The Early-Onset Alzheimer's Disease Whole-Genome Sequencing Project: Study design and methodology

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)4187-4195
Number of pages9
JournalAlzheimer's and Dementia
Volume19
Issue number9
DOIs
StatePublished - Sep 2023
Externally publishedYes

Keywords

  • Alzheimer's disease
  • early-onset Alzheimer's disease
  • genetics
  • study design
  • whole-genome sequencing

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