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Title | The Early-Onset Alzheimer's Disease Whole-Genome Sequencing Project: Study design and methodology. |
Publication Type | Journal Article |
Year of Publication | 2023 |
Authors | Ray NR, Ayodele T, Jean-Francois M, Baez P, Fernandez V, Bradley J, Crane PK, Dalgard CL, Kuzma A, Nicaretta H, Sims R, Williams J, Cuccaro ML, Pericak-Vance MA, Mayeux R, San Wang L-, Schellenberg GD, Cruchaga C, Beecham GW, Reitz C |
Journal | Alzheimers Dement |
Date Published | 06/2023 |
ISSN | 1552-5279 |
Abstract | INTRODUCTION: Sequencing efforts to identify genetic variants and pathways underlying Alzheimer's disease (AD) have largely focused on late-onset AD although early-onset AD (EOAD), accounting for ∼10% of cases, is largely unexplained by known mutations, resulting in a lack of understanding of its molecular etiology. METHODS: Whole-genome sequencing and harmonization of clinical, neuropathological, and biomarker data of over 5000 EOAD cases of diverse ancestries. RESULTS: A publicly available genomics resource for EOAD with extensive harmonized phenotypes. Primary analysis will (1) identify novel EOAD risk loci and druggable targets; (2) assess local-ancestry effects; (3) create EOAD prediction models; and (4) assess genetic overlap with cardiovascular and other traits. DISCUSSION: This novel resource complements over 50,000 control and late-onset AD samples generated through the Alzheimer's Disease Sequencing Project (ADSP). The harmonized EOAD/ADSP joint call will be available through upcoming ADSP data releases and will allow for additional analyses across the full onset range. HIGHLIGHTS: Sequencing efforts to identify genetic variants and pathways underlying Alzheimer's disease (AD) have largely focused on late-onset AD although early-onset AD (EOAD), accounting for ∼10% of cases, is largely unexplained by known mutations. This results in a significant lack of understanding of the molecular etiology of this devastating form of the disease. The Early-Onset Alzheimer's Disease Whole-genome Sequencing Project is a collaborative initiative to generate a large-scale genomics resource for early-onset Alzheimer's disease with extensive harmonized phenotype data. Primary analyses are designed to (1) identify novel EOAD risk and protective loci and druggable targets; (2) assess local-ancestry effects; (3) create EOAD prediction models; and (4) assess genetic overlap with cardiovascular and other traits. The harmonized genomic and phenotypic data from this initiative will be available through NIAGADS. |
DOI | 10.1002/alz.13370 |
Alternate Journal | Alzheimers Dement |
PubMed ID | 37390458 |
Grant List | MR/K013041/1 / MRC_ / Medical Research Council / United Kingdom RF1AG054080 / GF / NIH HHS / United States U19AG066567 / GF / NIH HHS / United States U01AG006781 / GF / NIH HHS / United States U54-HG003067 / GF / NIH HHS / United States U01AG032984 / GF / NIH HHS / United States RF1 AG054080 / AG / NIA NIH HHS / United States MR/L023784/1 / MRC_ / Medical Research Council / United Kingdom G0801418/1 / MRC_ / Medical Research Council / United Kingdom R01AG078964 / GF / NIH HHS / United States U24-AG041689 / GF / NIH HHS / United States R01AG064614 / GF / NIH HHS / United States R01 AG064614 / AG / NIA NIH HHS / United States U24AG056270 / GF / NIH HHS / United States |