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 × 10-7) 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 (r2 = - 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.

中文翻译：

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STXBP5-AS1基因在成人ADHD症状中的潜在作用。

我们旨在检测成年人的注意力缺陷/多动症（ADHD）风险赋予基因。在儿童中，多动症的特征是注意力不集中和/或冲动过度的年龄水平，并可能持续到成年。儿童和成人多动症是可遗传的，并且被认为代表了一般人群中多动症症状持续分布的临床极端情况。我们旨在利用基因型成年人中定量ADHD症状研究的力量。在SAGA（成人ADHD特质遗传研究）联盟中，我们估计了基于单核苷酸多态性（SNP）的遗传力，可自我报告量化的ADHD症状，并在9个成人人群中进行了全基因组关联荟萃分析和仅针对成年人的队列。共计n = 14,689个人。在两个SAGA队列中，我们发现自评多动症症状评分的基于SNP的显着遗传力分别为15％（n = 3656）和30％（n = 1841）。在长的非编码RNA基因STXBP5-AS1中，进行了全基因组荟萃分析（SNP rs12661753； p值= 3.02×10-7）的最高记录。在来自早期遗传和生命过程流行病学（EAGLE）ADHD联盟（n = 14,776）的八个以人群为基础的儿科队列的儿童ADHD症状评分的荟萃分析中也观察到这种关联。SAGA和EAGLE数据的全基因组荟萃分析（n = 29,465）提高了与SNP rs12661753关联的强度。在人HEK293细胞中，STXBP5-AS1的表达增强了STXBP5的报告基因构建体的表达，该基因已知与“ SNAP”（可溶性NSF附着蛋白）受体有关。（SNARE）复杂的形成。在具有不同冲动水平的小鼠品系中，直系同源物Gm28905的小鼠前额叶皮层中的转录水平与运动冲动呈极显着负相关，如在五种选择的连续反应时间任务中测得的（r2 =-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，并指出了与ADHD相关冲动水平有关的除反义RNA抑制以外的可能的生物学机制。