TY - JOUR
T1 - The Early-Onset Alzheimer's Disease Whole-Genome Sequencing Project
T2 - Study design and methodology
AU - Ray, Nicholas R.
AU - Ayodele, Temitope
AU - Jean-Francois, Melissa
AU - Baez, Penelope
AU - Fernandez, Victoria
AU - Bradley, Joseph
AU - Crane, Paul K.
AU - Dalgard, Clifton L.
AU - Kuzma, Amanda
AU - Nicaretta, Heather
AU - Sims, Rebecca
AU - Williams, Julie
AU - Cuccaro, Michael L.
AU - Pericak-Vance, Margaret A.
AU - Mayeux, Richard
AU - Wang, Li San
AU - Schellenberg, Gerard D.
AU - Cruchaga, Carlos
AU - Beecham, Gary W.
AU - Reitz, Christiane
N1 - Publisher Copyright:
© 2023 the Alzheimer's Association.
PY - 2023/9
Y1 - 2023/9
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - early-onset Alzheimer's disease
KW - genetics
KW - study design
KW - whole-genome sequencing
UR - http://www.scopus.com/inward/record.url?scp=85164177621&partnerID=8YFLogxK
U2 - 10.1002/alz.13370
DO - 10.1002/alz.13370
M3 - Article
C2 - 37390458
AN - SCOPUS:85164177621
SN - 1552-5260
VL - 19
SP - 4187
EP - 4195
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
IS - 9
ER -