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Nat Genet. 2019 Mar;51(3):404-413. doi: 10.1038/s41588-018-0311-9. Epub 2019 Jan 7.

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

Author information

1
Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University, Amsterdam, the Netherlands.
2
Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.
3
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
4
deCODE Genetics/Amgen, Reykjavik, Iceland.
5
Interdisciplinary Graduate Program, Vanderbilt University, Nashville, TN, USA.
6
Institute of Gerontology and Aging Research Network-Jönköping (ARN-J), School of Health and Welfare, Jönköping University, Jönköping, Sweden.
7
NORMENT, K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
8
Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
9
Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
10
Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
11
Center for Age-Related Diseases, Stavanger University Hospital, Stavanger, Norway.
12
Department of Neurology, Akershus University Hospital, Lørenskog, Norway.
13
AHUS Campus, University of Oslo, Oslo, Norway.
14
Department of Psychiatry of Old Age, Oslo University Hospital, Oslo, Norway.
15
Department of Community Medicine, University of Tromsø, Tromsø, Norway.
16
Norwegian National Advisory Unit on Ageing and Health, Vestfold Hospital Trust, Tønsberg, Norway.
17
Centre for Old Age Psychiatry Research, Innlandet Hospital Trust, Ottestad, Norway.
18
Department of Geriatric Medicine, Landspitali University Hospital, Reykjavik, Iceland.
19
Geriatric Department, Oslo University Hospital, Oslo, Norway.
20
Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway.
21
Department of Neurology, St Olav's Hospital, Trondheim University Hospital, Trondheim, Norway.
22
Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA.
23
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
24
Vanderbilt Memory & Alzheimer's Center, Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA.
25
Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
26
Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
27
MRC Biostatistics Unit, Cambridge Institute of Public Health, University of Cambridge, Cambridge, UK.
28
Department of Research and Innovation, Helse Fonna, Haugesund, Norway.
29
Department of Clinical Medicine, University of Bergen, Bergen, Norway.
30
Department of Geriatrics, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway.
31
Institute of Health and Society, University of Oslo, Oslo, Norway.
32
Department of Neurodegenerative Disorders, Institute of Neurology, UCL, London, UK.
33
Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
34
Department of Neuromuscular Diseases, Institute of Neurology, University College London, London, UK.
35
Department of Psychiatry, Namsos Hospital, Namsos, Norway.
36
Department of Mental Health, Norwegian University of Science and Technology, Trondheim, Norway.
37
Memory Clinic, Geriatric Department, Oslo University Hospital, Oslo, Norway.
38
Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
39
Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA.
40
NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, London, UK.
41
Institute of Health Informatics Research, University College London, London, UK.
42
Health Data Research UK London, University College London, London, UK.
43
Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
44
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
45
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
46
Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin, Berlin, Germany.
47
Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University, Amsterdam, the Netherlands. d.posthuma@vu.nl.
48
Department of Clinical Genetics, VU University Medical Center, Amsterdam, the Netherlands. d.posthuma@vu.nl.

Abstract

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 (rg = 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.

PMID:
30617256
PMCID:
PMC6836675
[Available on 2020-03-01]
DOI:
10.1038/s41588-018-0311-9
[Indexed for MEDLINE]

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