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12 results on '"GERAD Consortium"'

1. Polygenic risk and hazard scores for Alzheimer's disease prediction

Author

Leonenko, Ganna, Sims, Rebecca, Shoai, Maryam, Frizzati, Aura, Bossù, Paola, Spalletta, Gianfranco, Fox, Nick C, Williams, Julie, GERAD Consortium, Hardy, John, Escott-Price, Valentina, Leonenko, Ganna [0000-0001-8025-661X], and Apollo - University of Cambridge Repository

Subjects
Male, Multifactorial Inheritance, Apolipoproteins E, Alzheimer Disease, Risk Factors, Case-Control Studies, Humans, Female, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Proportional Hazards Models
Abstract

Objective: Genome‐wide association studies (GWAS) have identified over 30 susceptibility loci associated with Alzheimer's disease (AD). Using AD GWAS data from the International Genomics of Alzheimer's Project (IGAP), Polygenic Risk Score (PRS) was successfully applied to predict life time risk of AD development. A recently introduced Polygenic Hazard Score (PHS) is able to quantify individuals with age‐specific genetic risk for AD. The aim of this study was to quantify the age‐specific genetic risk for AD with PRS and compare the results generated by PRS with those from PHS. Methods: Quantification of individual differences in age‐specific genetic risk for AD identified by the PRS, was performed with Cox Regression on 9903 (2626 cases and 7277 controls) individuals from the Genetic and Environmental Risk in Alzheimer's Disease consortium (GERAD). Polygenic Hazard Scores were generated for the same individuals. The age‐specific genetic risk for AD identified by the PRS was compared with that generated by the PHS. This was repeated using varying SNPs P‐value thresholds for disease association. Results: Polygenic Risk Score significantly predicted the risk associated with age at AD onset when SNPs were preselected for association to AD at P ≤ 0.001. The strongest effect (B = 0.28, SE = 0.04, P = 2.5 × 10−12) was observed for PRS based upon genome‐wide significant SNPs (P ≤ 5 × 10−8). The strength of association was weaker with less stringent SNP selection thresholds. Interpretation: Both PRS and PHS can be used to predict an age‐specific risk for developing AD. The PHS approach uses SNP effect sizes derived with the Cox Proportional Hazard Regression model. When SNPs were selected based upon AD GWAS case/control P ≤ 10−3, we found no advantage of using SNP effects sizes calculated with the Cox Proportional Hazard Regression model in our study. When SNPs are selected for association with AD risk at P > 10−3, the age‐specific risk prediction results are not significant for either PRS or PHS. However PHS could be more advantageous than PRS of age specific AD risk predictions when SNPs are prioritized for association with AD age at onset (i.e., powerful Cox Regression GWAS study).

Published
2019

2. P2‐122: COMPARING RESULTS OF POLYGENIC RISK SCORE AND POLYGENIC HAZARD SCORE IN PREDICTION OF AGE SPECIFIC RISK FOR DEVELOPING ALZHEIMER'S DISEASE

Author

Ganna Leonenko, Aura Frizzati, Rebecca Sims, Maryam Shoai, Gerad Consortium, John Hardy, Julie Williams, and Valentina Escott-Price

Subjects
Epidemiology, business.industry, Health Policy, Disease, Age specific, Hazard, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Medicine, Polygenic risk score, Neurology (clinical), Geriatrics and Gerontology, business, Demography
Published
2018
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3. POLARIS: Polygenic LD-adjusted risk score approach for set-based analysis of GWAS data

Author

Emily, Baker, Karl Michael, Schmidt, Rebecca, Sims, Michael C, O'Donovan, Julie, Williams, Peter, Holmans, Valentina, Escott-Price, and With The Gerad, Consortium

Subjects
Multifactorial Inheritance, Principal Component Analysis, Phenotype, Models, Genetic, Risk Factors, Humans, Computer Simulation, Polymorphism, Single Nucleotide, Alleles, Linkage Disequilibrium, Genome-Wide Association Study
Abstract

Polygenic risk scores (PRSs) are a method to summarize the additive trait variance captured by a set of SNPs, and can increase the power of set-based analyses by leveraging public genome-wide association study (GWAS) datasets. PRS aims to assess the genetic liability to some phenotype on the basis of polygenic risk for the same or different phenotype estimated from independent data. We propose the application of PRSs as a set-based method with an additional component of adjustment for linkage disequilibrium (LD), with potential extension of the PRS approach to analyze biologically meaningful SNP sets. We call this method POLARIS: POlygenic Ld-Adjusted RIsk Score. POLARIS identifies the LD structure of SNPs using spectral decomposition of the SNP correlation matrix and replaces the individuals' SNP allele counts with LD-adjusted dosages. Using a raw genotype dataset together with SNP effect sizes from a second independent dataset, POLARIS can be used for set-based analysis. MAGMA is an alternative set-based approach employing principal component analysis to account for LD between markers in a raw genotype dataset. We used simulations, both with simple constructed and real LD-structure, to compare the power of these methods. POLARIS shows more power than MAGMA applied to the raw genotype dataset only, but less or comparable power to combined analysis of both datasets. POLARIS has the advantages that it produces a risk score per person per set using all available SNPs, and aims to increase power by leveraging the effect sizes from the discovery set in a self-contained test of association in the test dataset.

Published
2017

4. Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer’s disease

Author

Lambert, J. C., Grenier-Boley, B., Harold, D., Zelenika, D., Chouraki, V., Kamatani, Y., Sleegers, K., Ikram, M.A., Hiltunen, M., Reitz, Christiane, Mateo, I., Feulner, T., Bullido, M., Galimberti, D., Concari, L., Alvarez, V., Sims, R., Gerrish, A., Chapman, J., Deniz-Naranjo, C., Solfrizzi, V., Sorbi, S., Arosio, B., Spalletta, G., Siciliano, G., Epelbaum, J., Hannequin, D., Dartigues, J. F., Tzourio, C., Berr, C., Schrijvers, E. M. C., Rogers, R., Tosto, Giuseppe, Pasquier, F., Bettens, K., Van Cauwenberghe, C., Fratiglioni, L., Graff, C., Delepine, M., Ferri, R., Reynolds, C. A., Lannfelt, L., Ingelsson, M., Prince, J. A., Pilotto, A., Chillotti, C., Seripa, D., Boland, A., Mancuso, M., Bossu, P., Annoni, G., Nacmias, B., Bosco, P., Panza, F., Sanchez-Garcia, F., Del Zompo, M., Coto, E., Owen, M., Valdivieso, F., O'Donovan, M., Caffara, P., Scarpini, E., Campion, D., Buee, L., Combarros, O., Soininen, H., Breteler, M., Riemenschneider, M., Van Broeckhoven, C., Alperovitch, A., Williams, J., Lathrop, M., Tregouet, D. A., Amouyel, P., EADI Consortium, and GERAD Consortium

Subjects
Molecular biology, FOS: Biological sciences, Genetics, Psychobiology
Abstract

Recently, several genome-wide association studies (GWASs) have led to the discovery of nine new loci of genetic susceptibility in Alzheimer's disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP (single-nucleotide polymorphism) analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches. We performed a genome-wide haplotype association (GWHA) study in the EADI1 study (n=2025 AD cases and 5328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2820 AD cases and 6356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case–control studies (5093 AD cases and 4061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analyzed (OR: 1.68; 95% CI: (1.43–1.96); P=1.1 × 10−10). We finally searched for association between SNPs within the FRMD4A locus and Aβ plasma concentrations in three independent non-demented populations (n=2579). We reported that polymorphisms were associated with plasma Aβ42/Aβ40 ratio (best signal, P=5.4 × 10−7). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD.

Published
2012
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5. Genome-wide association study of Alzheimer's disease with psychotic symptoms

Author

Hollingworth, P., Sweet, R., Sims, R., Harold, D., Russo, G., Abraham, R., Stretton, A., Jones, N., Gerrish, A., Chapman, J., Ivanov, D., Moskvina, V., Lovestone, S., Priotsi, P., Lupton, M., Brayne, C., Gill, M., Lawlor, B., Lynch, A., Craig, D., McGuinness, B., Johnston, J., Holmes, C., Livingston, G., Bass, N. J., Gurling, H., McQuillin, A., GERAD Consortium, National Institute on Aging Late-Onset Alzheimer's Disease Family Study Group, Holmans, P., Devlin, B., Klei, L., Barmada, M. M., Demirci, F. Y., DeKosky, S. T., Lopez, O. L., Passmore, P., Owen, M. J., O'Donovan, M. C., Mayeux, R., Kamboh, M. I., Williams, J., Wiltfang, J. (Beitragende*r), Moebus, Susanne (Beitragende*r), and Jöckel, Karl-Heinz (Beitragende*r)

Subjects
Medizin
Published
2012

7. P1‐088: An examination of APP, PSEN1, PSEN2 and MAPT within a large genome‐wide association dataset

Author

Amy Gerrish, Jade Chapman, Denise Harold, Rebecca Sims, Paul Hollingworth, Richard Abraham, and null GERAD Consortium, Michael Owen, Julie Williams

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, PSEN2, PSEN1, Genome-wide association study, Neurology (clinical), Computational biology, Geriatrics and Gerontology, Biology
Published
2010
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8. Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology.

Author

UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, Chapuis, J, Hansmannel, F, Gistelinck, M, Mounier, A, Van Cauwenberghe, C, Kolen, K V, Geller, F, Sottejeau, Y, Harold, D, Dourlen, P, Grenier-Boley, B, Kamatani, Y, Delepine, B, Demiautte, F, Zelenika, D, Zommer, N, Hamdane, M, Bellenguez, C, Dartigues, J-F, Hauw, J-J, Letronne, F, Ayral, A-M, Sleegers, K, Schellens, A, Broeck, L V, Engelborghs, S, De Deyn, P P, Vandenberghe, R, O'Donovan, M, Owen, M, Epelbaum, J, Mercken, M, Karran, E, Bantscheff, M, Drewes, G, Joberty, G, Campion, D, Octave, Jean-Noël, Berr, C, Lathrop, M, Callaerts, P, Mann, D, Williams, J, Buée, L, Dewachter, Ilse, Van Broeckhoven, C, Amouyel, P, Moechars, D, Dermaut, B, Lambert, J-C, GERAD consortium, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, Chapuis, J, Hansmannel, F, Gistelinck, M, Mounier, A, Van Cauwenberghe, C, Kolen, K V, Geller, F, Sottejeau, Y, Harold, D, Dourlen, P, Grenier-Boley, B, Kamatani, Y, Delepine, B, Demiautte, F, Zelenika, D, Zommer, N, Hamdane, M, Bellenguez, C, Dartigues, J-F, Hauw, J-J, Letronne, F, Ayral, A-M, Sleegers, K, Schellens, A, Broeck, L V, Engelborghs, S, De Deyn, P P, Vandenberghe, R, O'Donovan, M, Owen, M, Epelbaum, J, Mercken, M, Karran, E, Bantscheff, M, Drewes, G, Joberty, G, Campion, D, Octave, Jean-Noël, Berr, C, Lathrop, M, Callaerts, P, Mann, D, Williams, J, Buée, L, Dewachter, Ilse, Van Broeckhoven, C, Amouyel, P, Moechars, D, Dermaut, B, Lambert, J-C, and GERAD consortium

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.

Published
2013

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

Author

Diana Zelenika, Luc Buée, C. Van Broeckhoven, Franck Hansmannel, A-M Ayral, Kristof Van Kolen, C. Van Cauwenberghe, P.P. De Deyn, Marcus Bantscheff, Y Kamatani, Julie Williams, Rik Vandenberghe, Claudine Berr, Dominique Campion, Benjamin Grenier-Boley, N Zommer, Jacques Epelbaum, Michael John Owen, M Hamdane, Diederik Moechars, Céline Bellenguez, J-J Hauw, Denise Harold, J-N Octave, Patrick Callaerts, Julien Chapuis, J. F. Dartigues, Yoann Sottejeau, David M. A. Mann, Michael Conlon O'Donovan, Ilse Dewachter, Pierre Dourlen, Gerard Joberty, Anais Mounier, Florie Demiautte, Sebastiaan Engelborghs, Marc Gistelinck, J-C Lambert, Florent Letronne, Eric Karran, A Schellens, Lies Vanden Broeck, Bart Dermaut, Kristel Sleegers, M Mercken, Philippe Amouyel, B Delepine, Mark Lathrop, F Geller, Gerard Drewes, Faculty of Psychology and Educational Sciences, Clinical sciences, Neuroprotection & Neuromodulation, Neurology, and GERAD Consortium

Subjects
Apolipoprotein E, Mathematics(all), BIN1, Gene Expression, Genome-wide association study, Plaque, Amyloid, Mice, 0302 clinical medicine, Gene expression, Drosophila Proteins, ALZHEIMER, Cells, Cultured, Medicine(all), 0303 health sciences, Nuclear Proteins, Human brain, 3. Good health, Psychiatry and Mental health, Chemistry, medicine.anatomical_structure, Drosophila melanogaster, Original Article, Drosophila, Alzheimer's disease, Endophenotypes, brain, tau Proteins, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Cellular and Molecular Neuroscience, Alzheimer Disease, Genetic predisposition, medicine, Animals, Humans, Genetic Predisposition to Disease, Allele, Molecular Biology, 030304 developmental biology, Adaptor Proteins, Signal Transducing, Tumor Suppressor Proteins, Neurotoxicity, medicine.disease, Molecular biology, Case-Control Studies, Nerve Degeneration, Alzheimer, Human medicine, Tau, Carrier Proteins, 030217 neurology & neurosurgery, Synaptosomes, Transcription Factors
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. ispartof: Molecular Psychiatry vol:18 issue:11 pages:1225-1234 ispartof: location:England status: published

Published
2013
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10. TREM2 variants in Alzheimer's disease

Author

Guerreiro, R, Wojtas, A, Bras, J, Carrasquillo, M, Rogaeva, E, Majounie, E, Cruchaga, C, Sassi, C, Kauwe, Js, Lupton, Mk, Ryten, M, Brown, K, Lowe, J, Ridge, Pg, Hammer, Mb, Wakutani, Y, Hazrati, L, Proitsi, P, Newhouse, S, Lohmann, E, Erginel Unaltuna, N, Medway, C, Hanagasi, H, Troakes, C, Gurvit, H, Bilgic, B, Al Sarraj, S, Benitez, B, Cooper, B, Carrell, D, Emre, M, Zou, F, Ma, L, Murray, M, Dickson, D, Younkin, S, Petersen, Rc, Corcoran, Cd, Cai, Y, Oliveira, C, Ribeiro, Mh, Santana, I, Tschanz, Jt, Gibbs, J, Norton, Mc, Kloszewska, I, Mecocci, Patrizia, Soininen, H, Tsolaki, M, Vellas, B, Munger, Rg, Mann, Dm, Pickering Brown, S, Lovestone, S, Beck, J, Mead, S, Collinge, J, Parsons, L, Pocock, J, Morris, Jc, Revesz, T, Lashley, T, Fox, Nc, Rossor, Mn, Grenier Boley, B, Bellenguez, C, Moskvina, V, Sims, R, Harold, D, Williams, J, Lambert, Jc, Amouyel, P, Graff Radford, N, Goate, A, Rademakers, R, Morgan, K, Powell, J, St George Hyslop, P, Singleton, A, Hardy, J, Gerrish, A, Chapman, J, Abraham, R, Hollingworth, P, Hamshere, M, Pahwa, Js, Dowzell, K, Williams, A, Jones, N, Thomas, C, Stretton, A, Morgan, A, Williams, K, Thomas, S, Brayne, C, Rubinsztein, Dc, Gill, M, Lawlor, B, Lynch, A, Passmore, P, Craig, D, Mcguinness, B, Johnston, Ja, Todd, S, Holmes, C, Smith, A, Love, S, Kehoe, Pg, Maier, W, Jessen, F, Heun, R, Kölsch, H, Schürmann, B, Ramirez, A, van den Bussche, H, Heuser, I, Kornhuber, J, Wiltfang, J, Dichgans, M, Frölich, L, Hampel, H, Hüll, M, Rujescu, D, Nowotny, P, Mayo, K, Livingston, G, Bass, Nj, Gurling, H, Mcquillin, A, Gwilliam, R, Deloukas, P, Nöthen, Mm, Holmans, P, O'Donovan, M, Owen, Mj, Zelenika, D, Epelbaum, J, Dartigues, Jf, Tzourio, C, Berr, C, Boland, A, Campion, D, Alpérovitch, A, Lathrop, M, Smith, C, Trabzuni, D, Walker, R, Weale, M., Wiltfang, J. (Beitragende*r), EADI Consortium, GERAD Consortium, UKBE Consortium, and Alzheimer Genetic Anal Grp

Subjects
Genetics, TREM2, SORL1, Medizin, Genome-wide association study, General Medicine, Biology, medicine.disease, PSEN2, medicine, Dementia, Human medicine, Alzheimer's disease, Exome, Common disease-common variant
Abstract

BACKGROUND Homozygous loss-of-function mutations in TREM2, encoding the triggering receptor expressed on myeloid cells 2 protein, have previously been associated with an autosomal recessive form of early-onset dementia. METHODS We used genome, exome, and Sanger sequencing to analyze the genetic variability in TREM2 in a series of 1092 patients with Alzheimer's disease and 1107 controls (the discovery set). We then performed a meta-analysis on imputed data for the TREM2 variant rs75932628 (predicted to cause a R47H substitution) from three genomewide association studies of Alzheimer's disease and tested for the association of the variant with disease. We genotyped the R47H variant in an additional 1887 cases and 4061 controls. We then assayed the expression of TREM2 across different regions of the human brain and identified genes that are differentially expressed in a mouse model of Alzheimer's disease and in control mice. RESULTS We found significantly more variants in exon 2 of TREM2 in patients with Alzheimer's disease than in controls in the discovery set (P = 0.02). There were 22 variant alleles in 1092 patients with Alzheimer's disease and 5 variant alleles in 1107 controls (P

Published
2013

11. Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease

Author

P. Bosco, Rebecca Sims, Monique M.B. Breteler, L. Concari, Giuseppe Tosto, María J. Bullido, Kristel Sleegers, Fernando Valdivieso, Diana Zelenika, T. Feulner, Raffaele Ferri, Christophe Tzourio, P. Caffara, Davide Seripa, Benjamin Grenier-Boley, Paola Bossù, C. Chillotti, Marc Delepine, C. Deniz-Naranjo, Daniela Galimberti, David-Alexandre Trégouët, Benedetta Nacmias, Elisabeth M. C. Schrijvers, Karolien Bettens, Anne Boland, Christiane Reitz, Florentino Sanchez-Garcia, Dominique Campion, R. Rogers, C. Van Broeckhoven, Jean-Charles Lambert, Denise Harold, Amy Gerrish, Didier Hannequin, Mohammad Arfan Ikram, Michael Conlon O'Donovan, Elio Scarpini, Giorgio Annoni, Vincent Chouraki, Marc Lathrop, Francesco Panza, Chandra A. Reynolds, Gabriele Siciliano, Sandro Sorbi, Philippe Amouyel, Florence Pasquier, Luc Buée, Mikko Hiltunen, Claudine Berr, Eliecer Coto, Victoria Alvarez, Caroline Graff, Vincenzo Solfrizzi, Julie Williams, Jonathan A. Prince, Martin Ingelsson, Michael John Owen, Laura Fratiglioni, Jennifer Chapman, Ignacio Mateo, Annick Alpérovitch, H. Soininen, Michelangelo Mancuso, G. Spalletta, Matthias Riemenschneider, Andrea Pilotto, C. Van Cauwenberghe, Jacques Epelbaum, M. Del Zompo, Onofre Combarros, Lars Lannfelt, Yoichiro Kamatani, Beatrice Arosio, Jean-François Dartigues, Inserm U744, Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Cardiff University, Bioinformatics, GlaxoSmithKline, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerpen, Belgium, Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium, University of Antwerp (UA), Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Eastern Finland, G.H. Sergievsky Center, Columbia University, New York, NY, USA, Columbia University Irving Medical Center (CUIMC), Service of Neurology, University Hospital Marques de Valdecilla, University of Cantabria, Santander, Spain, Department of Psychiatry and Psychotherapy, Universitätsklinikum des Saarlandes, Universität des Saarlandes Saarbruecken, Germany, Centro de Biología Molecular Severo Ochoa [Madrid] (CBMSO), Universidad Autónoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Centro Dino Ferrari [Milano], Università degli Studi di Milano = University of Milan (UNIMI)-Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Department of Neuroscience, University of Parma, Parma, Italy, Università degli studi di Parma = University of Parma (UNIPR), Genética Molecular-Laboratorio de Medicina, Hospital Universitario Central Asturias, Oviedo, Spain, Servicio de Inmunología. Hospital Unviersitario de Gran Canaria Dr Negrín. Bco, Las Palmas de Gran Canaria, Spain, Department of Geriatrics, Center for aging brain, Memory unit, University of Bari, Bari, Italy, Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), Department of neurological and psychiatric Sciences, University of Florence, Florence, Italy, Università degli Studi di Firenze = University of Florence (UniFI), Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Clinical and Behavioral Neurology, IRCCS Fondazione Santa Lucia, Roma, Italy, Clinical and Behavioral Neurology - Neuroscienze e riabilitazione, IRCCS Fondazione Santa Lucia [Roma], Neurological clinic, University of Pisa, Pisa, Italy, University of Pisa - Università di Pisa, Centre de Psychiatrie et Neurosciences (U894), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroépidémiologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Aging Research Center [Karolinska Institutet] (ARC ), Stockholm University-Karolinska Institutet [Stockholm], Department of Geriatric Medicine, Karolinska University Hospital, Stockholm, Sweden, KI-Alzheimer's Disease Reseach Center, Department NVS, Karolinska Institutet, KIADRC, Stockholm, Sweden, IRCCS Associazione Oasi Maria SS, Institute for Research on Mental Retardation and Brain Aging, Troina (EN), Italy, Department of Psychology [Riverside], University of California [Riverside] (UC Riverside), University of California (UC)-University of California (UC), Department of Public health and Caring Sciences, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden, Uppsala University, Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden, Unit of Clinical Pharmacology, Teaching Hospital of Cagliari, Cagliari, Italy, Geriatric Unit & Gerontology-Geriatrics Research Laboratory, Department of Medical Sciences, I.R.C.C.S. 'Casa Sollievo della Sofferenza', San Giovanni Rotondo, Italy, Università degli Studi di Cagliari = University of Cagliari (UniCa), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, DZNE, Bonn, Germany, Génomique cardiovasculaire, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), This work was supported by the National Foundation for Alzheimer's disease and related disorders, the Institut Pasteur de Lille, the Centre National de Génotypage, Inserm, FRC (fondation sur la recherche sur le cerveau) and Rotary., EADI consortium, GERAD consortium, Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and Genomics, Neurosciences and Mental Health Research Institute, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Department of neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland, Department of neurology, University of Eastern Finland-University Hospital of Kuopio-University of Eastern Finland-University Hospital of Kuopio, Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Università degli Studi di Milano [Milano] (UNIMI)-Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Università degli studi di Bari Aldo Moro (UNIBA), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Institut de psychiatrie et neurosciences (U894 / UMS 1266), University of California [Riverside] (UCR), University of California-University of California, Section of Clinical Pharmacology, Department of Neurosciences 'B.B. Brodie', University of Cagliari, Cagliari, Italy, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Lambert, J, Grenier Boley, B, Harold, D, Zelenika, D, Chouraki, V, Kamatani, Y, Sleegers, K, Ikram, M, Hiltunen, M, Reitz, C, Mateo, I, Feulner, T, Bullido, M, Galimberti, D, Concari, L, Alvarez, V, Sims, R, Gerrish, A, Chapman, J, Deniz Naranjo, C, Solfrizzi, V, Sorbi, S, Arosio, B, Spalletta, G, Siciliano, G, Epelbaum, J, Hannequin, D, Dartigues, J, Tzourio, C, Berr, C, Schrijvers, E, Rogers, R, Tosto, G, Pasquier, F, Bettens, K, Van Cauwenberghe, C, Fratiglioni, L, Graff, C, Delepine, M, Ferri, R, Reynolds, C, Lannfelt, L, Ingelsson, M, Prince, J, Chillotti, C, Pilotto, A, Seripa, D, Boland, A, Mancuso, M, Bossù, P, Annoni, G, Nacmias, B, Bosco, P, Panza, F, Sanchez Garcia, F, Del Zompo, M, Coto, E, Owen, M, O'Donovan, M, Valdivieso, F, Caffara, P, Scarpini, E, Combarros, O, Buée, L, Campion, D, Soininen, H, Breteler, M, Riemenschneider, M, Van Broeckhoven, C, Alpérovitch, A, Lathrop, M, Trégouët, D, Williams, J, Amouyel, P, Epidemiology, Radiology & Nuclear Medicine, Neurology, Grenier-Boley, Benjamin, Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé-Institut Pasteur de Lille, Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé, Centre National de Génotypage ( CNG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs ( INM ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Centre d'Etude du Polymorphisme Humain ( CEPH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut Universitaire d'Hématologie ( IUH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Fondation Jean Dausset, Departement of Epidemiology and Radiology, Erasmus MC, Rotterdam, Centro de Biologia Molecular Severo Ochoa (UAM-CSIC) and CIBERNED, Universidad Autonoma, Madrid, Spain, Università degli studi di Milano [Milano]-Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Department of Internal Medicine, Geriatric Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy, University of Pisa [Pisa], Centre de Psychiatrie et Neurosciences ( CPN - U894 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Génétique du cancer et des maladies neuropsychiatriques ( GMFC ), Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Neuropsychiatrie : recherche épidémiologique et clinique, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Montpellier 1 ( UM1 ) -Université de Montpellier ( UM ), Department of Epidemiology and Neurology, Erasmus MC, Rotterdam, Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Aging Reasearch Center, Department NVS, Karolinska Institutet and Stockholm University, Stockholm, Sweden, University of California [Riverside] ( UCR ), Centre de recherche Jean-Pierre Aubert-Neurosciences et Cancer, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé, Department of Epidemiology, Erasmus MC, Rotterdam, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition ( ICAN ), and Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Pitié-Salpêtrière [APHP]

Subjects
Apolipoprotein E, haplotype, FERM domain-containing protein 4A, human, genetics [Alzheimer Disease], Genome-wide association study, Disease, Genome, Plasma, 0302 clinical medicine, genetics [Adaptor Proteins, Signal Transducing], blood [Amyloid beta-Peptides], GWAS, genetics [Genetic Predisposition to Disease], [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, Genetics, 0303 health sciences, FRMD4A gene, amyloid, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, GWAS study, Alzheimer, FRMD4A, Alzheimer's disease, 3. Good health, Psychiatry and Mental health, Chemistry, genetics [Polymorphism, Single Nucleotide], Original Article, Corrigendum, medicine.medical_specialty, Amyloid, Single-nucleotide polymorphism, Locus (genetics), genome wide haplotype association study, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Cellular and Molecular Neuroscience, blood [Alzheimer Disease], Alzheimer Disease, genetics [Haplotypes], Genetic predisposition, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Psychiatry, Molecular Biology, plasma, Genetic association, Adaptor Proteins, Signal Transducing, 030304 developmental biology, Amyloid beta-Peptides, business.industry, Haplotype, Case-control study, Haplotypes, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Case-Control Studies, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Human medicine, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Recently, several genome-wide association studies (GWASs) have led to the discovery of nine new loci of genetic susceptibility in Alzheimer’s disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP (single-nucleotide polymorphism) analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches. We performed a genome-wide haplotype association (GWHA) study in the EADI1 study (n = 2025 AD cases and 5328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2820 AD cases and 6356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case– control studies (5093 AD cases and 4061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analyzed (OR: 1.68; 95% CI: (1.43–1.96); P= 1.11010). We finally searched for association between SNPs within the FRMD4A locus and Ab plasma concentrations in three independent non-demented populations (n = 2579). We reported that polymorphisms were associated with plasma Ab42/Ab40 ratio (best signal, P = 5.4107). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD.

Published
2012
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12. The Impact of Complement Genes on the Risk of Late-Onset Alzheimer's Disease.

Author

Carpanini SM, Harwood JC, Baker E, Torvell M, The Gerad Consortium, Sims R, Williams J, and Morgan BP

Subjects
Age of Onset, Complement Activation, Databases, Genetic, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Alzheimer Disease genetics, Clusterin genetics, Complement C1s genetics, Receptors, Complement 3b genetics
Abstract

Late-onset Alzheimer's disease (LOAD), the most common cause of dementia, and a huge global health challenge, is a neurodegenerative disease of uncertain aetiology. To deliver effective diagnostics and therapeutics, understanding the molecular basis of the disease is essential. Contemporary large genome-wide association studies (GWAS) have identified over seventy novel genetic susceptibility loci for LOAD. Most are implicated in microglial or inflammatory pathways, bringing inflammation to the fore as a candidate pathological pathway. Among the most significant GWAS hits are three complement genes: CLU , encoding the fluid-phase complement inhibitor clusterin; CR1 encoding complement receptor 1 (CR1); and recently, C1S encoding the complement enzyme C1s. Complement activation is a critical driver of inflammation; changes in complement genes may impact risk by altering the inflammatory status in the brain. To assess complement gene association with LOAD risk, we manually created a comprehensive complement gene list and tested these in gene-set analysis with LOAD summary statistics. We confirmed associations of CLU and CR1 genes with LOAD but showed no significant associations for the complement gene-set when excluding CLU and CR1 . No significant association with other complement genes, including C1S , was seen in the IGAP dataset; however, these may emerge from larger datasets.

Published
2021
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