School of Psychological Sciences and Monash Institute for Cognitive and Clinical Neurosciences (MICCN), Monash University, Melbourne, VIC, Australia.
Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Transl Psychiatry. 2018 Oct 4;8(1):207. doi: 10.1038/s41398-018-0262-z.
Intra-individual response time variability (IIRTV) is proposed as a viable endophenotype for many psychiatric disorders, particularly attention-deficit hyperactivity disorder (ADHD). Here we assessed whether IIRTV was associated with common DNA variation genome-wide and whether IIRTV mediated the relationship between any associated loci and self-reported ADHD symptoms. A final data set from 857 Australian young adults (489 females and 368 males; M = 22.14 years, SD = 4.82 years) who completed five response time tasks and self-reported symptoms of ADHD using the Conners' Adult ADHD Rating Scale was used. Principal components analysis (PCA) on these response time measures (standard deviation of reaction times and the intra-individual coefficient of variation) produced two variability factors (labelled response selection and selective attention). To understand the genetic drivers of IIRTV we performed a genome-wide association analysis (GWAS) on these PCA-derived indices of IIRTV. For the selective attention variability factor, we identified one single-nucleotide polymorphism (SNP) attaining genome-wide significance; rs62182100 in the HDAC4 gene located on chromosome 2q37. A bootstrapping mediation analysis demonstrated that the selective attention variability factor mediated the relationship between rs62182100 and self-reported ADHD symptoms. Our findings provide the first evidence of a genome-wide significant SNP association with IIRTV and support the potential utility of IIRTV as a valid endophenotype for ADHD symptoms. However, limitations of this study suggest that these observations should be interpreted with caution until replication samples become available.
个体内反应时变异性 (IIRTV) 被提议作为许多精神疾病的可行内表型，特别是注意缺陷多动障碍 (ADHD)。在这里，我们评估了 IIRTV 是否与全基因组常见 DNA 变异相关，以及 IIRTV 是否介导了与任何相关基因座相关的 ADHD 症状的关系。最终的数据来自 857 名澳大利亚年轻人（489 名女性和 368 名男性；M=22.14 岁，SD=4.82 岁），他们完成了五项反应时任务，并使用 Conners' Adult ADHD Rating Scale 报告了 ADHD 症状。对这些反应时测量值（反应时间的标准差和个体内变异系数）进行主成分分析 (PCA)，产生了两个变异性因素（反应选择和选择性注意）。为了了解 IIRTV 的遗传驱动因素，我们对这些 PCA 衍生的 IIRTV 指数进行了全基因组关联分析 (GWAS)。对于选择性注意变异性因素，我们确定了一个达到全基因组显著水平的单核苷酸多态性 (SNP)；位于染色体 2q37 上的 HDAC4 基因中的 rs62182100。bootstrap 中介分析表明，选择性注意变异性因素介导了 rs62182100 与自我报告的 ADHD 症状之间的关系。我们的研究结果首次提供了与 IIRTV 全基因组显著 SNP 关联的证据，并支持 IIRTV 作为 ADHD 症状有效内表型的潜力。然而，这项研究的局限性表明，在复制样本可用之前，这些观察结果应谨慎解释。
