Title | Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Damotte V, Naj AC, Boland A, Vronskaya M, van der Lee SJ, Amlie-Wolf A et al. |
Corporate Authors | Alzheimer Disease Genetics Consortium(ADGC),, European Alzheimer’s Disease Initiative(EADI),, Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium(CHARGE),, Genetic and Environmental Risk in AD/Defining Genetic, Polygenic and Environmental Risk for Alzheimer’s Disease Consortium(GERAD/PERADES), |
Journal | Nat Genet |
Volume | 51 |
Issue | 3 |
Pagination | 414-430 |
Date Published | 2019 03 |
ISSN | 1546-1718 |
Keywords | Aged, Alzheimer Disease, Amyloid beta-Peptides, Case-Control Studies, Female, Genetic Loci, Genetic Predisposition to Disease, Genetic Testing, Genome-Wide Association Study, Haplotypes, Humans, Immunity, Lipid Metabolism, Lipids, Male, tau Proteins |
Abstract | Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education. |
DOI | 10.1038/s41588-019-0358-2 |
Pubmed Link | https://www.ncbi.nlm.nih.gov/pubmed/30820047?dopt=Abstract |
Alternate Journal | Nat. Genet. |
PubMed ID | 30820047 |
PubMed Central ID | PMC6463297 |
Grant List | P30 AG010124 / AG / NIA NIH HHS / United States MC_U123160657 / MRC_ / Medical Research Council / United Kingdom MC_UU_00024/1 / MRC_ / Medical Research Council / United Kingdom P01 AG026276 / AG / NIA NIH HHS / United States G0500289 / MRC_ / Medical Research Council / United Kingdom P01 AG019724 / AG / NIA NIH HHS / United States P30 AG010161 / AG / NIA NIH HHS / United States R01 AG061796 / AG / NIA NIH HHS / United States G0900688 / MRC_ / Medical Research Council / United Kingdom SHAW/NOV14/985-797 / MNDA_ / Motor Neurone Disease Association / United Kingdom G0600237 / MRC_ / Medical Research Council / United Kingdom R01 AG018454 / AG / NIA NIH HHS / United States G9810900 / MRC_ / Medical Research Council / United Kingdom P30 AG013854 / AG / NIA NIH HHS / United States P30 AG053760 / AG / NIA NIH HHS / United States MR/K013041/1 / MRC_ / Medical Research Council / United Kingdom G0900421 / MRC_ / Medical Research Council / United Kingdom R01 NS017950 / NS / NINDS NIH HHS / United States U01 AG032438 / AG / NIA NIH HHS / United States R01 AG054076 / AG / NIA NIH HHS / United States ALCHALABI-DOBSON/APR14/829-791 / MNDA_ / Motor Neurone Disease Association / United Kingdom MR/L501529/1 / MRC_ / Medical Research Council / United Kingdom P01 AG017586 / AG / NIA NIH HHS / United States G0300429 / MRC_ / Medical Research Council / United Kingdom U01 AG016976 / AG / NIA NIH HHS / United States P01 AG003991 / AG / NIA NIH HHS / United States P50 AG005681 / AG / NIA NIH HHS / United States K25 AG055620 / AG / NIA NIH HHS / United States P30 AG017266 / AG / NIA NIH HHS / United States G0902227 / MRC_ / Medical Research Council / United Kingdom MR/L501517/1 / MRC_ / Medical Research Council / United Kingdom MR/L021803/1 / MRC_ / Medical Research Council / United Kingdom RF1 AG051504 / AG / NIA NIH HHS / United States R01 AG041232 / AG / NIA NIH HHS / United States UL1 TR001414 / TR / NCATS NIH HHS / United States U01 AG046139 / AG / NIA NIH HHS / United States MR/R024804/1 / MRC_ / Medical Research Council / United Kingdom P30 AG010129 / AG / NIA NIH HHS / United States MR/M009076/1 / MRC_ / Medical Research Council / United Kingdom G0801418 / MRC_ / Medical Research Council / United Kingdom |
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