Journal
NATURE GENETICS
Volume 51, Issue 3, Pages 404-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41588-018-0311-9
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Funding
- Netherlands Organization for Scientific Research [NWO VICI 453-14-005]
- Netherlands Scientific Organization [NWO: 480-05-003]
- VU University, Amsterdam, the Netherlands
- Dutch Brain Foundation
- Research Council of Norway [251134, 248778, 223273, 213837, 225989]
- KG Jebsen Stiftelsen
- Norwegian Health Association
- European Community's JPND Program
- ApGeM RCN grant [237250]
- European Community [PIAPP-GA-2011-286213 PsychDPC]
- MRC [MR/P021573/1, MC_PC_17214, UKDRI-1009] Funding Source: UKRI
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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.
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