Identification of shared and differentiating genetic architecture for autism spectrum disorder, attention-deficit hyperactivity disorder and case subgroups,Nature Genetics

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Identification of shared and differentiating genetic architecture for autism spectrum disorder, attention-deficit hyperactivity disorder and case subgroups
Nature Genetics ( IF 30.8 ) Pub Date : 2022-09-26 , DOI: 10.1038/s41588-022-01171-3
Manuel Mattheisen _{1,

2,

3} , Jakob Grove _{1,

4,

5,

6} , Thomas D Als _{1,

4,

5} , Joanna Martin ₇ , Georgios Voloudakis _{8,

9,

10} , Sandra Meier _{1,

2} , Ditte Demontis _{1,

4,

5} , Jaroslav Bendl _{8,

9,

10} , Raymond Walters _{11,

12} , Caitlin E Carey _{11,

12} , Anders Rosengren _{4,

13} , Nora I Strom _{1,

3,

14} , Mads Engel Hauberg _{8,

9,

10} , Biao Zeng _{8,

9,

10} , Gabriel Hoffman _{8,

9,

10} , Wen Zhang _{8,

9,

10} , Jonas Bybjerg-Grauholm _{4,

15} , Marie Bækvad-Hansen _{4,

15} , Esben Agerbo _{4,

16,

17} , Bru Cormand _{18,

19,

20,

21} , Merete Nordentoft _{4,

22,

23,

24} , Thomas Werge _{4,

13,

22,

25} , Ole Mors _{4,

26} , David M Hougaard _{4,

15} , Joseph D Buxbaum _{10,

27,

28,

29} , Stephen V Faraone _{30,

31} , Barbara Franke _{32,

33} , Søren Dalsgaard ₁₆ , Preben B Mortensen _{4,

5,

16,

17} , Elise B Robinson _{11,

12,

34} , Panos Roussos _{8,

9,

10,

29,

35} , Benjamin M Neale _{11,

12} , Mark J Daly _{11,

12,

36,

37} , Anders D Børglum _{1,

4,

5}

Affiliation

Department of Biomedicine - Human Genetics and the iSEQ Center, Aarhus University, Aarhus, Denmark.
Department of Community Health and Epidemiology & Department of Psychiatry, Dalhousie University, Halifax, NS, Canada.
Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany.
The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.
Center for Genomics and Personalized Medicine, Aarhus, Denmark.
Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark.
MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Icahn Institute for Data Science and Genomic Technology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Institute of Biological Psychiatry, Mental Health Services Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark.
Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark.
Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark.
Department of Genetics, Microbiology and Statistics, Faculty of Biology, University of Barcelona, Barcelona, Catalonia, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Catalonia, Spain.
Institut de Recerca Sant Joan de Déu (IR-SJD), Esplugues de Llobregat, Catalonia, Spain.
Department of Clinical Medicine, Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark.
Copenhagen Research Centre for Mental Health (CORE), Mental Health Centre Copenhagen, Copenhagen, Denmark.
University Hospital, Hellerup, Denmark.
GLOBE Institute, Center for GeoGenetics, University of Copenhagen, Copenhagen, Denmark.
Psychosis Research Unit, Aarhus University Hospital-Psychiatry, Aarhus, Denmark.
Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Psychiatry, State University of New York Upstate Medical University, Syracuse, NY, USA.
Department of Neuroscience and Physiology, State University of New York Upstate Medical University, Syracuse, NY, USA.
Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Department of Psychiatry, JJ Peters VA Medical Center, Bronx, NY, USA.
Department of Medicine, Harvard Medical School, Boston, MA, USA.
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.

Attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are highly heritable neurodevelopmental conditions, with considerable overlap in their genetic etiology. We dissected their shared and distinct genetic etiology by cross-disorder analyses of large datasets. We identified seven loci shared by the disorders and five loci differentiating them. All five differentiating loci showed opposite allelic directions in the two disorders and significant associations with other traits, including educational attainment, neuroticism and regional brain volume. Integration with brain transcriptome data enabled us to identify and prioritize several significantly associated genes. The shared genomic fraction contributing to both disorders was strongly correlated with other psychiatric phenotypes, whereas the differentiating portion was correlated most strongly with cognitive traits. Additional analyses revealed that individuals diagnosed with both ASD and ADHD were double-loaded with genetic predispositions for both disorders and showed distinctive patterns of genetic association with other traits compared with the ASD-only and ADHD-only subgroups. These results provide insights into the biological foundation of the development of one or both conditions and of the factors driving psychopathology discriminatively toward either ADHD or ASD.

中文翻译：

鉴定自闭症谱系障碍、注意力缺陷多动障碍和病例亚组的共享和差异遗传结构

注意缺陷多动障碍 (ADHD) 和自闭症谱系障碍 (ASD) 是高度遗传的神经发育疾病，其遗传病因学有相当大的重叠。我们通过对大型数据集的跨障碍分析来剖析它们共有的和不同的遗传病因。我们确定了 7 个由这些疾病共享的基因座和 5 个区分它们的基因座。所有五个分化基因座在两种疾病中都显示出相反的等位基因方向，并与其他特征显着相关，包括教育程度、神经质和局部脑容量。与脑转录组数据的整合使我们能够识别和优先考虑几个显着相关的基因。导致这两种疾病的共享基因组部分与其他精神病表型密切相关，而区分部分与认知特征的相关性最强。额外的分析表明，与仅患有 ASD 和仅患有 ADHD 的亚组相比，被诊断患有 ASD 和 ADHD 的个体具有两种疾病的双重遗传易感性，并且显示出与其他特征的独特遗传关联模式。这些结果提供了对一种或两种病症发展的生物学基础以及驱动精神病理学对 ADHD 或 ASD 进行歧视的因素的见解。额外的分析表明，被诊断患有 ASD 和 ADHD 的个体具有两种疾病的双重遗传易感性，并且与仅 ASD 和仅 ADHD 亚组相比，显示出与其他特征的独特遗传关联模式。这些结果提供了对一种或两种病症发展的生物学基础以及驱动精神病理学对 ADHD 或 ASD 进行歧视的因素的见解。额外的分析表明，与仅患有 ASD 和仅患有 ADHD 的亚组相比，被诊断患有 ASD 和 ADHD 的个体具有两种疾病的双重遗传易感性，并且显示出与其他特征的独特遗传关联模式。这些结果提供了对一种或两种病症发展的生物学基础以及驱动精神病理学对 ADHD 或 ASD 进行歧视的因素的见解。

更新日期：2022-09-27

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