Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors,Nature Genetics

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Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors
Nature Genetics ( IF 31.7 ) Pub Date : 2020-11-16 , DOI: 10.1038/s41588-020-00725-7
Mark K Bakker ₁ , Rick A A van der Spek ₁ , Wouter van Rheenen ₁ , Sandrine Morel _{2,

3} , Romain Bourcier _{4,

5} , Isabel C Hostettler _{6,

7} , Varinder S Alg ₆ , Kristel R van Eijk ₁ , Masaru Koido _{8,

9} , Masato Akiyama _{8,

10,

11} , Chikashi Terao ₈ , Koichi Matsuda _{12,

13} , Robin G Walters _{14,

15} , Kuang Lin ₁₄ , Liming Li ₁₆ , Iona Y Millwood _{14,

15} , Zhengming Chen _{14,

15} , Guy A Rouleau ₁₇ , Sirui Zhou ₁₈ , Kristiina Rannikmäe ₁₉ , Cathie L M Sudlow _{19,

20} , Henry Houlden ₂₁ , Leonard H van den Berg ₁ , Christian Dina ₄ , Olivier Naggara _{22,

23} , Jean-Christophe Gentric ₂₄ , Eimad Shotar ₂₅ , François Eugène ₂₆ , Hubert Desal _{4,

5} , Bendik S Winsvold _{27,

28} , Sigrid Børte _{28,

29,

30} , Marianne Bakke Johnsen _{28,

29,

30} , Ben M Brumpton ₂₈ , Marie Søfteland Sandvei _{31,

32} , Cristen J Willer ₃₃ , Kristian Hveem _{28,

34} , John-Anker Zwart _{27,

28,

30} , W M Monique Verschuren _{35,

36} , Christoph M Friedrich _{37,

38} , Sven Hirsch ₃₉ , Sabine Schilling ₃₉ , Jérôme Dauvillier ₄₀ , Olivier Martin ₄₀ , , , , , , , , Gregory T Jones ₄₁ , Matthew J Bown _{42,

43} , Nerissa U Ko ₄₄ , Helen Kim _{45,

46,

47} , Jonathan R I Coleman _{48,

49} , Gerome Breen _{48,

49} , Jonathan G Zaroff ₅₀ , Catharina J M Klijn ₅₁ , Rainer Malik ₅₂ , Martin Dichgans _{53,

54} , Muralidharan Sargurupremraj _{55,

56} , Turgut Tatlisumak ₅₇ , Philippe Amouyel ₅₈ , Stéphanie Debette _{55,

56} , Gabriel J E Rinkel ₁ , Bradford B Worrall ₅₉ , Joanna Pera ₆₀ , Agnieszka Slowik ₆₀ , Emília I Gaál-Paavola _{61,

62} , Mika Niemelä ₆₁ , Juha E Jääskeläinen _{63,

64} , Mikael von Und Zu Fraunberg _{63,

64} , Antti Lindgren _{63,

64} , Joseph P Broderick ₆₅ , David J Werring ₆ , Daniel Woo ₆₅ , Richard Redon ₄ , Philippe Bijlenga ₃ , Yoichiro Kamatani _{8,

12} , Jan H Veldink ₁ , Ynte M Ruigrok ₁

Affiliation

Department of Neurology and Neurosurgery, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, the Netherlands.
Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
Neurosurgery Division, Department of Clinical Neurosciences, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland.
l'institut du thorax Université de Nantes, CHU Nantes, INSERM, CNRS, Nantes, France.
CHU Nantes, Department of Neuroradiology, Nantes, France.
Stroke Research Centre, University College London Queen Square Institute of Neurology, London, UK.
Department of Neurosurgery, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Department of Cancer Biology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Department of Ocular Pathology and Imaging Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
Laboratory of Clinical Genome Sequencing, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
Medical Research Council Population Health Research Unit, University of Oxford, Oxford, UK.
Department of Epidemiology, School of Public Health, Peking University Health Science Center, Beijing, China.
Montréal Neurological Institute and Hospital, McGill University, Montréal, QC, Canada.
Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, QC, Canada.
Centre for Medical Informatics, Usher Institute, University of Edinburgh, Edinburgh, UK.
UK Biobank, Cheadle, Stockport, UK.
Neurogenetics Laboratory, The National Hospital of Neurology and Neurosurgery, London, UK.
Pediatric Radiology, Necker Hospital for Sick Children, Université Paris Descartes, Paris, France.
Department of Neuroradiology, Sainte-Anne Hospital and Université Paris Descartes, INSERM UMR, S894, Paris, France.
Department of Neuroradiology, University Hospital of Brest, Brest, France.
Department of Neuroradiology, Pitié-Salpêtrière Hospital, Paris, France.
Department of Neuroradiology, University Hospital of Rennes, Rennes, France.
Department of Research, Innovation and Education, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway.
K. G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
Research and Communication Unit for Musculoskeletal Health (FORMI), Department of Research, Innovation and Education, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway.
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
The Cancer Clinic, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI, USA.
HUNT Research Center, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
National Institute for Public Health and the Environment, Bilthoven, the Netherlands.
Dortmund University of Applied Science and Arts, Dortmund, Germany.
Institute for Medical Informatics, Biometry and Epidemiology (IMIBE), University Hospital Essen, Essen, Germany.
Zurich University of Applied Sciences, School of Life Sciences and Facility Management, Zurich, Switzerland.
SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.
Department of Surgery, University of Otago, Dunedin, New Zealand.
Department of Cardiovascular Sciences and National Institute for Health Research, University of Leicester, Leicester, UK.
Leicester Biomedical Research Centre, University of Leicester, Glenfield Hospital, Leicester, UK.
Department of Neurology, University of California at San Francisco, San Francisco, CA, USA.
Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California, San Francisco, CA, USA.
Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA.
Institute for Human Genetics, University of California, San Francisco, CA, USA.
Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
UK National Institute for Health Research (NIHR) Biomedical Research Centre (BRC), South London and Maudsley NHS Foundation Trust, London, UK.
Division of Research, Kaiser Permanente of Northern California, Oakland, CA, USA.
Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
Institute for Stroke and Dementia Research, University Hospital, Ludwig-Maximilians-University, Munich, Germany.
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Munich, Germany.
INSERM U1219 Bordeaux Population Health Research Center, University of Bordeaux, Bordeaux, France.
Department of Neurology, Institute for Neurodegenerative Disease, Bordeaux University Hospital, Bordeaux, France.
Department of Clinical Neuroscience at Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
Institut Pasteur de Lille, UMR1167 LabEx DISTALZ - RID-AGE Université de Lille, INSERM, Centre Hospitalier Université de Lille Lille, Lille Lille, France.
Departments of Neurology and Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, USA.
Department of Neurology, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland.
Department of Neurosurgery, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
Clinical Neurosciences, University of Helsinki, Helsinki, Finland.
Neurosurgery NeuroCenter, Kuopio University Hospital, Kuopio, Finland.
Institute of Clinical Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
University of Cincinnati College of Medicine, Cincinnati, OH, USA.

Rupture of an intracranial aneurysm leads to subarachnoid hemorrhage, a severe type of stroke. To discover new risk loci and the genetic architecture of intracranial aneurysms, we performed a cross-ancestry, genome-wide association study in 10,754 cases and 306,882 controls of European and East Asian ancestry. We discovered 17 risk loci, 11 of which are new. We reveal a polygenic architecture and explain over half of the disease heritability. We show a high genetic correlation between ruptured and unruptured intracranial aneurysms. We also find a suggestive role for endothelial cells by using gene mapping and heritability enrichment. Drug-target enrichment shows pleiotropy between intracranial aneurysms and antiepileptic and sex hormone drugs, providing insights into intracranial aneurysm pathophysiology. Finally, genetic risks for smoking and high blood pressure, the two main clinical risk factors, play important roles in intracranial aneurysm risk, and drive most of the genetic correlation between intracranial aneurysms and other cerebrovascular traits.

中文翻译：

颅内动脉瘤的全基因组关联研究确定了 17 个风险位点和与临床风险因素的遗传重叠

颅内动脉瘤破裂会导致蛛网膜下腔出血，这是一种严重的中风。为了发现新的风险位点和颅内动脉瘤的遗传结构，我们对 10,754 例欧洲和东亚血统的 306,882 例对照进行了跨血统、全基因组关联研究。我们发现了 17 个风险基因座，其中 11 个是新的。我们揭示了多基因结构并解释了超过一半的疾病遗传性。我们显示破裂和未破裂的颅内动脉瘤之间存在高度遗传相关性。我们还通过使用基因定位和遗传力富集发现内皮细胞的暗示作用。药物靶标富集显示颅内动脉瘤与抗癫痫药和性激素药物之间的多效性，提供了对颅内动脉瘤病理生理学的见解。最后，

更新日期：2020-11-16

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