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

Harold, Denise; Abraham, Richard; Hollingworth, Paul; Sims, Rebecca; Gerrish, Amy; Hamshere, Marian L.; Pahwa, Jaspreet Singh; Moskvina, Valentina; Dowzell, Kimberley; Williams, Amy L.; Jones, Nicola; Thomas, Charlene; Stretton, Alexandra; Morgan, Angharad R.; Lovestone, Simon; Powell, John; Proitsi, Petroula; Lupton, Michelle K.; Brayne, Carol; Rubinsztein, David C.; Gill, Michael; Lawlor, Brian A.; Lynch, Aoibhinn; Morgan, Kevin; Brown, Kristelle; Passmore, Peter; Craig, David; McGuinness, Bernadette; Todd, Stephen; Holmes, Clive; Mann, David; Smith, A.D.; Love, Seth; Kehoe, Patrick Gavin; Hardy, John; Mead, Simon; Fox, Nick C.; Rossor, Martin N.; Collinge, John; Maier, Wolfgang; Jessen, Frank; Schürmann, Britta; Bussche, Hendrik van den; Heuser, Isabella; Kornhuber, Johannes; Wiltfang, Jens; Dichgans, Martin; Frölich, Lutz; Hampel, Harald; Hüll, Michael; Rujescu, Dan; Goate, Alison M.; Kauwe, John; Cruchaga, Carlos; Nowotny, Petra; Morris, John C.; Mayo, Kevin H.; Sleegers, Kristel; Bettens, Karolien; Engelborghs, Sebastiaan; Deyn, Peter Paul De; Broeckhoven, Christine Van; Livingston, Gill; Bass, Nicholas; Gurling, Hugh; McQuillin, Andrew; Gwilliam, Rhian; Deloukas, Panos; Al‐Chalabi, Ammar; Shaw, Christopher E.; Tsolaki, Magda; Singleton, Andrew B.; Guerreiro, Rita; Mühleisen, Thomas W.; Nöthen, Markus M.; Moebus, Susanne; Jöckel, Karl‐Heinz; Klopp, Norman; Wichmann, H‐Erich; Carrasquillo, Minerva M.; Pankratz, V. Shane; Younkin, Steven G.; Holmans, Peter Alan; O'Donovan, Michael Conlon; Williams, Julie

doi:10.1038/ng.440

Cited by 2,769 publications

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References 57 publications

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“…Of the genes identified within the 2 Mb region surrounding the previously identified GWAS loci from the IGAP study,1, 2, 3, 4, 5, 6 several were nominally significant. CYP3A43 is a member of the cytochrome P450 superfamily of enzymes.…”

Section: Discussionmentioning

confidence: 95%

“…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%

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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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Section: Discussionmentioning

confidence: 95%

Section: Methodsmentioning

confidence: 99%

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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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“…It has previously been reported that the genetic structure in a population can be correlated with age 27. We investigated the possibility of this adversely affecting our results by performing an analogous analysis that compared the distribution of the PD score alleles between the oldest and youngest 5% (corresponding to <50 years and >87 years, respectively) of an independent cohort of Alzheimer disease (AD) patients (3,177 AD cases and 7,277 controls) 28. This failed to identify a significant difference in the distribution of the PD score alleles between the 2 age groups (minimum p = 0.49, data not presented).…”

Section: Resultsmentioning

confidence: 99%

Polygenic risk of Parkinson disease is correlated with disease age at onset

Escott‐Price¹,

Nalls

Morris

et al. 2015

Annals of Neurology

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125

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ObjectiveWe have investigated the polygenic architecture of Parkinson disease (PD) and have also explored the potential relationship between an individual's polygenic risk score and their disease age at onset.MethodsThis study used genotypic data from 4,294 cases and 10,340 controls obtained from the meta‐analysis of PD genome‐wide association studies. Polygenic score analysis was performed as previously described by the International Schizophrenia Consortium, testing whether the polygenic score alleles identified in 1 association study were significantly enriched in the cases relative to the controls of 3 independent studies. Linear regression was used to investigate the relationship between an individual's polygenic score for PD risk alleles and disease age at onset.ResultsOur polygenic score analysis has identified significant evidence for a polygenic component enriched in the cases of each of 3 independent PD genome‐wide association cohorts (minimum p = 3.76 × 10−6). Further analysis identified compelling evidence that the average polygenic score in patients with an early disease age at onset was significantly higher than in those with a late age at onset (p = 0.00014).InterpretationThis provides strong support for a large polygenic contribution to the overall heritable risk of PD and also suggests that early onset forms of the illness are not exclusively caused by highly penetrant Mendelian mutations, but can also be contributed to by an accumulation of common polygenic alleles with relatively low effect sizes. Ann Neurol 2015;77:582–591

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“…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

135

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

Cited by 2,769 publications

References 57 publications

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

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

Polygenic risk of Parkinson disease is correlated with disease age at onset

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

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