Investigating Shared Genetic Basis Across Tourette Syndrome and Comorbid Neurodevelopmental Disorders Along the Impulsivity-Compulsivity Spectrum.
Investigating Shared Genetic Basis Across Tourette Syndrome and Comorbid Neurodevelopmental Disorders Along the Impulsivity-Compulsivity Spectrum.
复制标题
DOI：
10.1016/j.biopsych.2020.12.028
复制
发表时间：
2021-09-01
影响因子：
10.6
通讯作者：
Paschou, Peristera
中科院分区：
文献类型：
--
作者：
Yang, Zhiyu;Wu, Hanrui;Lee, Phil H.;Tsetsos, Fotis;Davis, Lea K.;Yu, Dongmei;Lee, Sang Hong;Dalsgaard, Soren;Haavik, Jan;Barta, Csaba;Zayats, Tetyana;Eapen, Valsamma;Wray, Naomi R.;Devlin, Bernie;Daly, Mark;Neale, Benjamin;Borglum, Anders D.;Crowley, James J.;Scharf, Jeremiah;Mathews, Carol A.;V. Faraone, Stephen;Franke, Barbara;Mattheisen, Manuel;Smoller, Jordan W.;Paschou, Peristera
抽动秽语综合征（TS）常常在冲动 - 强迫谱系中与其他神经发育障碍共病，其中注意缺陷/多动障碍（ADHD）、自闭症谱系障碍（ASD）和强迫症（OCD）最为常见。这表明在冲动 - 强迫连续统上可能存在共同的病因线索。
为了研究TS、ADHD、ASD和OCD之间共有的遗传基础，我们对跨疾病的遗传结构进行了评估和系统的荟萃分析，整合了来自最新全基因组关联研究（93,294人，6,788,510个标记）的汇总统计数据。
如先前已确定的，一个共同的统一因素将TS、ADHD和ASD联系起来，而在这些疾病中两两测试时，TS和OCD显示出最高的遗传相关性。由于一组更具同质性的疾病以及由遗传相关性指导的针对性方法，我们能够识别出多个新的位点和区域，这些位点和区域似乎对在此分析的特定疾病具有多效性作用，并且无法通过先前的研究识别出来。在基于单核苷酸多态性和基于基因的TS - ADHD - ASD全基因组关联研究的荟萃分析中，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具有高后验关联概率（m值>0.9）的单核苷酸多态性，其中11个在先前的跨疾病分析中未被识别出来。相比之下，我们在TS - OCD荟萃分析中还识别出另外两个多效性区域。通过条件分析，我们强调了在TS - ADHD - ASD遗传因素与TS - OCD中起特定作用的基因和遗传区域。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传统诊断类别研究框架的价值。
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.
登录
查看更多内容
影响因子：
11
作者：
International Obsessive Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC) and OCD Collaborative Genetics Association Studies (OCGAS)
通讯作者：
International Obsessive Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC) and OCD Collaborative Genetics Association Studies (OCGAS)
影响因子：
6.2
作者：
Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium
通讯作者：
Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium
遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
影响因子：
30.8
作者：
Finucane HK;Bulik-Sullivan B;Gusev A;Trynka G;Reshef Y;Loh PR;Anttila V;Xu H;Zang C;Farh K;Ripke S;Day FR;ReproGen Consortium;Schizophrenia Working Group of the Psychiatric Genomics Consortium;RACI Consortium;Purcell S;Stahl E;Lindstrom S;Perry JR;Okada Y;Raychaudhuri S;Daly MJ;Patterson N;Neale BM;Price AL
通讯作者：
Price AL
影响因子：
4
作者：
Dong, Lifeng;Qian, Junbin;Long, Jingpei
通讯作者：
Long, Jingpei