OBJECTIVE Although attention deficit hyperactivity disorder (ADHD) is highly heritable, genome-wide association studies (GWAS) have not yet identified any common genetic variants that contribute to risk. There is evidence that aggression or conduct disorder in children with ADHD indexes higher genetic loading and clinical severity. The authors examine whether common genetic variants considered en masse as polygenic scores for ADHD are especially enriched in children with comorbid conduct disorder. METHOD Polygenic scores derived from an ADHD GWAS meta-analysis were calculated in an independent ADHD sample (452 case subjects, 5,081 comparison subjects). Multivariate logistic regression analyses were employed to compare polygenic scores in the ADHD and comparison groups and test for higher scores in ADHD case subjects with comorbid conduct disorder relative to comparison subjects and relative to those without comorbid conduct disorder. Association with symptom scores was tested using linear regression. RESULTS Polygenic risk for ADHD, derived from the meta-analysis, was higher in the independent ADHD group than in the comparison group. Polygenic score was significantly higher in ADHD case subjects with conduct disorder relative to ADHD case subjects without conduct disorder. ADHD polygenic score showed significant association with comorbid conduct disorder symptoms. This relationship was explained by the aggression items. CONCLUSIONS Common genetic variation is relevant to ADHD, especially in individuals with comorbid aggression. The findings suggest that the previously published ADHD GWAS meta-analysis contains weak but true associations with common variants, support for which falls below genome-wide significance levels. The findings also highlight the fact that aggression in ADHD indexes genetic as well as clinical severity.

译文

目的尽管注意力缺陷多动障碍 (ADHD) 是高度可遗传的,但全基因组关联研究 (GWAS) 尚未发现任何导致风险的常见遗传变异。有证据表明,患有ADHD的儿童攻击或行为障碍指数更高的遗传负荷和临床严重程度。作者研究了在患有合并症行为障碍的儿童中,被视为多基因多基因评分的常见遗传变异是否特别丰富。方法在独立的ADHD样本 (452例受试者,5,081例比较受试者) 中计算来自ADHD GWAS荟萃分析的多基因得分。采用多变量logistic回归分析来比较ADHD和比较组的多基因得分,并测试相对于比较受试者和相对于没有合并症行为障碍的ADHD病例受试者的更高得分。使用线性回归测试与症状评分的相关性。结果meta分析得出的ADHD多基因风险在独立ADHD组高于对照组。与没有行为障碍的ADHD病例相比,有行为障碍的ADHD病例受试者的多基因得分明显更高。ADHD多基因评分显示与合并症行为障碍症状显着相关。攻击项目解释了这种关系。结论常见的遗传变异与多动症有关,尤其是在合并攻击的个体中。研究结果表明,先前发表的ADHD GWAS荟萃分析包含与常见变体的弱但真实的关联,对它们的支持低于全基因组显着性水平。研究结果还强调了一个事实,即ADHD攻击指标是遗传和临床严重程度。

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