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


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Type
Article
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Authors
Watanabe, Kyoko 
Bryois, Julien 
Williams, Dylan M 
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.

Description
Keywords
Adult, Alzheimer Disease, Case-Control Studies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk, Young Adult
Journal Title
Nat Genet
Conference Name
Journal ISSN
1061-4036
1546-1718
Volume Title
51
Publisher
Springer Science and Business Media LLC
Sponsorship
Medical Research Council (MR/P021573/1)
Medical Research Council (MC_PC_17214)
Wellcome Trusrt, ERC ESCR EPSRC