Dataset Information

Alzheimer's Disease Sequencing Project (ADSP)

ABSTRACT:

The overarching goals of the ADSP are to: (1) identify new genomic variants contributing to increased risk of developing AD, (2) identify new genomic variants contributing to protection against developing AD, and (3) provide insight as to why individuals with known risk factor variants escape from developing AD. Such a study of human genomic variation and its relationship to health and disease requires examination of a large number of study participants and needs to capture information about common and rare variants (both single nucleotide and copy number). Using existing samples from NIH funded and other studies, the NHGRI LSSC will produce the DNA sequence data and generate variant calls that will be made available to the scientific community through NIH-approved data repositories. Statistical analysis of the sequence data is anticipated to identify new genetic risk and protective factors. Both fundamental scientific discovery and leading edge analytic approaches will be needed to achieve the research goals. The ADSP will conduct and facilitate analysis of sequence data to extend previous discoveries that may ultimately result in new directions for AD therapeutics.

The specific aims of the ADSP are to: (1) identify protective genomic variants in older adults at risk for AD, (2) identify new risk variants among AD cases, and (3) examine these factors in multi-ethnic populations as applicable in order to identify new pathways for disease prevention.

For more information, please visit https://www.niagads.org/adsp/.

PROVIDER: phs000572.v1.p1 | EGA |

REPOSITORIES: EGA

ACCESS DATA

Publications

Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease.

Hollingworth Paul P Harold Denise D Sims Rebecca R Gerrish Amy A Lambert Jean-Charles JC Carrasquillo Minerva M MM Abraham Richard R Hamshere Marian L ML Pahwa Jaspreet Singh JS Moskvina Valentina V Dowzell Kimberley K Jones Nicola N Stretton Alexandra A Thomas Charlene C Richards Alex A Ivanov Dobril D Widdowson Caroline C Chapman Jade J Lovestone Simon S Powell John J Proitsi Petroula P Lupton Michelle K MK Brayne Carol C Rubinsztein David C DC Gill Michael M Lawlor Brian B Lynch Aoibhinn A Brown Kristelle S KS Passmore Peter A PA Craig David D McGuinness Bernadette B Todd Stephen S Holmes Clive C Mann David D Smith A David AD Beaumont Helen H Warden Donald D Wilcock Gordon G Love Seth S Kehoe Patrick G PG Hooper Nigel M NM Vardy Emma R L C ER Hardy John J Mead Simon S Fox Nick C NC Rossor Martin M Collinge John J Maier Wolfgang W Jessen Frank F Rüther Eckart E Schürmann Britta B Heun Reiner R Kölsch Heike H van den Bussche Hendrik H Heuser Isabella I Kornhuber Johannes J Wiltfang Jens J Dichgans Martin M Frölich Lutz L Hampel Harald H Gallacher John J Hüll Michael M Rujescu Dan D Giegling Ina I Goate Alison M AM Kauwe John S K JS Cruchaga Carlos C Nowotny Petra P Morris John C JC Mayo Kevin K Sleegers Kristel K Bettens Karolien K Engelborghs Sebastiaan S De Deyn Peter P PP Van Broeckhoven Christine C Livingston Gill G Bass Nicholas J NJ Gurling Hugh H McQuillin Andrew A Gwilliam Rhian R Deloukas Panagiotis P Al-Chalabi Ammar A Shaw Christopher E CE Tsolaki Magda M Singleton Andrew B AB Guerreiro Rita R Mühleisen Thomas W TW Nöthen Markus M MM Moebus Susanne S Jöckel Karl-Heinz KH Klopp Norman N Wichmann H-Erich HE Pankratz V Shane VS Sando Sigrid B SB Aasly Jan O JO Barcikowska Maria M Wszolek Zbigniew K ZK Dickson Dennis W DW Graff-Radford Neill R NR Petersen Ronald C RC van Duijn Cornelia M CM Breteler Monique M B MM Ikram M Arfan MA DeStefano Anita L AL Fitzpatrick Annette L AL Lopez Oscar O Launer Lenore J LJ Seshadri Sudha S Berr Claudine C Campion Dominique D Epelbaum Jacques J Dartigues Jean-François JF Tzourio Christophe C Alpérovitch Annick A Lathrop Mark M Feulner Thomas M TM Friedrich Patricia P Riehle Caterina C Krawczak Michael M Schreiber Stefan S Mayhaus Manuel M Nicolhaus S S Wagenpfeil Stefan S Steinberg Stacy S Stefansson Hreinn H Stefansson Kari K Snaedal Jon J Björnsson Sigurbjörn S Jonsson Palmi V PV Chouraki Vincent V Genier-Boley Benjamin B Hiltunen Mikko M Soininen Hilkka H Combarros Onofre O Zelenika Diana D Delepine Marc M Bullido Maria J MJ Pasquier Florence F Mateo Ignacio I Frank-Garcia Ana A Porcellini Elisa E Hanon Olivier O Coto Eliecer E Alvarez Victoria V Bosco Paolo P Siciliano Gabriele G Mancuso Michelangelo M Panza Francesco F Solfrizzi Vincenzo V Nacmias Benedetta B Sorbi Sandro S Bossù Paola P Piccardi Paola P Arosio Beatrice B Annoni Giorgio G Seripa Davide D Pilotto Alberto A Scarpini Elio E Galimberti Daniela D Brice Alexis A Hannequin Didier D Licastro Federico F Jones Lesley L Holmans Peter A PA Jonsson Thorlakur T Riemenschneider Matthias M Morgan Kevin K Younkin Steven G SG Owen Michael J MJ O'Donovan Michael M Amouyel Philippe P Williams Julie J

Nature genetics 20110403 5

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed ...[more]

PMID: 21460840

Publication: 1/5

Similar Datasets

Project description:LOCATION CHANGE FOR ALZHEIMER'S DISEASE SEQUENCING PROJECT (ADSP) DATA: Please go to <a href="https://dss.niagads.org/" target="_blank">NIAGADS DSS</a> to apply for build 38 ADSP genetic and phenotypic data. See Background below for more details. For instructions on how to access the additional ADSP data that are shared through <a href="https://dss.niagads.org/" target="_blank">NIAGADS DSS</a>, visit the <a href="https://dss.niagads.org/documentation/" target="_blank">Application Instructions</a> page. Background: Additional sequencing data are continuously being generated by the ADSP. These data are mapped to the latest Genome Reference Consortium human genome build GRCh38 (hg38) and are being shared through the NIA Genetics of Alzheimer's Disease Data Storage Site (<a href="https://www.niagads.org/" target="_blank">NIAGADS</a>) Data Sharing Service (<a href="https://dss.niagads.org/" target="_blank">DSS</a>). As of May 1, 2020 there are 4,789 whole genomes and 19,922 whole exomes available to the research community. Later in 2020 there will be a total of ~17,000 whole genomes and 19,922 whole exomes available through NIAGADS DSS (<a href="https://dss.niagads.org/datasets/ng00067/" target="_blank">ng00067</a>). The total number of genomes from multi-ethnic cohorts is anticipated to exceed 50,000. Please see the <a href="https://www.niagads.org/adsp/content/study-design">ADSP Design</a> page for the complete study description. ADSP whole exome and whole genome sequence data that were shared through dbGaP were mapped to the GRCh37 (build 37). These data are from the Discovery Phase of the project (described below) and will continue to be available at this site. STUDY DESCRIPTION FOR dbGaP BUILD 37 ADSP DATA: The overarching goals of the Alzheimer's Disease Sequencing Project (ADSP) are to: (1) identify new genomic variants contributing to increased risk of developing Alzheimer's Disease (AD), (2) identify new genomic variants contributing to protection against developing AD, and (3) provide insight as to why individuals with known risk factor variants escape from developing AD. These factors will be studied in multi-ethnic populations in order to identify new pathways for disease prevention. Such a study of human genomic variation and its relationship to health and disease requires examination of a large number of study participants and needs to capture information about common and rare variants (both single nucleotide and copy number) in well phenotyped individuals. Using existing samples from NIH funded and other studies, three NHGRI funded Large Scale Sequencing and Analysis Centers (LSAC) - Broad, Baylor, and Washington University - produced the DNA sequence data. Variant call data are being made available to the scientific community through NIH-approved data repositories. Statistical analysis of the sequence data is anticipated to identify new genetic risk and protective factors. The ADSP will conduct and facilitate analysis of sequence data to extend previous discoveries that may ultimately result in new directions for AD therapeutics. Analysis of ADSP data will be done in two phases. The Discovery Phase analysis (2014-2018) is funded under <a href="http://grants.nih.gov/grants/guide/pa-files/PAR-12-183.html">PAR-12-183</a>. The entire Discovery dataset contains whole-genome sequencing data on 584 subjects from 113 families, and pedigree data for > 4000 subjects; whole exome sequencing data on 5096 cases 4965 controls; and whole exome sequence data on an additional 853 (682 Cases [510 Non-Hispanic, 172 Hispanic]), and 171 Hispanic Control subjects from families that are multiply affected with AD. The Replication Phase (2016-2021) analysis will be funded under <a href="http://grants.nih.gov/grants/guide/rfa-files/RFA-AG-16-001.html">RFA-AG-16-001</a> and <a href="http://grants.nih.gov/grants/guide/rfa-files/RFA-AG-16-002.html">RFA-AG-16-002</a> and is expected to include a combination of genotyping and sequencing approaches on at least 30,000 subjects. Targeted sequencing will be done by the LSACs. GRCh37 Data Releases <ul> <li>The first ADSP data release occurred on November 25, 2013. It included the whole-genome sequencing data in BAM file format on 410 individuals.</li> <li>The second ADSP data release occurred on March 31, 2014, and included the whole-genome sequencing data in BAM file format for an additional 168 individuals.</li> <li>The third ADSP data release occurred on November 03, 2014 and included whole-exome sequencing data in BAM file format for 10,939 individuals.</li> <li>The fourth ADSP data release occurred on February 13, 2015 and included revised ethnic data for subjects with whole-exome sequencing data.</li> <li>The fifth ADSP data release occurred on July 13, 2015 and included whole-genome genotypes and updated phenotypes as well as changes to pedigree structures and sample IDs.</li> <li>The sixth ADSP data release occurred on December 8, 2015, and included whole-exome genotypes and updated phenotypes as well as changes to subject IDs.</li> </ul> This seventh ADSP data release on April 12, 2016 includes: <ul> (1) WES and WGS SNV VCF files (2) WES and WGS Indel PLINK files </ul> ADSP Data Available through dbGaP: <table border="1"> <tr> <th></th> <th>ADSP - Whole Genome Sequencing</th> <th>ADSP - Whole Exome Sequencing</th> <th>Comments</th> </tr> <tr> <td>DNA-Seq (BAM)</td> <td>n=578</td> <td>n=10913</td> <td>Sequence data available (plus n=38 replications w/out genotype data)</td> </tr> <tr> <td>Concordant SNV Genotypes (PLINK format)</td> <td>N/A</td> <td>n=10913</td> <td>QC'ed genotypes that are concordant between the Atlas (Baylor's) and GATK (Broad's) calling pipelines (a subset of the consensus genotype set)</td> </tr> <tr> <td>Consensus Genotypes (PLINK and VCF format)</td> <td>n=578</td> <td>n=10913</td> <td>QC'ed genotypes that are concordant between Atlas and GATK pipelines as well as those that that were called uniquely by Atlas or GATK</td> </tr> <tr> <td>Concordant Indel Genotypes (PLINK format)</td> <td>n=578</td> <td>n=10913</td> <td>QC'ed genotypes that are concordant between the Atlas and GATK calling pipelines</td> </tr> <tr> <td>Phenotype Data</td> <td>n=4735</td> <td>n=10913</td> <td>Data of n=53 phenotype variables available (plus administrative data), including APOE genotype. WGS phenotypes include data of connecting family members.</td> </tr> </table> Please use the <a href="ftp://ftp.ncbi.nlm.nih.gov/dbgap/studies/phs000572/phs000572.v7.p4/">release notes</a> provided by dbGaP to obtain detailed information about study release updates. The <a href="https://www.niagads.org/adsp/portal/">ADSP data portal</a> provides a customized interface for users to quickly identify and retrieve files by covariates, phenotypes, and data properties such as sequencing facility or coverage. For more information about the ADSP study and the data portal, please visit <a href="https://www.niagads.org/adsp/">https://www.niagads.org/adsp/</a>.

Project description:Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by a progressive cognitive decline. Epidemiological studies have suggested a protective role of caffeine consumption against age-related cognitive impairments and the risk of developing AD. Effects of caffeine have been particularly ascribed to its ability to block adenosine A2A receptors (A2ARs). Early pathological upregulation of these receptors by neurons is thought to be involved in the development of synaptic and memory deficits in AD but this remains ill-defined. To tackle this question, we employed a novel transgenic mouse model allowing to promote a neuronal upregulation of A2AR in the hippocampus of APP/PS1 mice, developing AD-like amyloidogenesis. This new model was used to determine the impact of an early upregulation of A2AR on the progression of neuropathological lesions, associated behavior and underlying mechanisms in APP/PS1 mice. Our findings revealed that the early upregulation of A2AR in the presence of an ongoing amyloid pathology exacerbates memory impairments of APP/PS1 mice. These behavioral changes were not linked to major change in the development of amyloid pathology but rather associate with an increased p-tau at neuritic plaques. Moreover, proteomic and transcriptomic analysis coupled to quantitative immunofluorescence studies indicated that neuronal impairment of the receptor promoted both neuronal- and non-neuronal autonomous alterations i.e. loss of excitatory synapses and neuroinflammatory response, respectively, both presumably accounting for the detrimental effect on memory. Overall, our results provide compelling evidence that neuronal A2AR dysfunction as seen in the brain of patients contributes to AD pathogenesis, favoring synaptic deficits promoted by both amyloid (this study) and tau lesions (our previous study). In addition to provide new insights into the complex pathophysiology of AD, the present findings underscore the potential of A2AR as a relevant therapeutic target for mitigating early synaptic loss in this neurodegenerative disorder.

Dataset Information

Alzheimer's Disease Sequencing Project (ADSP)

Publications

Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease.

Similar Datasets

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