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Exome sequencing identifies novel AD-associated genes
NIH| The Electronic Medical Records and Genomics (eMERGE) Network, Phase III ,
NIH| Modifier Genes that Influence Age at Onset or Protect Against Development of Alzheimer's Disease (AD) ,
NIH| Consequences of Self-Neglect in a Biracial Population of Older People ,
NIH| Sequence-based Discovery of AD Risk & Protective Alleles ,
NIH| Clinical Core ,
NIH| Large Scale Genome Sequencing ,
NIH| ROLE FOR FIBROBLAST GROWTH FACTOR IN ALZHEIMERS DISEASE ,
NIH| Multi-ethnic genome-wide Alzheimer association study ,
NIH| ARIC Neurocognitive Study (ARIC-NCS) ,
NIH| ALZHEIMERS DISEASE RESEARCH CENTER ,
NIH| A Proteogenomic Approach to Understanding AD GWAS Results ,
NIH| CORONARY HEART DISEASE AND STROKE ,
NIH| CORONARY HEART DISEASE &STROKE IN PEOPLE AGED 65-84 ,
NIH| Role of LRP &its ligand tPA in LTP &aging ,
ANR| GENMED ,
NIH| Statistical Methods for Next-Gen Sequencing in Disease Association Studies ,
NWO| 100-plus ,
NWO| 100-plus ,
NIH| Building Research Infrastructure &Network in Chicago Chinatown ,
CIHR ,
NIH| Genetic Studies of Alzheimer's Disease in Caribbean Hispanics ,
NIH| UCLA Alzheimers Disease Research Center ,
NIH| Genetic Studies of Alzheimer Disease in Koreans ,
NIH| Alzheimers Disease in Mild Cognitive Impairment ,
NIH| CHS-Transition Phase -268055222 ,
NIH| Administrative Core ,
NIH| GENETIC DIFFERENCES IN ALZHEIMERS CASES AND CONTROLS ,
NIH| CHARGE consortium: gene discovery for CVD and aging phenotypes ,
NIH| Alzheimers Disease and Gene Discovery on Chromosome 9 ,
NIH| GENETIC EPIDEMIOLOGICAL STUDIES OF ALZHEIMERS DISEASE ,
NWO| NCHA Subsidiebesluit 2008-2012 ,
NIH| GENES, AGING, LEARNING AND DEMENTIA ,
NIH| CORONARY HEART DISEASE &STROKE IN PEOPLE AGED 65-84 ,
NIH| Gene discovery in PSP by transcriptome, neuropathology and sequence analysis ,
NIH| Genomes and Genetics at the BCM-HGSC ,
NIH| Mayo Alzheimers Disease Research Center ,
NIH| CORE--CLINICAL ,
NIH| Genetic Epidemiology of Alzheimers Disease in African Americans ,
NIH| Genetic Epidemiology of Early-Onset Alzheimers disease in Caribbean Hispanics and non-Hispanic Whites ,
NIH| Risk Factors, Pathology, and Clinical Expressions of AD ,
NIH| ARIC Neurocognitive Study (ARIC-NCS) ,
NIH| Genome wide association study of gene expression levels in Alzheimers disease ,
NIH| Consortium for Alzheimers Sequence Analysis (CASA) ,
NIH| Metabolic Factors in AD ,
FWF| Genetics of Cerebral Small Vessel Disease ,
NIH| Genomic Convergence in Alzheimer Disease ,
NIH| DATA MANAGEMENT AND BIOSTATISTICS ,
NIH| Epidemiologic Study of Neural Reserve and Neurobiology of Aging ,
NIH| Replication and Extension of ADSP Discoveries in African-Americans ,
NIH| AMYLOID DEPOSTION, VASCULAR DISEASE AND CLINICAL PROGRESSION OF AD ,
NIH| CORONARY HEART DISEASE AND STROKE ,
NIH| ALZHEIMERS DISEASE AND ANIMAL MODELS ,
FWF| MRI white matter abnormalities in the elderly: Genetic risk factors, rate of progression and neuropsychologic consequences ,
NIH| Large Scale Sequencing and Analysis of Genomes ,
NIH| THE FRAMINGHAM HEART STUDY-268025195 ,
NIH| Stanford Alzheimer's Disease Research Center ,
NIH| Next Generation gene discovery in neurogenetics ,
NIH| CENTRAL BLOOD ANALYSIS LABORATORY FOR CHS ,
NIH| Alzheimers Disease Center Core ,
NIH| Genetic Studies of Dementia in the Amish ,
NIH| A system approach to targeting innate immunity in AD ,
NIH| RISK FACTORS FOR INCIDENT AD IN A BIRACIAL COMMUNITY ,
NIH| Collaborative GWAS of Dementia, AD and related MRI and Cognitive Endophenotypes ,
NIH| Boston University Alzheimer's Disease Center ,
NIH| CHS research resources for the cardiovascular health of older adults ,
NIH| Exceptional aging: 12 year trajectories to function ,
NIH| Coordinating Center for Genetics and Genomics of Alzheimer's Disease (CGAD) ,
NIH| CORE--CLINICAL ,
NIH| QUANTITATIVE INDICES OF NEURON VULNERABILITY IN DEMENTIA ,
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NIH| ARIC Neurocognitive Study (ARIC-NCS) ,
NWO| Dissecting genetic complexity of Alzheimer's disease and cognitive function ,
WT| BRAINEACv2: a resource for the interpretation of genetic variation in multiple regions of the adult human brain ,
NIH| CORE--CLINICAL ,
NIH| CHARGE: Identifying Risk & Protective SNV for AD in ADSP Case-control Sample ,
NIH| The ARIC and Neurocognitive Longitudinal Study ,
NIH| MRI, Cognitive, Genetic and Biomarker Precursors of AD & Dementia in Young Adults ,
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NIH| ADSP Follow-up in Multi-Ethnic Cohorts via Endophenotypes, Omics & Model Systems ,
NIH| Temporal Trends, Novel Imaging and Molecular Characterization of Preclinical and Clinical Alzheimer's Disease in the Framingham Cohorts ,
NIH| COGNITIVE TESTS, APOE, BRAIN MRI AND RISKS OF DEMENTIA ,
NIH| Clinical Core ,
NIH| Epidemiology of Familial Late-Onset Alzheimer's Disease ,
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NIH| Whole Genome Sequencing in Ethnically Diverse Cohorts for the ADSP Follow-Up Study (FUS) ,
FWF| Mechanisms of Small Vessel Related Brain Damage and Cognitive Impairment ,
NIH| INDIANAPOLIS/IBADAN DEMENTIA PROJECT ,
NIH| Admin Supplement for University of Florida -Mt. Sinai Medical Center AD Research Center ,
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NIH| Sequence-based Discovery of AD Risk & Protective Alleles ,
NIH| Alzheimer Disease Genetic Architecture in African Americans ,
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NIH| Identification and characterization of AD risk networks using multi-dimensional 'omics' data ,
NIH| Alzheimer's Disease Genetics Consortium ,
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NIH| GENETIC LINKAGE STUDIES IN NEUROGENETIC DISORDERS ,
NIH| An Integrated Genomic Approach to Alzheimer Disease ,
NIH| PRECURSORS OF STROKE INCIDENCE AND PROGNOSIS ,
NIH| Genomic and Biological Studies of APOE ?2 in Alzheimer Disease ,
NIH| National Cell Repository for Alzheimer's Disease (NCRAD) ,
NIH| ALZHEIMERS DISEASE RESEARCH CENTER ,
NIH| Genetic Epidemiology and Multi-Omics Analyses in Familial and Sporadic Alzheimer's Disease Among Secular Caribbean Hispanics and Religious Order ,
NIH| Education and Information Transfer Core
Holstege, Henne; Grozeva, Detelina; Sims, Rebecca; Luckcuck, Lauren; Denning, Nicola; Marshall, Rachel; Saad, Salha; +82 Authors
Holstege, Henne; Grozeva, Detelina; Sims, Rebecca; Luckcuck, Lauren; Denning, Nicola; Marshall, Rachel; Saad, Salha; Williams, Julie; Meggy, Alun; Lambert, Jean-Charles; Hulsman, M.; Charbonnier, C.; Grenier-Boley, B.; Quenez, O.; van Rooij, J.; Ahmad, S.; Amin, N.; Norsworthy, P.; Dols, O.; Hummerich, H.; Kawalia, A.; Amouyel, P.; Beecham, G.; Berr, C.; Bis, J.; Boland, A.; Bossu, P.; Bouwman, F.; Campion, D.; Daniele, A.; Dartigues, J. F.; Debette, S.; Deleuze, J. F.; Destefano, A.; Farrer, L.; Fox, N.; Glimberti, D.; Genin, E.; Haines, J.; Holmes, C.; Arfan Ikram, M.; Ikram, M.; Jansen, I.; Kraaij, R.; Lathrop, M.; Lemstra, A.; Lleo, A.; Luckcuck, L.; Marschall, R.; Martin, E.; Masullo, C.; Mayeux, R.; Mecocci, P.; Mol, M.; Morgan, K.; Nacmia, B.; Naj, A.; Pastor, P.; Pericak-Vance, M.; Redon, R; Richard, A. C.; Riedel-Heller, S.; Rivadeneira, F.; Rousseau, S.; Ryan, N.; Sanchez-Juan, P.; Schellenberg, G.; Scheltens, P.; Scott, J.; Seripa, D.; Spalletta, G.; Tijms, B.; Uitterlinden, A.; van der Lee, S.; Wagner, M.; Wallon, D.; Wang, L. S.; Zarea, A.; Reinders, M.; Clarimon, J.; van Swieten, J.; Hardy, J.; Ramirez, A.; Mead, S. H.; van der Flier, W.; van Duijn, C.; Nicolas, G.; Bellenguez, C.; Lambert, J. C.;
Exome sequencing identifies novel AD-associated genes
The genetic component of Alzheimer’s disease (AD) has been mainly assessed using Genome Wide Association Studies (GWAS), which do not capture the risk contributed by rare variants. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals —16,036 AD cases and 16,522 controls— in a two-stage analysis. Next to known genes TREM2, SORL1 and ABCA7, we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10. Next to these genes, the rare variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential driver genes in AD-GWAS loci. Rare damaging variants in these genes, and in particular loss-of-function variants, have a large effect on AD-risk, and they are enriched in early onset AD cases. The newly identified AD-associated genes provide additional evidence for a major role for APP-processing, Aβ-aggregation, lipid metabolism and microglial function in AD.
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1. Bintener C, Miller O. Estimating the prevalence of dementia in Europe. Alzheimer Europe. 2020.
2. Gatz M, Reynolds CA, Fratiglioni L, Johansson B, Mortimer JA, Berg S, et al. Role of genes and environments for explaining Alzheimer disease. Archives of general psychiatry. 2006;63(2):168-74.
3. Lambert J, Ibrahim-Verbaas C, Harold D, Naj A, Sims R, Bellenguez C, et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nature genetics. 2013;45(12):1452-8.
4. Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Damotte V, Naj AC, et al. Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nature genetics. 2019;51(3):414-30.
5. Pottier C, Hannequin D, Coutant S, Rovelet-Lecrux A, Wallon D, Rousseau S, et al. High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease. Molecular psychiatry. 2012;17(9):875-9.
6. Cuyvers E, De Roeck A, Van den Bossche T, Van Cauwenberghe C, Bettens K, Vermeulen S, et al. Mutations in ABCA7 in a Belgian cohort of Alzheimer's disease patients: a targeted resequencing study. Lancet neurology. 2015;14(8):814-22.
7. Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, et al. Variant of TREM2 associated with the risk of Alzheimer's disease. The New England journal of medicine. 2013;368(2):107-16.
8. Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, et al. TREM2 variants in Alzheimer's disease. The New England journal of medicine. 2013;368(2):117-27.
9. Holstege H, van der Lee SJ, Hulsman M, Wong TH, van Rooij JG, Weiss M, et al. Characterization of pathogenic SORL1 genetic variants for association with Alzheimer's disease: a clinical interpretation strategy. European journal of human genetics : EJHG. 2017;25(8):973-81.
10. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993;261(5123):921-3.
citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).0 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Average influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Average impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Average views 0 downloads 163 citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).0 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Average influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Average impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Average - 163downloads
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This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
Citations provided by BIP!popularityPopularity provided by BIP!
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
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This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
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This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
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NIH| The Electronic Medical Records and Genomics (eMERGE) Network, Phase III, NIH| Modifier Genes that Influence Age at Onset or Protect Against Development of Alzheimer's Disease (AD), NIH| Consequences of Self-Neglect in a Biracial Population of Older People, NIH| Sequence-based Discovery of AD Risk & Protective Alleles
Project
- National Institutes of Health (NIH)
- 7U01HG008657-04
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE
Project
- National Institutes of Health (NIH)
- 5U01AG049508-03
- NATIONAL INSTITUTE ON AGING
Project
- National Institutes of Health (NIH)
- 3K23AG030944-02S1
- NATIONAL INSTITUTE ON AGING
Project
- National Institutes of Health (NIH)
- 5U01AG049507-03
- NATIONAL INSTITUTE ON AGING
Related to Research communities
The genetic component of Alzheimer’s disease (AD) has been mainly assessed using Genome Wide Association Studies (GWAS), which do not capture the risk contributed by rare variants. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals —16,036 AD cases and 16,522 controls— in a two-stage analysis. Next to known genes TREM2, SORL1 and ABCA7, we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10. Next to these genes, the rare variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential driver genes in AD-GWAS loci. Rare damaging variants in these genes, and in particular loss-of-function variants, have a large effect on AD-risk, and they are enriched in early onset AD cases. The newly identified AD-associated genes provide additional evidence for a major role for APP-processing, Aβ-aggregation, lipid metabolism and microglial function in AD.