A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease,Nature Genetics

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A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease
Nature Genetics ( IF 31.7 ) Pub Date : 2021-09-07 , DOI: 10.1038/s41588-021-00921-z
Douglas P Wightman ₁ , Iris E Jansen ₁ , Jeanne E Savage ₁ , Alexey A Shadrin _{2,

3} , Shahram Bahrami _{2,

3,

4} , Dominic Holland ₅ , Arvid Rongve _{6,

7} , Sigrid Børte _{3,

8,

9} , Bendik S Winsvold _{9,

10,

11} , Ole Kristian Drange _{12,

13} , Amy E Martinsen _{3,

9,

10} , Anne Heidi Skogholt _{9,

14} , Cristen Willer ₁₅ , Geir Bråthen _{16,

17,

18} , Ingunn Bosnes _{12,

19} , Jonas Bille Nielsen _{9,

15,

20} , Lars G Fritsche ₂₁ , Laurent F Thomas _{9,

14} , Linda M Pedersen ₁₀ , Maiken E Gabrielsen ₉ , Marianne Bakke Johnsen _{3,

8,

9} , Tore Wergeland Meisingset _{16,

17} , Wei Zhou _{22,

23} , Petroula Proitsi ₂₄ , Angela Hodges ₂₄ , Richard Dobson _{25,

26,

27,

28,

29} , Latha Velayudhan ₂₄ , Karl Heilbron ₃₀ , Adam Auton ₃₀ , , Julia M Sealock _{31,

32} , Lea K Davis _{31,

32} , Nancy L Pedersen ₃₃ , Chandra A Reynolds ₃₄ , Ida K Karlsson _{33,

35} , Sigurdur Magnusson ₃₆ , Hreinn Stefansson ₃₆ , Steinunn Thordardottir ₃₇ , Palmi V Jonsson _{37,

38} , Jon Snaedal ₃₇ , Anna Zettergren ₃₉ , Ingmar Skoog _{39,

40} , Silke Kern _{39,

40} , Margda Waern _{39,

41} , Henrik Zetterberg _{42,

43,

44,

45} , Kaj Blennow _{44,

45} , Eystein Stordal _{12,

19} , Kristian Hveem _{9,

46} , John-Anker Zwart _{3,

9,

10} , Lavinia Athanasiu _{2,

4} , Per Selnes ₄₇ , Ingvild Saltvedt _{16,

18} , Sigrid B Sando _{16,

17} , Ingun Ulstein ₄₈ , Srdjan Djurovic _{49,

50} , Tormod Fladby _{3,

47} , Dag Aarsland _{24,

51} , Geir Selbæk _{3,

48,

52} , Stephan Ripke _{23,

53,

54} , Kari Stefansson ₃₆ , Ole A Andreassen _{2,

3,

4} , Danielle Posthuma _{1,

55}

Affiliation

Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU Amsterdam, Amsterdam, the Netherlands.
NORMENT Centre, University of Oslo, Oslo, Norway.
Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.
Department of Research and Innovation, Helse Fonna, Haugesund Hospital, Haugesund, Norway.
The University of Bergen, Institute of Clinical Medicine (K1), Bergen, Norway.
Research and Communication Unit for Musculoskeletal Health (FORMI), 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.
Department of Research, Innovation and Education, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway.
Department of Neurology, Oslo University Hospital, Oslo, Norway.
Department of Mental Health, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
Division of Mental Health Care, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI, USA.
Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway.
Department of Neurology and Clinical Neurophysiology, University Hospital of Trondheim, Trondheim, Norway.
Department of Geriatrics, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway.
Department of Psychiatry, Hospital Namsos, Nord-Trøndelag Health Trust, Namsos, Norway.
Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
Institute of Psychiatry Psychology and Neurosciences, King's College London, London, UK.
Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, UK.
NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, London, UK.
Health Data Research UK London, University College London, London, UK.
Institute of Health Informatics, University College London, London, UK.
NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust, London, UK.
23andMe Inc., Sunnyvale, CA, USA.
Division of Genetic Medicine, Department of Medicine Vanderbilt University Medical Center Nashville, Nashville, TN, USA.
Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Department of Psychology, University of California-Riverside, Riverside, CA, USA.
Institute of Gerontology and Aging Research Network - Jönköping (ARN-J), School of Health and Welfare, Jönköping University, Jönköping, Sweden.
deCODE Genetics/Amgen, Reykjavik, Iceland.
Department of Geriatric Medicine, Landspitali University Hospital, Reykjavik, Iceland.
Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, Centre for Ageing and Health (AGECAP) at the University of Gothenburg, Gothenburg, Sweden.
Region Västra Götaland, Sahlgrenska University Hospital, Psychiatry, Cognition and Old Age Psychiatry Clinic, Gothenburg, Sweden.
Region Västra Götaland, Sahlgrenska University Hospital, Psychosis Clinic, Gothenburg, Sweden.
Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
UK Dementia Research Institute at UCL, London, UK.
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
HUNT Research Center, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
Department of Neurology, Akershus University Hospital, Lørenskog, Norway.
Department of Geriatric Medicine, Oslo University Hospital, Oslo, Norway.
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway.
Centre of Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway.
Norwegian National Advisory Unit on Ageing and Health, Vestfold Hospital Trust, Tønsberg, Norway.
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin, Berlin, Germany.
Department of Child and Adolescent Psychiatry and Pediatric Psychology, Section Complex Trait Genetics, Amsterdam Neuroscience, Vrije Universiteit Medical Center, Amsterdam University Medical Center, Amsterdam, the Netherlands.

Late-onset Alzheimer’s disease is a prevalent age-related polygenic disease that accounts for 50–70% of dementia cases. Currently, only a fraction of the genetic variants underlying Alzheimer’s disease have been identified. Here we show that increased sample sizes allowed identification of seven previously unidentified genetic loci contributing to Alzheimer’s disease. This study highlights microglia, immune cells and protein catabolism as relevant to late-onset Alzheimer’s disease, while identifying and prioritizing previously unidentified genes of potential interest. We anticipate that these results can be included in larger meta-analyses of Alzheimer’s disease to identify further genetic variants that contribute to Alzheimer’s pathology.

中文翻译：

一项针对 1,126,563 人的全基因组关联研究确定了阿尔茨海默病的新风险位点

晚发性阿尔茨海默病是一种常见的与年龄相关的多基因疾病，占痴呆病例的 50-70%。目前，仅发现了阿尔茨海默病的一小部分遗传变异。在这里，我们表明，增加的样本量可以识别七个先前未识别的导致阿尔茨海默氏病的基因位点。这项研究强调了小胶质细胞、免疫细胞和蛋白质分解代谢与迟发性阿尔茨海默氏病的相关性，同时识别和优先考虑先前未识别的潜在感兴趣的基因。我们预计这些结果可以被纳入对阿尔茨海默病的更大规模的荟萃分析中，以进一步识别导致阿尔茨海默病病理学的遗传变异。

更新日期：2021-09-07

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