This repository is under review for potential modification in compliance with Administration directives.

← Back to Approved DARs

ADSP extension

PI
Tanzi, Rudolph
DAR ID
10049
Initial Approval Date
December 3, 2019
Current DAR Status
Active
PI Institution
Massachusetts General Hospital
PI Institution Country
United States
PI Institution Type
Non-Profit

Requested Datasets (1)

NG00067Alzheimer's Disease Sequencing Project Umbrella Study

Research Use Statement
Late-onset AD (LOAD) is caused by a complex polygenic and environmental background. Whole genome sequencing provides comprehensive coverage of the genome and has several advantages over exome sequencing and genotyping. We plan to use an aggregated collection of whole genome sequenced family-based and case-control datasets to address the following goals. 1) Identify variants (specifically rare) and regions associated with AD (and related or derived phenotypes) or showing an interaction pattern; 2) Functionally finemap associated loci and identify the functional impact of associated variants in non-coding regions; 3) Use identified variants to validate them in a 3D neural-glial culture model. We will utilize several datasets with whole genome sequencing data, including AD datasets from National Institiute of Mental Health (NIMH) AD family sample and Alzheimer’s Disease Sequencing Project. We will use family-based association tests robust to population confounding and other approaches suitable for case-control studies. Novel analysis approaches will be developed and tested. Analysis results and derived data will be made available to the research community.

Non-Technical Summary
Alzheimer’s disease (AD) is the most common neurodegenerative disorder with a huge burden on the healthcare system and the 6th leading cause of death in the United States. Sequenced DNA from people will help us to better describe the genetic architecture of AD. We will utilize two types of genomic datasets: genomes from related individuals (family-based) and genomes from unrelated individuals (case/control). Identified functional variants will be validated in a 3D neural-glial culture model and enhance the biological understanding of AD.

Reported Publications (10)

Publications shown are those reported by investigators through NIAGADS DAR reporting and renewal processes and may not represent a complete list of publications associated with the project.

  1. Polygenic hazard score models for the prediction of Alzheimer's free survival using the lasso for Cox's proportional hazards model. Hahn G, et al. Genetic epidemiology. 2025. PMID: 38982682
  2. On the effect heterogeneity of established disease susceptibility loci for Alzheimer's disease across different genetic ancestries. Lee S, et al. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2024. PMID: 38563508
  3. A comparison between similarity matrices for principal component analysis to assess population stratification in sequenced genetic data sets. Lee S, et al. Briefings in bioinformatics. 2023. PMID: 36585781
  4. PILRA polymorphism modifies the effect of APOE4 and GM17 on Alzheimer's disease risk. Lopatko Lindman K, et al. Scientific reports. 2022. PMID: 35918447
  5. Region-based analysis of rare genomic variants in whole-genome sequencing datasets reveal two novel Alzheimer's disease-associated genes: DTNB and DLG2. Prokopenko D, et al. Molecular psychiatry. 2022. PMID: 35246634
  6. Reply to Neupane et al.: Replication study of AD-associated rare variants. Prokopenko D, et al. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2022. PMID: 35142036
  7. An APP ectodomain mutation outside of the Aβ domain promotes Aβ production in vitro and deposition in vivo. Zhang X, et al. The Journal of experimental medicine. 2021. PMID: 33822840
  8. Whole-genome sequencing reveals new Alzheimer's disease-associated rare variants in loci related to synaptic function and neuronal development. Prokopenko D, et al. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2021. PMID: 33797837
  9. Gga3 deletion and a GGA3 rare variant associated with late onset Alzheimer's disease trigger BACE1 accumulation in axonal swellings. Lomoio S, et al. Science translational medicine. 2020. PMID: 33208500
  10. Identification of Novel Alzheimer's Disease Loci Using Sex-Specific Family-Based Association Analysis of Whole-Genome Sequence Data. Prokopenko D, et al. Scientific reports. 2020. PMID: 32193444