Department of Biological Sciences, Purdue University, West Lafayette, Indiana.
Psychiatric and Neurodevelopmental Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; Department of Psychiatry, Harvard Medical School, Boston, Massachusetts.
Biol Psychiatry. 2021 Sep 1;90(5):317-327. doi: 10.1016/j.biopsych.2020.12.028. Epub 2021 Jan 8.
Tourette syndrome (TS) is often found comorbid with other neurodevelopmental disorders across the impulsivity-compulsivity spectrum, with attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) as most prevalent. This points to the possibility of a common etiological thread along an impulsivity-compulsivity continuum.
Investigating the shared genetic basis across TS, ADHD, ASD, and OCD, we undertook an evaluation of cross-disorder genetic architecture and systematic meta-analysis, integrating summary statistics from the latest genome-wide association studies (93,294 individuals, 6,788,510 markers).
As previously identified, a common unifying factor connects TS, ADHD, and ASD, while TS and OCD show the highest genetic correlation in pairwise testing among these disorders. Thanks to a more homogeneous set of disorders and a targeted approach that is guided by genetic correlations, we were able to identify multiple novel hits and regions that seem to play a pleiotropic role for the specific disorders analyzed here and could not be identified through previous studies. In the TS-ADHD-ASD genome-wide association study single nucleotide polymorphism-based and gene-based meta-analysis, we uncovered 13 genome-wide significant regions that host single nucleotide polymorphisms with a high posterior probability for association with all three studied disorders (m-value > 0.9), 11 of which were not identified in previous cross-disorder analysis. In contrast, we also identified two additional pleiotropic regions in the TS-OCD meta-analysis. Through conditional analysis, we highlighted genes and genetic regions that play a specific role in a TS-ADHD-ASD genetic factor versus TS-OCD. Cross-disorder tissue specificity analysis implicated the hypothalamus-pituitary-adrenal gland axis in TS-ADHD-ASD.
Our work underlines the value of redefining the framework for research across traditional diagnostic categories.
抽动秽语综合征（TS）常与冲动-强迫谱系中的其他神经发育障碍共病，其中注意力缺陷/多动障碍（ADHD）、自闭症谱系障碍（ASD）和强迫症（OCD）最为常见。这表明沿着冲动-强迫连续体存在共同的病因线索。
为了研究 TS、ADHD、ASD 和 OCD 之间的共同遗传基础，我们评估了跨疾病的遗传结构并进行了系统的荟萃分析，整合了来自最新全基因组关联研究的汇总统计数据（93294 人，6788510 个标记）。
如前所述，一个共同的统一因素将 TS、ADHD 和 ASD 联系在一起，而在这些疾病中，TS 和 OCD 在两两测试中显示出最高的遗传相关性。由于一组更同质的疾病和受遗传相关性指导的靶向方法，我们能够识别出多个新的关联和区域，这些区域似乎对这里分析的特定疾病具有多效性作用，而以前的研究无法识别这些关联和区域。在 TS-ADHD-ASD 全基因组关联研究基于单核苷酸多态性和基于基因的荟萃分析中，我们发现了 13 个全基因组显著区域，这些区域包含与所有三种研究疾病高度相关的单核苷酸多态性（m 值>0.9），其中 11 个区域在以前的跨疾病分析中未被识别。相比之下，我们还在 TS-OCD 荟萃分析中发现了另外两个多效性区域。通过条件分析，我们突出了在 TS-ADHD-ASD 遗传因素中发挥特定作用的基因和遗传区域与 TS-OCD 相比。跨疾病组织特异性分析表明，下丘脑-垂体-肾上腺轴在 TS-ADHD-ASD 中起作用。
我们的工作强调了重新定义跨越传统诊断类别的研究框架的价值。
