个变异在平均效应大小方面具有名义上的显著性，其中8个变异的P值低于0.01的显著性阈值。在这15个变异中，有11个在更大的精神基因组学联盟数据集中重新研究了效应大小和显著性，结果均不显著。在这11个变异中，有8个变异在两个数据集中的效应方向一致，尽管两个数据集的效应大小之间的相关性较差且无显著性。
这是第一项通过荟萃分析全面研究ASC候选基因常见变异的研究。虽然大多数变异的总样本量超过500例病例和500例对照，但总样本量仍不足以准确识别导致ASC病因的常见变异。
