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Journal ArticleDOI

Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology.

TL;DR: BIN1 transcript levels were increased in AD brains and a novel 3 bp insertion allele upstream of BIN1 was identified, which increased transcriptional activity in vitro and expression levels in human brain and AD risk in three independent case-control cohorts.
Abstract: Genome-wide association studies (GWAS) have identified a region upstream the BIN1 gene as the most important genetic susceptibility locus in Alzheimer’s disease (AD) after APOE. We report that BIN1 transcript levels were increased in AD brains and identified a novel 3 bp insertion allele ~28 kb upstream of BIN1, which increased (i) transcriptional activity in vitro, (ii) BIN1 expression levels in human brain and (iii) AD risk in three independent case-control cohorts (Meta-analysed Odds ratio of 1.20 (1.14–1.26) (P=3.8 × 10−11)). Interestingly, decreased expression of the Drosophila BIN1 ortholog Amph suppressed Tau-mediated neurotoxicity in three different assays. Accordingly, Tau and BIN1 colocalized and interacted in human neuroblastoma cells and in mouse brain. Finally, the 3 bp insertion was associated with Tau but not Amyloid loads in AD brains. We propose that BIN1 mediates AD risk by modulating Tau pathology.

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Citations
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Journal ArticleDOI
TL;DR: In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10−8) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.
Abstract: Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10−8) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.

3,726 citations

Journal ArticleDOI
07 Nov 2013-Cell
TL;DR: The super-enhancers are large clusters of transcriptional enhancers that drive expression of genes that define cell identity and play key roles in human cell identity in health and in disease as mentioned in this paper.

2,832 citations

Journal ArticleDOI
TL;DR: Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer’s disease but also with LOAD.
Abstract: Risk for late-onset Alzheimer’s disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer’s or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer’s disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10−7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

1,641 citations

Journal ArticleDOI
TL;DR: This poster aims to demonstrate the efforts towards in-situ applicability of EMMARM, which aims to provide real-time information about the physical and cognitive properties of Alzheimer's disease and other dementias.
Abstract: Defeating Alzheimer's disease and other dementias : a priority for European science and society

1,215 citations

Journal ArticleDOI
TL;DR: Understanding the mechanisms underlying the association of these genes with risk for disease will provide the most meaningful targets for therapeutic development to date.

935 citations


Cites background from "Increased expression of BIN1 mediat..."

  • ...BIN1 and tau interact in neuroblastoma cells and mouse brains (110)....

    [...]

  • ...The SNP rs59335482, in linkage disequilibrium with rs744373, is associated with elevated BIN1 mRNA expression and tau loads, but not tangles, in brains with AD (110)....

    [...]

  • ...Alterations in BIN1 protein levels are found in aged mice, AD mouse models, and human brains with AD (110,111)....

    [...]

  • ...BIN1 knockdown suppresses tau-induced toxicity in a Drosophila model of AD (110)....

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References
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Journal ArticleDOI
Denise Harold1, Richard Abraham2, Paul Hollingworth2, Rebecca Sims2, Amy Gerrish2, Marian L. Hamshere3, Jaspreet Singh Pahwa2, Valentina Moskvina2, Kimberley Dowzell2, Amy L. Williams2, Nicola L. Jones2, Charlene Thomas2, Alexandra Stretton2, Angharad R. Morgan2, Simon Lovestone4, John Powell5, Petroula Proitsi5, Michelle K. Lupton5, Carol Brayne6, David C. Rubinsztein7, Michael Gill6, Brian A. Lawlor6, Aoibhinn Lynch6, Kevin Morgan8, Kristelle Brown8, Peter Passmore9, David Craig9, Bernadette McGuinness9, Stephen Todd9, Clive Holmes10, David M. A. Mann11, A. David Smith12, Seth Love3, Patrick G. Kehoe3, John Hardy, Simon Mead13, Nick C. Fox13, Martin N. Rossor13, John Collinge13, Wolfgang Maier14, Frank Jessen14, Britta Schürmann14, Hendrik van den Bussche15, Isabella Heuser16, Johannes Kornhuber17, Jens Wiltfang18, Martin Dichgans19, Lutz Frölich20, Harald Hampel19, Harald Hampel21, Michael Hüll22, Dan Rujescu19, Alison Goate23, John S. K. Kauwe24, Carlos Cruchaga23, Petra Nowotny23, John C. Morris23, Kevin Mayo23, Kristel Sleegers25, Karolien Bettens25, Sebastiaan Engelborghs25, Peter Paul De Deyn25, Christine Van Broeckhoven25, Gill Livingston26, Nicholas Bass26, Hugh Gurling26, Andrew McQuillin26, Rhian Gwilliam27, Panagiotis Deloukas27, Ammar Al-Chalabi28, Christopher Shaw28, Magda Tsolaki29, Andrew B. Singleton30, Rita Guerreiro30, Thomas W. Mühleisen14, Markus M. Nöthen14, Susanne Moebus18, Karl-Heinz Jöckel18, Norman Klopp, H-Erich Wichmann19, Minerva M. Carrasquillo31, V. Shane Pankratz31, Steven G. Younkin31, Peter Holmans2, Michael Conlon O'Donovan2, Michael John Owen2, Julie Williams2 
TL;DR: A two-stage genome-wide association study of Alzheimer's disease involving over 16,000 individuals, the most powerful AD GWAS to date, produced compelling evidence for association with Alzheimer's Disease in the combined dataset.
Abstract: We undertook a two-stage genome-wide association study (GWAS) of Alzheimer's disease (AD) involving over 16,000 individuals, the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the apolipoprotein E (APOE) locus (most significant SNP, rs2075650, P = 1.8 10-157) and observed genome-wide significant association with SNPs at two loci not previously associated with the disease: at the CLU (also known as APOJ) gene (rs11136000, P = 1.4 10-9) and 5' to the PICALM gene (rs3851179, P = 1.9 10-8). These associations were replicated in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with Alzheimer's disease in the combined dataset (rs11136000, P = 8.5 10-10, odds ratio = 0.86; rs3851179, P = 1.3 10-9, odds ratio = 0.86).

2,956 citations

Journal ArticleDOI
TL;DR: In the version of this article initially published online, Simonetta Guarrera and Silvia Polidoro were inadvertently omitted from the author list, and an affiliation was omitted for Paolo Vineis as mentioned in this paper.
Abstract: Nat. Genet. 41, 991–995 (2009); published online 2 August; corrected online 23 August 2009 In the version of this article initially published online, Simonetta Guarrera and Silvia Polidoro were inadvertently omitted from the author list, and an affiliation was omitted for Paolo Vineis. These errors have been corrected in all versions of this article.

1,460 citations

Journal ArticleDOI
12 May 2010-JAMA
TL;DR: Although CLU and PICALM were confirmed to be associated with AD in this independent sample, they did not improve the ability of a model that included age, sex, and APOE to predict incident AD.
Abstract: Context Genome-wide association studies (GWAS) have recently identified CLU, PICALM, and CR1 as novel genes for late-onset Alzheimer disease (AD). Objectives To identify and strengthen additional loci associated with AD and confirm these in an independent sample and to examine the contribution of recently identified genes to AD risk prediction in a 3-stage analysis of new and previously published GWAS on more than 35 000 persons (8371 AD cases). Design, Setting, and Participants In stage 1, we identified strong genetic associations (P < 10−3) in a sample of 3006 AD cases and 14 642 controls by combining new data from the population-based Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (1367 AD cases [973 incident]) with previously reported results from the Translational Genomics Research Institute and the Mayo AD GWAS. We identified 2708 single-nucleotide polymorphisms (SNPs) with P<10−3. In stage 2, we pooled results for these SNPs with the European AD Initiative (2032 cases and 5328 controls) to identify 38 SNPs (10 loci) with P<10−5. In stage 3, we combined data for these 10 loci with data from the Genetic and Environmental Risk in AD consortium (3333 cases and 6995 controls) to identify 4 SNPs with P<1.7×10−8. These 4 SNPs were replicated in an independent Spanish sample (1140 AD cases and 1209 controls). Genome-wide association analyses were completed in 2007-2008 and the meta-analyses and replication in 2009. Main Outcome Measure Presence of Alzheimer disease. Results Two loci were identified to have genome-wide significance for the first time: rs744373 near BIN1 (odds ratio [OR],1.13; 95% confidence interval [CI],1.06-1.21 per copy of the minor allele; P = 1.59×10−11) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (OR, 1.18; 95% CI, 1.07-1.29; P = 6.45×10−9). Associations of these 2 loci plus the previously identified loci CLU and PICALM with AD were confirmed in the Spanish sample (P < .05). However, although CLU and PICALM were confirmed to be associated with AD in this independent sample, they did not improve the ability of a model that included age, sex, and APOE to predict incident AD (improvement in area under the receiver operating characteristic curve from 0.847 to 0.849 in the Rotterdam Study and 0.702 to 0.705 in the Cardiovascular Health Study). Conclusions Two genetic loci for AD were found for the first time to reach genome-wide statistical significance. These findings were replicated in an independent population. Two recently reported associations were also confirmed. These loci did not improve AD risk prediction. While not clinically useful, they may implicate biological pathways useful for future research.

1,194 citations

Journal ArticleDOI
Denise Harold, Richard Abraham, Paul Hollingworth, Rebecca Sims, Amy Gerrish, Marian L. Hamshere, Jaspreet Singh Pahwa, Valentina Moskvina, Kimberley Dowzell, Amy L. Williams, Nicola Jones, Charlene Thomas, Alexandra Stretton, Angharad R. Morgan, Simon Lovestone, John Powell, Petroula Proitsi, Michelle K. Lupton, Carol Brayne, David C. Rubinsztein, Michael Gill, Brian A. Lawlor, Aoibhinn Lynch, Kevin Morgan1, Kristelle Brown, Peter Passmore, David Craig1, Bernadette McGuinness, Stephen Todd, Clive Holmes, David G. Mann, A. David Smith1, Seth Love, Patrick G. Kehoe, John Hardy, Simon Mead, Nick C. Fox, Martin N. Rossor, John Collinge, Wolfgang Maier, Frank Jessen, Britta Schürmann, Reinhard Heun, Hendrik van den Bussche, Isabella Heuser, Johannes Kornhuber, Jens Wiltfang, Martin Dichgans, Lutz Frölich, Harald Hampel, Michael Hüll, Dan Rujescu, Alison Goate, John S. K. Kauwe, Carlos Cruchaga, Petra Nowotny, John C. Morris, Kevin Mayo, Kristel Sleegers, Karolien Bettens, Sebastiaan Engelborghs, Peter Paul De Deyn, Christine Van Broeckhoven, Gill Livingston, Nicholas Bass, Hugh Gurling, Andrew McQuillin, Rhian Gwilliam, Panagiotis Deloukas, Ammar Al-Chalabi, Christopher Shaw, Magda Tsolaki, Andrew B. Singleton, Rita Guerreiro, Thomas W Mühleisen, Markus M Nöthen, Susanne Moebus, Karl-Heinz Jöckel, Norman Klopp, H-Erich Wichmann, Minerva M. Carrasquillo, V. Shane Pankratz, Steven G. Younkin, Peter Holmans, Michael OtextquotesingleDonovan, Michael John Owen, Julie Williams 
TL;DR: A two-stage genome-wide association study of Alzheimer's disease involving over 16,000 individuals, the most powerful AD GWAS to date, produced compelling evidence for association with Alzheimer’s disease in the combined dataset.
Abstract: Nature GeNetics ADVANCE ONLINE PUBLICATION We undertook a two-stage genome-wide association study (GWAS) of Alzheimer’s disease (AD) involving over 16,000 individuals, the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the apolipoprotein E (APOE) locus (most significant SNP, rs2075650, P = 1.8 × 10−157) and observed genome-wide significant association with SNPs at two loci not previously associated with the disease: at the CLU (also known as APOJ) gene (rs11136000, P = 1.4 × 10−9) and 5 to the PICALM gene (rs3851179, P = 1.9 × 10−8). These associations were replicated in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with Alzheimer’s disease in the combined dataset (rs11136000, P = 8.5 × 10−10, odds ratio = 0.86; rs3851179, P = 1.3 × 10−9, odds ratio = 0.86).

1,185 citations

Related Papers (5)
Denise Harold, Richard Abraham, Paul Hollingworth, Rebecca Sims, Amy Gerrish, Marian L. Hamshere, Jaspreet Singh Pahwa, Valentina Moskvina, Kimberley Dowzell, Amy L. Williams, Nicola L. Jones, Charlene Thomas, Alexandra Stretton, Angharad R. Morgan, Simon Lovestone, John Powell, Petroula Proitsi, Michelle K. Lupton, Carol Brayne, David C. Rubinsztein, Michael Gill, Brian A. Lawlor, Aoibhinn Lynch, Kevin Morgan, Kristelle Brown, Peter Passmore, David Craig, Bernadette McGuinness, Stephen Todd, Clive Holmes, David M. A. Mann, A. David Smith, Seth Love, Patrick G. Kehoe, John Hardy, Simon Mead, Nick C. Fox, Martin N. Rossor, John Collinge, Wolfgang Maier, Frank Jessen, Britta Schürmann, Hendrik van den Bussche, Isabella Heuser, Johannes Kornhuber, Jens Wiltfang, Martin Dichgans, Lutz Frölich, Harald Hampel, Harald Hampel, Michael Hüll, Dan Rujescu, Alison Goate, John S. K. Kauwe, Carlos Cruchaga, Petra Nowotny, John C. Morris, Kevin Mayo, Kristel Sleegers, Karolien Bettens, Sebastiaan Engelborghs, Peter Paul De Deyn, Christine Van Broeckhoven, Gill Livingston, Nicholas Bass, Hugh Gurling, Andrew McQuillin, Rhian Gwilliam, Panagiotis Deloukas, Ammar Al-Chalabi, Christopher Shaw, Magda Tsolaki, Andrew B. Singleton, Rita Guerreiro, Thomas W. Mühleisen, Markus M. Nöthen, Susanne Moebus, Karl-Heinz Jöckel, Norman Klopp, H-Erich Wichmann, Minerva M. Carrasquillo, V. Shane Pankratz, Steven G. Younkin, Peter Holmans, Michael Conlon O'Donovan, Michael John Owen, Julie Williams