Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Route 855, Postbus 9101, 6500 HB, Nijmegen, The Netherlands.
Behav Genet. 2019 May;49(3):270-285. doi: 10.1007/s10519-018-09947-2. Epub 2019 Jan 18.
We aimed to detect Attention-deficit/hyperactivity (ADHD) risk-conferring genes in adults. In children, ADHD is characterized by age-inappropriate levels of inattention and/or hyperactivity-impulsivity and may persists into adulthood. Childhood and adulthood ADHD are heritable, and are thought to represent the clinical extreme of a continuous distribution of ADHD symptoms in the general population. We aimed to leverage the power of studies of quantitative ADHD symptoms in adults who were genotyped. Within the SAGA (Study of ADHD trait genetics in adults) consortium, we estimated the single nucleotide polymorphism (SNP)-based heritability of quantitative self-reported ADHD symptoms and carried out a genome-wide association meta-analysis in nine adult population-based and case-only cohorts of adults. A total of n = 14,689 individuals were included. In two of the SAGA cohorts we found a significant SNP-based heritability for self-rated ADHD symptom scores of respectively 15% (n = 3656) and 30% (n = 1841). The top hit of the genome-wide meta-analysis (SNP rs12661753; p-value = 3.02 × 10) was present in the long non-coding RNA gene STXBP5-AS1. This association was also observed in a meta-analysis of childhood ADHD symptom scores in eight population-based pediatric cohorts from the Early Genetics and Lifecourse Epidemiology (EAGLE) ADHD consortium (n = 14,776). Genome-wide meta-analysis of the SAGA and EAGLE data (n = 29,465) increased the strength of the association with the SNP rs12661753. In human HEK293 cells, expression of STXBP5-AS1 enhanced the expression of a reporter construct of STXBP5, a gene known to be involved in "SNAP" (Soluble NSF attachment protein) Receptor" (SNARE) complex formation. In mouse strains featuring different levels of impulsivity, transcript levels in the prefrontal cortex of the mouse ortholog Gm28905 strongly correlated negatively with motor impulsivity as measured in the five choice serial reaction time task (r = - 0.61; p = 0.004). Our results are consistent with an effect of the STXBP5-AS1 gene on ADHD symptom scores distribution and point to a possible biological mechanism, other than antisense RNA inhibition, involved in ADHD-related impulsivity levels.
我们旨在检测成人注意力缺陷/多动障碍（ADHD）风险相关基因。在儿童中，ADHD 的特征是注意力不集中和/或多动冲动的年龄不适当水平，并且可能持续到成年。儿童和成年 ADHD 是可遗传的，被认为代表了一般人群中 ADHD 症状的连续分布的临床极端。我们旨在利用在已基因分型的成人中研究定量 ADHD 症状的力量。在 SAGA（成人 ADHD 特质遗传学研究）联盟内，我们估计了定量自我报告 ADHD 症状的基于单核苷酸多态性（SNP）的遗传率，并在九个成人基于人群和仅病例的成人队列中进行了全基因组关联荟萃分析。总共纳入了 n = 14689 个人。在 SAGA 两个队列中，我们发现自我评定 ADHD 症状评分的基于 SNP 的遗传率分别为 15%（n = 3656）和 30%（n = 1841）。全基因组荟萃分析的主要命中（SNP rs12661753；p 值 = 3.02×10）存在于长非编码 RNA 基因 STXBP5-AS1 中。该关联也在来自早期遗传学和生命历程流行病学（EAGLE）ADHD 联盟的八个基于人群的儿科队列的儿童 ADHD 症状评分荟萃分析中观察到（n = 14776）。SAGA 和 EAGLE 数据的全基因组荟萃分析（n = 29465）增加了与 SNP rs12661753 的关联强度。在人类 HEK293 细胞中，STXBP5-AS1 的表达增强了已知参与“SNAP”（可溶性 NSF 附着蛋白）受体”（SNARE）复合物形成的 STXBP5 报告基因构建体的表达。在具有不同冲动水平的小鼠品系中，鼠标同源物 Gm28905 的前额叶皮层中的转录水平与在五项选择连续反应时间任务中测量的运动冲动性呈强烈负相关（r = -0.61；p = 0.004）。我们的结果与 STXBP5-AS1 基因对 ADHD 症状评分分布的影响一致，并指出了除反义 RNA 抑制以外可能涉及 ADHD 相关冲动水平的生物学机制。
