Attention deficit hyperactivity disorder (ADHD) is a complex disorder with heterogeneous clinical presentations that manifest variability in long-term outcomes. The genetic contributions to this clinical heterogeneity, however, are not well understood. Here, we study 14 084 individuals diagnosed with ADHD to identify several genetic factors underlying clinical heterogeneity. One genome-wide significant locus was specifically associated with an autism spectrum disorder (ASD) diagnosis among individuals diagnosed with ADHD and it was not previously associated with ASD nor ADHD, individually. We used a novel approach to compare profiles of polygenic scores for groups of individuals diagnosed with ADHD and uncovered robust evidence that biology is an important factor in on-going clinical debates. Specifically, individuals diagnosed with ASD and ADHD, substance use disorder (SUD) and ADHD, or first diagnosed with ADHD in adulthood had different profiles of polygenic scores for ADHD and multiple other psychiatric, cognitive, and socio-behavioral traits. A polygene overlap between an ASD diagnosis in ADHD and cognitive performance was replicated in an independent, typically developing cohort. Our unique approach uncovered evidence of genetic heterogeneity in a widely studied complex disorder, allowing for timely contributions to the understanding of ADHD etiology and providing a model for similar studies of other disorders.

中文翻译：

---

多基因谱定义了 ADHD 临床异质性的各个方面

注意缺陷多动障碍 (ADHD) 是一种复杂的疾病，具有异质的临床表现，其长期结果表现出变异性。然而，对这种临床异质性的遗传贡献尚不清楚。在这里，我们研究了 14 084 名被诊断患有多动症的个体，以确定临床异质性背后的几个遗传因素。一个全基因组显着位点与被诊断患有 ADHD 的个体中的自闭症谱系障碍 (ASD) 诊断特别相关，并且之前单独与 ASD 或 ADHD 无关。我们使用了一种新方法来比较被诊断患有 ADHD 的人群的多基因评分概况，并发现了强有力的证据，表明生物学是正在进行的临床辩论中的一个重要因素。具体来说，被诊断为 ASD 和 ADHD 的个体，物质使用障碍 (SUD) 和 ADHD，或在成年时首次被诊断为 ADHD，在 ADHD 和多种其他精神、认知和社会行为特征的多基因评分方面具有不同的特征。ADHD 中的 ASD 诊断与认知能力之间的多基因重叠在一个独立的、典型的发展队列中被复制。我们独特的方法揭示了广泛研究的复杂疾病中遗传异质性的证据，从而有助于及时了解 ADHD 病因，并为其他疾病的类似研究提供模型。ADHD 中的 ASD 诊断与认知能力之间的多基因重叠在一个独立的、典型的发展队列中被复制。我们独特的方法揭示了广泛研究的复杂疾病中遗传异质性的证据，从而有助于及时了解 ADHD 病因，并为其他疾病的类似研究提供模型。ADHD 中的 ASD 诊断与认知能力之间的多基因重叠在一个独立的、典型的发展队列中被复制。我们独特的方法揭示了广泛研究的复杂疾病中遗传异质性的证据，从而有助于及时了解 ADHD 病因，并为其他疾病的类似研究提供模型。