Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk.

Autor: Jansen IE; Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University, Amsterdam, the Netherlands.; Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands., Savage JE; Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University, Amsterdam, the Netherlands., Watanabe K; Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University, Amsterdam, the Netherlands., Bryois J; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden., Williams DM; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden., Steinberg S; deCODE Genetics/Amgen, Reykjavik, Iceland., Sealock J; Interdisciplinary Graduate Program, Vanderbilt University, Nashville, TN, USA., Karlsson IK; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.; Institute of Gerontology and Aging Research Network-Jönköping (ARN-J), School of Health and Welfare, Jönköping University, Jönköping, Sweden., Hägg S; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden., Athanasiu L; NORMENT, K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway., Voyle N; Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK., Proitsi P; Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK., Witoelar A; NORMENT, K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.; Institute of Clinical Medicine, University of Oslo, Oslo, Norway., Stringer S; Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University, Amsterdam, the Netherlands., Aarsland D; Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.; Center for Age-Related Diseases, Stavanger University Hospital, Stavanger, Norway., Almdahl IS; Department of Neurology, Akershus University Hospital, Lørenskog, Norway.; AHUS Campus, University of Oslo, Oslo, Norway.; Department of Psychiatry of Old Age, Oslo University Hospital, Oslo, Norway., Andersen F; Department of Community Medicine, University of Tromsø, Tromsø, Norway., Bergh S; Norwegian National Advisory Unit on Ageing and Health, Vestfold Hospital Trust, Tønsberg, Norway.; Centre for Old Age Psychiatry Research, Innlandet Hospital Trust, Ottestad, Norway., Bettella F; NORMENT, K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.; Institute of Clinical Medicine, University of Oslo, Oslo, Norway., Bjornsson S; Department of Geriatric Medicine, Landspitali University Hospital, Reykjavik, Iceland., Brækhus A; Norwegian National Advisory Unit on Ageing and Health, Vestfold Hospital Trust, Tønsberg, Norway.; Geriatric Department, Oslo University Hospital, Oslo, Norway., Bråthen G; Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway.; Department of Neurology, St Olav's Hospital, Trondheim University Hospital, Trondheim, Norway., de Leeuw C; Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University, Amsterdam, the Netherlands., Desikan RS; Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA., Djurovic S; NORMENT, K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.; Department of Medical Genetics, Oslo University Hospital, Oslo, Norway., Dumitrescu L; Vanderbilt Memory & Alzheimer's Center, Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA.; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA., Fladby T; Department of Neurology, Akershus University Hospital, Lørenskog, Norway.; AHUS Campus, University of Oslo, Oslo, Norway., Hohman TJ; Vanderbilt Memory & Alzheimer's Center, Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA.; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA., Jonsson PV; Department of Geriatric Medicine, Landspitali University Hospital, Reykjavik, Iceland.; Faculty of Medicine, University of Iceland, Reykjavik, Iceland., Kiddle SJ; MRC Biostatistics Unit, Cambridge Institute of Public Health, University of Cambridge, Cambridge, UK., Rongve A; Department of Research and Innovation, Helse Fonna, Haugesund, Norway.; Department of Clinical Medicine, University of Bergen, Bergen, Norway., Saltvedt I; Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway.; Department of Geriatrics, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway., Sando SB; Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway.; Department of Neurology, St Olav's Hospital, Trondheim University Hospital, Trondheim, Norway., Selbæk G; Norwegian National Advisory Unit on Ageing and Health, Vestfold Hospital Trust, Tønsberg, Norway.; Institute of Health and Society, University of Oslo, Oslo, Norway., Shoai M; Department of Neurodegenerative Disorders, Institute of Neurology, UCL, London, UK., Skene NG; Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.; Department of Neuromuscular Diseases, Institute of Neurology, University College London, London, UK., Snaedal J; Department of Geriatric Medicine, Landspitali University Hospital, Reykjavik, Iceland., Stordal E; Department of Psychiatry, Namsos Hospital, Namsos, Norway.; Department of Mental Health, Norwegian University of Science and Technology, Trondheim, Norway., Ulstein ID; Memory Clinic, Geriatric Department, Oslo University Hospital, Oslo, Norway., Wang Y; NORMENT, K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.; Institute of Clinical Medicine, University of Oslo, Oslo, Norway., White LR; Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway.; Department of Neurology, St Olav's Hospital, Trondheim University Hospital, Trondheim, Norway., Hardy J; Department of Neurodegenerative Disorders, Institute of Neurology, UCL, London, UK., Hjerling-Leffler J; Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden., Sullivan PF; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.; Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.; Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA., van der Flier WM; Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands., Dobson R; Institute of Psychiatry, Psychology and Neuroscience, 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.; Institute of Health Informatics Research, University College London, London, UK.; Health Data Research UK London, University College London, London, UK., Davis LK; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.; Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA., Stefansson H; deCODE Genetics/Amgen, Reykjavik, Iceland., Stefansson K; deCODE Genetics/Amgen, Reykjavik, Iceland., Pedersen NL; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden., Ripke S; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin, Berlin, Germany., Andreassen OA; NORMENT, K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.; Institute of Clinical Medicine, University of Oslo, Oslo, Norway., Posthuma D; Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University, Amsterdam, the Netherlands. d.posthuma@vu.nl.; Department of Clinical Genetics, VU University Medical Center, Amsterdam, the Netherlands. d.posthuma@vu.nl.
Jazyk: angličtina
Zdroj: Nature genetics [Nat Genet] 2019 Mar; Vol. 51 (3), pp. 404-413. Date of Electronic Publication: 2019 Jan 07.
DOI: 10.1038/s41588-018-0311-9
Abstrakt: Alzheimer's disease (AD) is highly heritable and recent studies have identified over 20 disease-associated genomic loci. Yet these only explain a small proportion of the genetic variance, indicating that undiscovered loci remain. Here, we performed a large genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 cases, 383,378 controls). AD-by-proxy, based on parental diagnoses, showed strong genetic correlation with AD (r g  = 0.81). Meta-analysis identified 29 risk loci, implicating 215 potential causative genes. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver, and microglia). Gene-set analyses indicate biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomization results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD.
Databáze: MEDLINE