The Early‐Onset Alzheimer's Disease Whole‐Genome Sequencing Project: Study design and methodology
Year: 2023
Type: article
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.
Source: Alzheimer s & Dementia
DOI: 10.1002/alz.13370
Authors: Nicholas R. Ray, Temitope Ayodele, Melissa Jean‐Francois, Penelope Baez, Victoria Fernandez, Joseph Bradley, Paul K. Crane, Clifton L. Dalgard, Amanda Kuzma, Heather Nicaretta, Rebecca Sims, Julie Williams, Michael L. Cuccaro, Margaret A. Pericak‐Vance, Richard Mayeux, Li‐San Wang, Gerard D. Schellenberg, Carlos Cruchaga, Gary W. Beecham, Christiane Reitz
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: University of Miami, Cardiff University, Eisai, National Institutes of Health, Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University in St. Louis, Medical Research Council, National Institute on Aging, National Institute of Mental Health, National Human Genome Research Institute
Awards: G100543330, UK Dementias Platform, Identifying Rare Variants that Increase Risk for Alzheimer's Disease, G1309605592, G1609525565, G1647015270, G2464394541, G3338037799, G3677674694, Further defining the genetic architecture of Alzheimer's disease, Neuroanatomical associations with the factor structure underlying neuropsychiatric symptoms in Alzheimer's disease, G4000272535, Genetic Epidemiology and Multi-Omics Analyses in Familial and Sporadic Alzheimer's Disease Among Secular Caribbean Hispanics and Religious Order, G4122177659, G4375501919, The Centre for Neuropsychiatric Genetics and Genomics, G5130436076, Alzheimer's Disease Genetics Consortium, G5334782909, G6680420078, G7880223742, G8900867631, G9000000447, G9000003964, G9000022338, G9000030467, G9000036899, G9000062434, G9000172347, G9000217379, Adult Changes in Thought (ACT) Research Program, National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD)
OpenAlex ID: W4382653380