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Description

To better capture the polygenic architecture of Alzheimer’s Disease (AD), we developed a joint genetic score, MetaGRS. We incorporated genetic variants for AD and 24 other traits from two independent cohorts, NACC (n = 3,174, training set) and UPitt (n = 2,053, validation set). We also conducted APOE-stratified analyses to assess the role of the e4 allele on risk prediction. This dataset includes regression results for the MetaGRS to predict Alzheimer’s disease survival (Cox regression) or disease status (logistic regression).

Available Filesets

NameAccessionLatest ReleaseDescription
MetaGRSfsa000048NG00144.v1MetaGRS files and readme

View the File Manifest for a full list of files released in this dataset.

Consent LevelNumber of Subjects
DS-ADRD-IRB-PUB-NPUNA

Visit the Data Use Limitations page for definitions of the consent levels above.

Total number of approved DARs: 3
  • Investigator:
    Cruchaga, Carlos
    Institution:
    Washington University School of Medicine
    Project Title:
    The Familial Alzheimer Sequencing (FASe) Project
    Date of Approval:
    May 9, 2024
    Request status:
    Approved
    Research use statements:
    Show statements
    Technical Research Use Statement:
    The goal of this study is to identify new genes and mutations that cause or increase risk for Alzheimer disease (AD), as well as protective factors. Individuals and families were selected from the Knight-ADRC (Washington University) and the NIA-LOAD study. Only families with at least three first-degree affected individuals were included. Families with pathogenic variants in the known AD or FTD genes, or in which APOE4 segregated with disease were excluded. At least two cases and one control were selected per family. Cases had an age at onset (AAO) after 65 yo and controls had a larger age at last assessment than the latest AAO within the family. Whole exome (WES) and whole genome sequencing (WGS) was generated for 1,235 individuals (285 families) that together with data from our collaborators and the ADSP family-based cohort (3,449 individuals and 757 families) will provide enough statistical power to identify new genes for AD. Dr. Tanzi (Harvard Medical School) will provide WGS from 400 families from the NIMH Alzheimer disease genetics initiative study. We will perform single variant and gene-based analyses to identify genes and variants that increase risk for disease in AD families. Single variant analysis will consist of a combination of association and segregation analyses. We will run family-based gene-based methods to identify genes that show and overall enrichment of variants in AD cases. We will also look for protective and modifier variants. To do this we will identify families loaded with AD cases, that also include individuals with a high burden of known risk variants but that do not develop the disease (escapees). We will use the sequence data and the family structure to identify variants that segregate with the escapee phenotype. The most promising variants and genes will be replicated in independent datasets (ADSP case-control, ADNI, Knight-ADRC, NIA-LOAD ). We will perform single variant and gene-based analyses to replicate the initial findings, and survival analysis to replicate the protective variants. We will select the most promising variants/genes for functional studies
    Non-Technical Research Use Statement:
    Family-based approaches led to the identification of disease-causing Alzheimer’s Disease (AD) variants in the genes encoding APP, PSEN1 and PSEN2. The identification of these genes led to the A?-cascade hypothesis and to the development of drugs that target this pathway. Recently, we have identified rare coding variants in TREM2, ABCA7, PLD3 and SORL1 with large effect sizes for risk for AD, confirming that rare coding variants play a role in the etiology of AD. In this proposal, we will identify rare risk and protective alleles using sequence data from families densely affected by AD. We hypothesize that these families are enriched for genetic risk factors. We already have sequence data from 695 families (2,462 individuals), that combined with the ADSP and the NIMH dataset will lead to a dataset of more than 1,042 families (4,684 individuals). Our preliminary results support the flexibility of this approach and strongly suggest that protective and risk variants with large effect size will be found, which will lead to a better understanding of the biology of the disease.
  • Investigator:
    Wainberg, Michael
    Institution:
    Sinai Health System
    Project Title:
    Uncovering the causal genetic variants, genes and cell types underlying brain disorders
    Date of Approval:
    September 5, 2024
    Request status:
    Approved
    Research use statements:
    Show statements
    Technical Research Use Statement:
    We propose a multifaceted approach to elucidate and interpret genetic risk factors for Alzheimer's disease. First, we propose to perform a whole-genome sequencing meta-analysis of the Alzheimer's Disease Sequencing Project with the UK Biobank and All of Us to associate rare coding and non-coding variants with Alzheimer's disease and related dementias. We will explore a variety of case definitions in the UK Biobank and All of Us, including those based on ICD codes from electronic medical records (inpatient, primary care and/or death), self-report of Alzheimer's disease or Alzheimer's disease and related dementias, and/or family history of Alzheimer's disease or Alzheimer's disease and related dementias. We will perform single-variant, coding-variant burden, and non-coding variant burden tests using the REGENIE genome-wide association study toolkit.Second, we propose to develop statistical and machine learning models that can effectively infer (“fine-map”) the causal gene(s), variant(s), and cell type(s) underlying each association we find, as well as associations from existing genome-wide association studies and other Alzheimer's- and aging-related cohorts found in NIAGADS. In particular, we propose to improve causal gene identification by incorporating knowledge of gene function as a complement to functional genomics. For instance, we plan to develop improved methods for inferring biological networks, particularly from single-cell data, and integrate these networks with the results of the non-coding associations from our first aim to fine-map causal genes. To fine-map causal variants and cell types, we plan to integrate the associations from our first aim with single-nucleus chromatin accessibility data from postmortem brain cohorts to simultaneously infer which variant(s) are causal for each discovered locus and which cell type(s) they act through.
    Non-Technical Research Use Statement:
    We have a comprehensive plan to understand and explain the genetic factors that contribute to Alzheimer's disease. Our approach involves two main steps.First, we'll analyze genetic information from large research databases to identify rare genetic changes associated with Alzheimer's and related memory disorders. We'll look at both specific changes in genes and other parts of the genetic code. We'll use data from different studies and combine them to get a clearer picture.Second, we'll create advanced computer models that can help us figure out which specific genes, genetic changes, and cell types are responsible for these associations. This will help us pinpoint the most important factors contributing to Alzheimer's disease. We'll also analyze data from previous studies to build a more complete understanding of these genetic links.
  • Investigator:
    Zhao, Jinying
    Institution:
    University of Florida
    Project Title:
    Identifying novel biomarkers for human complex diseases using an integrated multi-omics approach
    Date of Approval:
    November 21, 2023
    Request status:
    Expired
    Research use statements:
    Show statements
    Technical Research Use Statement:
    GWAS, WES and WGS have identified many genes associated with Alzheimer’s Dementia (AD) and its related traits. However, the identified genes thus far collectively explain only a small proportion of disease heritability, suggesting that more genes remained to be identified. Moreover, there is a clear gender and ethnic disparity for AD susceptibility, but little research has been done to identify gender- and ethnic-specific variants associated with AD. Of the many challenges for deciphering AD pathology, lacking of efficient and power statistical methods for genetic association mapping and causal inference represents a major bottleneck. To tackle this challenge, we have developed a set of novel statistical and bioinformatics approaches for genetic association mapping and multi-omics causation inference in large-scale ethnicity-specific epidemiological studies. The goal of this project is to leverage the multi-omics and clinical data archived by the ADSP, ADNI, ADGC as well as other AD-related data repositories to identify novel genes and molecular markers for AD. Specifically, we will (1) validate our novel methods for identifying novel risk and protective genomic variants and multi-omics causal pathways of AD; (2) identify novel ethnicity- and gender-specific genes and molecular causal pathways of AD. We will share our results, statistical methods and computational software with the scientific community.
    Non-Technical Research Use Statement:
    Although many genes have been associated with Alzheimer’s Dementia (AD), these genes altogether explain only a small fraction of disease etiology, suggesting more genes remained to be identified. Of the many challenges for deciphering AD pathology, lacking of power statistical methods represents a major bottleneck. To tackle this challenge, we have developed a set of novel statistical and bioinformatics approaches for genetic association mapping and multi-omics causation inference in large-scale ethnicity-specific epidemiological studies. The goal of this project is to leverage the rich genetic and other omic data along with clinical data archived by the ADSP, ADNI, ADGC as well as other AD-related data repositories to identify novel genes and molecular markers for AD. Such results will enhance our understanding of AD pathogenesis and may also serve as biomarkers for early diagnosis and therapeutic targets.

Acknowledgment statement for any data distributed by NIAGADS:

Data for this study were prepared, archived, and distributed by the National Institute on Aging Alzheimer’s Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24-AG041689), funded by the National Institute on Aging.

Use the study-specific acknowledgement statements below (as applicable):

For investigators using any data from this dataset:

Please cite/reference the use of NIAGADS data by including the accession NG00144.

For investigators using The Prediction of Alzheimer’s Disease through Multi-Trait Genetic Modeling (sa000033) data:

The National Institutes of Health, National Institute on Aging (NIH-NIA) supported this work through the following grants: ADGC, U01 AG032984; samples from the National Centralized Repository for Alzheimer’s Disease and Related Dementias (NCRAD), which receives government support under a cooperative agreement grant (U24 AG21886) awarded by the National Institute on Aging (NIA), were used in this study. Sequencing data generation and harmonization is supported by the Genome Center for Alzheimer’s Disease, U54AG052427, and data sharing is supported by NIAGADS, U24AG041689. We thank contributors who collected samples used in this study, as well as patients and their families, whose help and participation made this work possible.

The NACC database is funded by NIA/NIH Grant U24 AG072122. NIH grants supported enrollment and data collection for the individual studies including the Alzheimer’s Disease Centers (ADC, P30 AG062429 (PI James Brewer, MD, PhD), P30 AG066468 (PI Oscar Lopez, MD), P30 AG062421 (PI Bradley Hyman, MD, PhD), P30 AG066509 (PI Thomas Grabowski, MD), P30 AG066514 (PI Mary Sano, PhD), P30 AG066530 (PI Helena Chui, MD), P30 AG066507 (PI Marilyn Albert, PhD), P30 AG066444 (PI John Morris, MD), P30 AG066518 (PI Jeffrey Kaye, MD), P30 AG066512 (PI Thomas Wisniewski, MD), P30 AG066462 (PI Scott Small, MD), P30 AG072979 (PI David Wolk, MD), P30 AG072972 (PI Charles DeCarli, MD), P30 AG072976 (PI Andrew Saykin, PsyD), P30 AG072975 (PI David Bennett, MD), P30 AG072978 (PI Neil Kowall, MD), P30 AG072977 (PI Robert Vassar, PhD), P30 AG066519 (PI Frank LaFerla, PhD), P30 AG062677 (PI Ronald Petersen, MD, PhD), P30 AG079280 (PI Eric Reiman, MD), P30 AG062422 (PI Gil Rabinovici, MD), P30 AG066511 (PI Allan Levey, MD, PhD), P30 AG072946 (PI Linda Van Eldik, PhD), P30 AG062715 (PI Sanjay Asthana, MD, FRCP), P30 AG072973 (PI Russell Swerdlow, MD), P30 AG066506 (PI Todd Golde, MD, PhD), P30 AG066508 (PI Stephen Strittmatter, MD, PhD), P30 AG066515 (PI Victor Henderson, MD, MS), P30 AG072947 (PI Suzanne Craft, PhD), P30 AG072931 (PI Henry Paulson, MD, PhD), P30 AG066546 (PI Sudha Seshadri, MD), P20 AG068024 (PI Erik Roberson, MD, PhD), P20 AG068053 (PI Justin Miller, PhD), P20 AG068077 (PI Gary Rosenberg, MD), P20 AG068082 (PI Angela Jefferson, PhD), P30 AG072958 (PI Heather Whitson, MD), P30 AG072959 (PI James Leverenz, MD). The Miami ascertainment and research were supported in part through: RF1AG054080, R01AG027944, R01AG019085, R01AG028786-02, RC2AG036528. The Columbia ascertainment and research were supported in part through R37AG015473 and U24AG056270. The University of Washington ascertainment and research were supported in part through R01AG044546, RF1AG053303, RF1AG058501, U01AG058922 and R01AG064877. The University of Pittsburgh ascertainment and research were supported in part through AG030653 and AG005133.

  • Clark K, Leung YY, Lee WP, Voight B, Wang LS. Polygenic Risk Scores in Alzheimer’s Disease Genetics: Methodology, Applications, Inclusion, and Diversity. J Alzheimers Dis. 2022. doi: 10.3233/JAD-220025. PubMed link