NG00050 - GWAS of CLU, A potential endophenotype for Alzheimer's disease

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Description

This dataset is part of a genome-wide association study investigating the role of Clusterin (CLU – Endophenotype for AD) in Alzheimer’s Disease. It includes imputed genotype data with 6,015,512 SNPs, using the 1000 Genomes Project data (June 2011 release) CEU (build 37) as a reference for the 673 participants included in the study.

The files provided within this dataset includes the genotypes for 50 out of 400 ADRC individuals, and, together with data from 283 ADNI subjects, accounts for the total of 673 subjects involved in the study. Data for the ADNI subjects can be requested from adni.loni.usc.edu, while the remaining 350 ADRC subjects can be obtained by applying for the NG00035 dataset.

Additional data in the Knight ADRC Collection can be accessed through https://www.niagads.org/knight-adrc-collection.

This dataset was originally published on the NIAGADS archive site and was moved to DSS on 02/03/2025.

Sample Summary per Data Type

Sample Set	Accession	Data Type	Number of Samples
Knight ADRC GWAS of CLU	snd10112	GWAS-Imputation	50

Available Filesets

Name	Accession	Latest Release	Description
Knight GWAS of CLU: 1000 Genome imputation and phenotypes	fsa000122	NG00050.v1	1000 Genome GWAS, imputation and phenotypes

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

Data Dictionary Files

Phenotype Data Dictionary

Genome-wide association studies have associated clusterin (CLU) variants with Alzheimer's disease (AD). However, the role of CLU on AD pathogenesis is not totally understood. We used cerebrospinal fluid (CSF) and plasma CLU levels as endophenotypes for genetic studies to understand the role of CLU in AD. CSF, but not plasma, CLU levels were significantly associated with AD status and CSF tau/amyloid-beta ratio, and highly correlated with CSF apolipoprotein E (APOE) levels. Several loci showed almost genome-wide significant associations including LINC00917 (p = 3.98 × 10(-7)) and interleukin 6 (IL6, p = 9.94 × 10(-6), in the entire data set and in the APOE ε4- individuals p = 7.40 × 10(-8)). Gene ontology analyses suggest that CSF CLU levels may be associated with wound healing and immune response which supports previous functional studies that demonstrated an association between CLU and IL6. CLU may play a role in AD by influencing immune system changes that have been observed in AD or by disrupting healing after neurodegeneration.

Sample Set	Accession Number	Number of Subjects	Number of Samples
Knight ADRC GWAS of CLU	snd10112	50	50

Available Subject Data	Consent Level	Number of Subjects
Genotypes	DS-ADRD-IRB-PUB	43
Genotypes	GRU-IRB-PUB	7
Phenotypes	DS-ADRD-IRB-PUB	388
Phenotypes	GRU-IRB-PUB	12

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

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 NG00050.

For investigators using Charles F. and Joanne Knight Alzheimer’s Disease Research Center (sa000008) data:

This work was supported by grants from the National Institutes of Health (R01AG044546, P01AG003991, RF1AG053303, R01AG058501, U01AG058922, RF1AG058501 and R01AG057777). The recruitment and clinical characterization of research participants at Washington University were supported by NIH P50 AG05681, P01 AG03991, and P01 AG026276. This work was supported by access to equipment made possible by the Hope Center for Neurological Disorders, and the Departments of Neurology and Psychiatry at Washington University School of Medicine.

We thank the contributors who collected samples used in this study, as well as patients and their families, whose help and participation made this work possible. This work was supported by access to equipment made possible by the Hope Center for Neurological Disorders, and the Departments of Neurology and Psychiatry at Washington University School of Medicine.

See below for additional dataset specific acknowledgments:

For use of the ADSP-PHC harmonized phenotypes deposited within dataset, ng00067, use the following statement:

The Memory and Aging Project at the Knight-ADRC (Knight-ADRC), supported by NIH grants R01AG064614, R01AG044546, RF1AG053303, RF1AG058501, U01AG058922 and R01AG064877 to Carlos Cruchaga. The recruitment and clinical characterization of research participants at Washington University was supported by NIH grants P30AG066444, P01AG03991, and P01AG026276. Data collection and sharing for this project was supported by NIH grants RF1AG054080, P30AG066462, R01AG064614 and U01AG052410. This work was supported by access to equipment made possible by the Hope Center for Neurological Disorders, the Neurogenomics and Informatics Center (NGI: https://neurogenomics.wustl.edu/) and the Departments of Neurology and Psychiatry at Washington University School of Medicine.

For use of ng00050 and ng00052, use the following statement:
This work was supported by Pfizer and grants from the National Institutes of Health (R01-AG044546, P01-AG003991), and the Alzheimer's Association (NIRG-11–200110). This research was conducted while Carlos Cruchaga was a recipient of a New Investigator Award in Alzheimer's disease from the American Federation for Aging Research. Carlos Cruchaga is a recipient of a BrightFocus Foundation Alzheimer's Disease Research Grant (A2013359S). The recruitment and clinical characterization of research participants at Washington University were supported by NIHP50 AG05681, P01 AG03991, and P01 AG026276. Some of the samples used in this study were genotyped by the ADGC and GERAD. ADGC is supported by grants from the NIH (#U01AG032984) and GERAD from the Wellcome Trust (GR082604MA) and the Medical Research Council (G0300429). Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen Idec; Bristol-Myers Squibb Company; Eisai; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd. and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC; Johnson & Johnson Pharmaceutical Research & Development LLC; Medpace; Merck; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Rev December 5, 2013 Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.

Total number of approved DARs: 4

Investigator:
Cruchaga, Carlos
Institution:
Washington University School of Medicine
Project Title:
The Familial Alzheimer Sequencing (FASe) Project
Date of Approval:
January 21, 2026
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:
Konermann, Silvana
Institution:
Arc institute
Project Title:
Modeling Alzheimer’s disease risk and associated molecular phenotypes
Date of Approval:
August 8, 2025
Request status:
Approved
Research use statements:
Show statements
Technical Research Use Statement:
The objective of the proposed research is to determine the relationship between Alzheimer’s disease (AD) genetic risk and associated molecular phenotypes. Genotype data will be used to compute a polygenic risk score (PRS) for disease-affected and control (non-disease-affected) participants. Statistical regression and mediation analyses will be used to model variation of molecular phenotypes with respect to PRS and, where available, pathology stage or cognitive impairment. Molecular phenotypes to be analyzed include bulk/single-cell/single-nucleus transcriptome, epigenome, proteome, metabolome, lipidome, amyloid, and tau. Molecular phenotypes of participants, including controls, will be matched with molecular phenotypes of in vitro cellular models, informing the design of in vitro perturbation experiments that recapitulate the genetic drivers of AD risk.
Non-Technical Research Use Statement:
Our goal is to determine the relationship between human genetic profiles associated with Alzheimer’s disease (AD) risk and specific measurable characteristics of human cells. Using multiple statistical analysis methods, we will build quantitative models that describe how those characteristics vary as a function of AD genetic risk. The models we build will help us design in vitro cellular systems that reflect different levels of AD risk, enabling experiments that inform new strategies for treating or preventing AD.
Investigator:
Seshadri, Sudha
Institution:
Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio, TX
Project Title:
Therapeutic target discovery in ADSP data via comprehensive whole-genome analysis incorporating ethnic diversity and systems approaches
Date of Approval:
August 12, 2025
Request status:
Approved
Research use statements:
Show statements
Technical Research Use Statement:
Objective: Utilize ADSP data sets to identify genes & specific genetic variants that confer risk for or protection from Alzheimer disease. Aim 1: Using combined WGS/WES across the ADSP Discovery, Disc-Ext, and FUS Phases, including single nucleotide variants, small insertion/deletions, and structural variants. We will: Aim 1a. Perform whole genome single variant and rare variant case/control association analyses of AD using ADSP and other available data; Aim 1b. Target protective variant identification via association analysis using selected controls within the ADSP data and performing meta analysis across association results based on selected controls from non-ADSP data sets. Aim 1c. Perform endophenotype analyses including cognitive function measures, hippocampal volume and circulation beta-amyloid ADSP data in subjects for which these measures are available. Meta analysis will be conducted across ADSP and non-ADSP analysis results. Aim 2: To leverage ethnically-diverse and admixed populations to identify AD variants we will: Aim 2a. Estimate and account for global and local ancestry in all analyses; Aim 2b. Perform admixture mapping in samples of admixed ancestry; and Aim 2c. Perform ethnicity-specific and trans-ethnic meta-analyses. Aim 3: To identify putative therapeutic targets through functional characterization of genes and networks via bioinformatics, integrative ‘omics analyses. We will: Aim 3a. Annotate variants with their functional consequences using bioinformatic tools and publicly available “omics” data. Aim 3b. Prioritize results, group variants with shared function, and identify key genes functionally related to AD via weighted association analyses and network approaches. Analyses will be performed in coordination with the following PIs. Coordination will involve sharing expertise, analysis plans or analysis results. No individual level data will be shared across institutions. Philip De Jager, Columbia University; Eric Boerwinkle & Myriam Fornage, U of Texas Health Science Center, Houston; Sudha Seshadri, U of Texas, San Antonio; Ellen Wijsman, U of Washington. William Salerno, Baylor College of Medicine
Non-Technical Research Use Statement:
This proposal seeks to analyze existing genetic sequencing data generated as part of the Alzheimer’s Disease Sequencing Project (ADSP) including the ADSP Follow-up Study (FUS) with the goal of identifying genes and specific changes within those genes that either confer risk for Alzheimer’s Disease or provide protection from Alzheimer’s Disease. Analytic challenges include analysis of whole genome sequencing data, appropriately accounting for population structure across European ancestry, Hispanic, and African American participants, and interpreting results in the context of other genomic data available.
Investigator:
Shelton, Janie
Institution:
Bristol Myers Squibb
Project Title:
A longitudinal study of Alzheimer’s Disease and other dementing illnesses – KnightADRC GWAS
Date of Approval:
January 30, 2026
Request status:
Approved
Research use statements:
Show statements
Technical Research Use Statement:
Recently approved Alzheimer’s disease (AD) therapies, such as lecanemab (Leqembi) and donanemab (Kisunla), represent a significant advancement toward disease-modifying treatment. However, their impact on cognitive decline remains modest, and both are associated with potentially serious adverse events, including amyloid-related imaging abnormalities (ARIA). These limitations underscore the urgent need for additional therapeutic strategies to reduce disease burden. Genetic approaches offer a powerful avenue for drug target discovery, with evidence suggesting that genetically supported targets are at least twice as likely to progress successfully through clinical development to FDA approval (Nelson et al., 2015, Nat Genet; King et al., 2019, PLoS Genet; Minikel et al., 2024, Nature). To date, most genetic studies in AD have focused on identifying loci associated with disease risk. Large-scale genome-wide association studies (GWAS) have uncovered approximately 75 risk loci (Bellenguez et al., 2022, Nat Genet), providing valuable insights into disease etiology. However, therapeutic interventions are typically aimed at individuals already diagnosed with AD, making the genetics of disease progression a critical—yet underexplored—complementary approach for target discovery. Progression-focused genetic studies face challenges due to limited availability of longitudinal phenotypic data. To address this, meta-analysis of multiple GWAS datasets offers a practical strategy to increase statistical power and detect robust associations. We propose to incorporate summary statistics from the Knight Alzheimer Disease Research Center (Knight-ADRC) AD progression GWAS into a meta-analysis alongside several publicly available and proprietary datasets. Our objective is to identify novel genetic drivers of AD progression, prioritize new therapeutic targets, and assess the impact of existing pipeline candidates on disease trajectory.
Non-Technical Research Use Statement:
New Alzheimer’s treatments like lecanemab (Leqembi) and donanemab (Kisunla) are an important step forward in the search for ways to help patients, but these drugs have only moderate benefits and can come with serious side effects. Better therapies are still needed to reduce the impact of the disease. Genetics offers a powerful way to discover new drugs—studies show that treatments based on genetic findings are more likely to succeed. So far most genetic research has focused on the genes which increase the risk of developing Alzheimer’s, but understanding genes that drive how the disease progresses in Alzheimer’s patients may be even more beneficial. However this type of data, which involves following participants over time, is limited, combining results from multiple smaller studies (a meta-analysis) can help uncover important patterns. We plan to add data from the Knight Alzheimer Disease Research Center to a larger analysis to find new genetic clues, identify better treatment targets, and evaluate how current and future drugs may slow disease progression.

Total number of samples: 50

Female 30 60.0 %

Male 20 40.0 %

Unknown: 0

Dementia
Control	30	60.0%
Case	20	40.0%

NG00050 – GWAS of CLU, A potential endophenotype for Alzheimer’s disease

Overview

Description

Sample Summary per Data Type

Available Filesets

Data Dictionary Files

Sample information

Related Studies

Cohorts

Consent Levels

Acknowledgement

Acknowledgment statement for any data distributed by NIAGADS:

For investigators using any data from this dataset:

For investigators using Charles F. and Joanne Knight Alzheimer’s Disease Research Center (sa000008) data:

Related Publications

Approved Users

Total number of samples: 50