Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease

Lambert, Jean‐Charles; Heath, Simon; Even, Gael; Campion, Dominique; Sleegers, Kristel; Hiltunen, Mikko; Cambarros, O; Zélénika, Diana; Bullido, María J.; Tavernier, B; Letenneur, Luc; Bettens, Karolien; Berr, Claudine; Pasquier, Florence; Fiévet, Nathalie; Barbager-Gateau, P; Engelborghs, S.; Deyn, PP De; Mateo, Ignacio; Franck, Alan R.; Helisalmi, Seppo; Porcellini, Elisa; Hanon, Olivier; Pancorbo, Marian de; Lendon, Corinne; Dufouil, Carole; Jaillard, C.; Léveillard, Thierry; Álvarez, Victoria; Bosco, Paolo; Mancuso, Michelangelo; Panza, Francesco; Nacmias, Benedetta; Bossù, Paola; Piccardi, Paola; Annoni, Giorgio; Seripa, Davide; Galimberti, Daniela; Hannequin, Didier; Licastro, Federico; Soininen, Hilkka; Ritchie, Karen; Blanché, Hél'ne; Jf, Dartigues; Tzourio, Christophe; Gut, Ivo; Broeckhoven, Christine Van; Alpérovitch, Annick; Amouyel, Philippe

doi:10.1038/ng.439

Cited by 2,081 publications

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References 77 publications

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“…Carbonyl reductase is elevated in hippocampi of 3xTg‐AD mice, which have markedly elevated levels of protein carbonylation (Shen et al ., 2015). Clusterin (ApoJ) polymorphism is associated with AD (Lambert et al ., 2009), and its circulating levels predict AD progression (Thambisetty et al ., 2010). Other apolipoproteins are also strongly linked to AD risk: ApoD catalyzes reduction of peroxidized lipids and its levels increase with age and AD, while ApoE has allele‐specific effects on Aβ levels and AD risk (Tai et al ., 2013; Dassati et al ., 2014).…”

Section: Discussionmentioning

confidence: 99%

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

et al. 2016

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SummaryNeurodegenerative diseases are distinguished by characteristic protein aggregates initiated by disease‐specific ‘seed’ proteins; however, roles of other co‐aggregated proteins remain largely unexplored. Compact hippocampal aggregates were purified from Alzheimer's and control‐subject pools using magnetic‐bead immunoaffinity pulldowns. Their components were fractionated by electrophoretic mobility and analyzed by high‐resolution proteomics. Although total detergent‐insoluble aggregates from Alzheimer's and controls had similar protein content, within the fractions isolated by tau or Aβ1–42 pulldown, the protein constituents of Alzheimer‐derived aggregates were more abundant, diverse, and post‐translationally modified than those from controls. Tau‐ and Aβ‐containing aggregates were distinguished by multiple components, and yet shared >90% of their protein constituents, implying similar accretion mechanisms. Alzheimer‐specific protein enrichment in tau‐containing aggregates was corroborated for individuals by three analyses. Five proteins inferred to co‐aggregate with tau were confirmed by precise in situ methods, including proximity ligation amplification that requires co‐localization within 40 nm. Nematode orthologs of 21 proteins, which showed Alzheimer‐specific enrichment in tau‐containing aggregates, were assessed for aggregation‐promoting roles in C. elegans by RNA‐interference ‘knockdown’. Fifteen knockdowns (71%) rescued paralysis of worms expressing muscle Aβ, and 12 (57%) rescued chemotaxis disrupted by neuronal Aβ expression. Proteins identified in compact human aggregates, bound by antibody to total tau, were thus shown to play causal roles in aggregation based on nematode models triggered by Aβ1–42. These observations imply shared mechanisms driving both types of aggregation, and/or aggregate‐mediated cross‐talk between tau and Aβ. Knowledge of protein components that promote protein accrual in diverse aggregate types implicates common mechanisms and identifies novel targets for drug intervention.

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Section: Discussionmentioning

confidence: 99%

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

et al. 2016

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“…The effect sizes of these genetic associations were much smaller than for APOE ,2, 6 with odds ratios ranging from 1.16 to 1.20. Follow‐up GWAS identified additional LOAD susceptibility variants 7, 8.…”

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confidence: 80%

“…The first large‐scale genome‐wide association studies (GWAS) using common single nucleotide polymorphisms (SNPs) identified CLU , PICALM , CR1, and BIN1 as late onset Alzheimer disease (LOAD) susceptibility loci,1, 2, 3 which were widely confirmed by others 4, 5. The effect sizes of these genetic associations were much smaller than for APOE ,2, 6 with odds ratios ranging from 1.16 to 1.20.…”

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confidence: 99%

Rare coding mutations identified by sequencing of Alzheimer disease genome‐wide association studies loci

Vardarajan

Ghani

Kahn

et al. 2015

Annals of Neurology

132

117

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ObjectiveTo detect rare coding variants underlying loci detected by genome‐wide association studies (GWAS) of late onset Alzheimer disease (LOAD).MethodsWe conducted targeted sequencing of ABCA7, BIN1, CD2AP, CLU, CR1, EPHA1, MS4A4A/MS4A6A, and PICALM in 3 independent LOAD cohorts: 176 patients from 124 Caribbean Hispanics families, 120 patients and 33 unaffected individuals from the 129 National Institute on Aging LOAD Family Study; and 263 unrelated Canadian individuals of European ancestry (210 sporadic patients and 53 controls). Rare coding variants found in at least 2 data sets were genotyped in independent groups of ancestry‐matched controls. Additionally, the Exome Aggregation Consortium was used as a reference data set for population‐based allele frequencies.ResultsOverall we detected a statistically significant 3.1‐fold enrichment of the nonsynonymous mutations in the Caucasian LOAD cases compared with controls (p = 0.002) and no difference in synonymous variants. A stop‐gain mutation in ABCA7 (E1679X) and missense mutation in CD2AP (K633R) were highly significant in Caucasian LOAD cases, and mutations in EPHA1 (P460L) and BIN1 (K358R) were significant in Caribbean Hispanic families with LOAD. The EPHA1 variant segregated completely in an extended Caribbean Hispanic family and was also nominally significant in the Caucasians. Additionally, BIN1 (K358R) segregated in 2 of the 6 Caribbean Hispanic families where the mutations were discovered.InterpretationTargeted sequencing of confirmed GWAS loci revealed an excess burden of deleterious coding mutations in LOAD, with the greatest burden observed in ABCA7 and BIN1. Identifying coding variants in LOAD will facilitate the creation of tractable models for investigation of disease‐related mechanisms and potential therapies. Ann Neurol 2015;78:487–498

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“…We also included known early‐onset AD genes and genes implicated in earlier sequencing efforts in LOAD 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16. Candidate genes evaluated included: APP, PSEN1, PSEN2, GRN, MAPT, TREM2, PLD3, APOE, ABCA7, SORL1, CR1, BIN1, CD2AP, EPHA1, CLU, MS4A6A, PICALM, CD33, HLA‐DRB5, HLA‐DRB1, PTK2B, SLC24A4, RIN3, INPP5D, MEF2C, NME8, ZCWPW1, CELF1, FERMT2, CASS4, TREML2, and AKAP9 .…”

Section: Methodsmentioning

confidence: 99%

“…Several genes within LOAD susceptibility loci cluster in specific pathways,1, 2, 3, 4, 5, 6 including amyloid processing, oxidative stress and immune or inflammatory pathways. Collectively, GWAS demonstrates that apart from the strongest risk factor, APOE‐ε4 a large number of loci with modest effect size also contribute to LOAD risk.…”

Section: Introductionmentioning

confidence: 99%

Whole genome sequencing of Caribbean Hispanic families with late‐onset Alzheimer's disease

Vardarajan

Barral

Jaworski

et al. 2018

Ann Clin Transl Neurol

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ObjectiveTo identify rare causal variants underlying known loci that segregate with late‐onset Alzheimer's disease (LOAD) in multiplex families.MethodsWe analyzed whole genome sequences (WGS) from 351 members of 67 Caribbean Hispanic (CH) families from Dominican Republic and New York multiply affected by LOAD. Members of 67 CH and additional 47 Caucasian families underwent WGS as a part of the Alzheimer's Disease Sequencing Project (ADSP). All members of 67 CH families, an additional 48 CH families and an independent CH case‐control cohort were subsequently genotyped for validation. Patients met criteria for LOAD, and controls were determined to be dementia free. We investigated rare variants segregating within families and gene‐based associations with disease within LOAD GWAS loci.ResultsA variant in AKAP9, p.R434W, segregated significantly with LOAD in two large families (OR = 5.77, 95% CI: 1.07–30.9, P = 0.041). In addition, missense mutations in MYRF and ASRGL1 under previously reported linkage peaks at 7q14.3 and 11q12.3 segregated completely in one family and in follow‐up genotyping both were nominally significant (P < 0.05). We also identified rare variants in a number of genes associated with LOAD in prior genome wide association studies, including CR1 (P = 0.049), BIN1 (P = 0.0098) and SLC24A4 (P = 0.040).Conclusions and RelevanceRare variants in multiple genes influence the risk of LOAD disease in multiplex families. These results suggest that rare variants may underlie loci identified in genome wide association studies.

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Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease

Cited by 2,081 publications

References 77 publications

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

Rare coding mutations identified by sequencing of Alzheimer disease genome‐wide association studies loci

Whole genome sequencing of Caribbean Hispanic families with late‐onset Alzheimer's disease

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