Investigating Shared Genetic Basis Across Tourette Syndrome and Comorbid Neurodevelopmental Disorders Along the Impulsivity-Compulsivity Spectrum,Biological Psychiatry

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Investigating Shared Genetic Basis Across Tourette Syndrome and Comorbid Neurodevelopmental Disorders Along the Impulsivity-Compulsivity Spectrum
Biological Psychiatry ( IF 10.6 ) Pub Date : 2021-01-08 , DOI: 10.1016/j.biopsych.2020.12.028
Zhiyu Yang ₁ , Hanrui Wu ₁ , Phil H Lee ₂ , Fotis Tsetsos ₃ , Lea K Davis ₄ , Dongmei Yu ₂ , Sang Hong Lee ₅ , Søren Dalsgaard ₆ , Jan Haavik ₇ , Csaba Barta ₈ , Tetyana Zayats ₉ , Valsamma Eapen ₁₀ , Naomi R Wray ₁₁ , Bernie Devlin ₁₂ , Mark Daly ₁₃ , Benjamin Neale ₁₄ , Anders D Børglum ₁₅ , James J Crowley ₁₆ , Jeremiah Scharf ₂ , Carol A Mathews ₁₇ , Stephen V Faraone ₁₈ , Barbara Franke ₁₉ , Manuel Mattheisen ₂₀ , Jordan W Smoller ₂₁ , Peristera Paschou ₁

Affiliation

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.
Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupoli, Greece.
Division of Genetic Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee.
Queensland Brain Institute, University of Queensland, Brisbane, Queensland; Australian Centre for Precision Health, University of South Australia Cancer Research Institute, University of South Australia, Adelaide, South Australia.
Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark; National Centre for Register-based Research, Aarhus University, Aarhus, Denmark; Department of Child and Adolescent Psychiatry, Hospital of Telemark, Kragerø, Norway.
K.G. Jebsen Centre for Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, Bergen, Norway; Division of Psychiatry, Haukeland University Hospital, Bergen, Norway.
Institute of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary.
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; K.G. Jebsen Centre for Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, Bergen, Norway.
Academic Unit of Child Psychiatry South West Sydney, School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia.
Queensland Brain Institute, University of Queensland, Brisbane, Queensland; Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland.
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Massachusetts.
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Massachusetts; Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts.
Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark; Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, Denmark; Center for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark; Center for Genomics and Personalized Medicine, Aarhus, Denmark.
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Department of Psychiatry, University of Florida, Gainesville, Florida; Department of Genetics Institute, University of Florida, Gainesville, Florida.
Departmentof Psychiatry, SUNY Upstate Medical University, Syracuse, New York; Departmentof Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, New York.
Department of Human Genetics, Radboud University Medical Center, Radboud University, Nijmegen, The Netherlands; Department of Psychiatry, Radboud University Medical Center, Radboud University, Nijmegen, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.
Department of Biomedicine, Aarhus University, Aarhus, Denmark; Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital Wuerzburg, Wuerzburg, Germany; Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
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; Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Massachusetts.

Background

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.

Methods

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).

Results

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.

Conclusions

Our work underlines the value of redefining the framework for research across traditional diagnostic categories.

中文翻译：

沿着冲动 - 强迫谱调查图雷特综合症和共病神经发育障碍的共同遗传基础

背景

抽动秽语综合征 (TS) 经常与冲动 - 强迫症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) 最为普遍。这表明沿着冲动 - 强迫连续统一体的共同病因线索的可能性。

方法

通过研究 TS、ADHD、ASD 和 OCD 的共同遗传基础，我们对跨疾病遗传结构和系统荟萃分析进行了评估，整合了最新全基因组关联研究（93,294 个人，6,788,510 个标记）的汇总统计数据。

结果

如前所述，一个共同的统一因素将 TS、ADHD 和 ASD 联系起来，而 TS 和 OCD 在这些疾病的配对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以遗传相关性为指导的有针对性的方法，我们能够识别出多个新的命中和区域，这些命中和区域似乎对此处分析的特定疾病起多效性作用，并且无法通过以前的研究确定. 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 个全基因组重要区域，这些区域具有与所有三种研究疾病相关的高后验概率的单核苷酸多态性（m 值 > 0.9），其中 11 个在之前的交叉障碍分析中未发现。相比之下，我们还在 TS-OCD 荟萃分析中确定了两个额外的多效性区域。通过条件分析，我们强调了在 TS-ADHD-ASD 遗传因子与 TS-OCD 中发挥特定作用的基因和遗传区域。跨疾病组织特异性分析涉及 TS-ADHD-ASD 中的下丘脑-垂体-肾上腺轴。