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1. Cerebrospinal fluid A beta 1–40 peptides increase in Alzheimer’s disease and are highly correlated with phospho-tau in control individuals

Author

Sylvain Lehmann, Julien Dumurgier, Xavier Ayrignac, Cecilia Marelli, Daniel Alcolea, Juan Fortea Ormaechea, Eric Thouvenot, Constance Delaby, Christophe Hirtz, Jérôme Vialaret, Nelly Ginestet, Elodie Bouaziz-Amar, Jean-Louis Laplanche, Pierre Labauge, Claire Paquet, Alberto Lleo, Audrey Gabelle, and for the Alzheimer’s Disease Neuroimaging Initiative (ADNI)

Subjects
Alzheimer’s disease, Amyloid peptides, Tau proteins, Biomarkers, Cerebrospinal fluid (CSF), Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background Amyloid pathology, which is one of the characteristics of Alzheimer’s disease (AD), results from altered metabolism of the beta-amyloid (Aβ) peptide in terms of synthesis, clearance, or aggregation. A decrease in cerebrospinal fluid (CSF) level Aβ1–42 is evident in AD, and the CSF ratio Aβ42/Aβ40 has recently been identified as one of the most reliable diagnostic biomarkers of amyloid pathology. Variations in inter-individual levels of Aβ1–40 in the CSF have been observed in the past, but their origins remain unclear. In addition, the variation of Aβ40 in the context of AD studied in several studies has yielded conflicting results. Methods Here, we analyzed the levels of Aβ1–40 using multicenter data obtained on 2466 samples from six different cohorts in which CSF was collected under standardized protocols, centrifugation, and storage conditions. Tau and p-tau (181) concentrations were measured using commercially available in vitro diagnostic immunoassays. Concentrations of CSF Aβ1–42 and Aβ1–40 were measured by ELISA, xMAP technology, chemiluminescence immunoassay (CLIA), and mass spectrometry. Statistical analyses were calculated for parametric and non-parametric comparisons, linear regression, correlation, and odds ratios. The statistical tests were adjusted for the effects of covariates (age, in particular). Results Regardless of the analysis method used and the cohorts, a slight but significant age-independent increase in the levels of Aβ40 in CSF was observed in AD. We also found a strong positive correlation between the levels of Aβ1–40 and p-tau (181) in CSF, particularly in control patients. Conclusions These results indicate that an increase in the baseline level of amyloid peptides, which are associated with an increase in p-tau (181), may be a biological characteristic and possibly a risk factor for AD. Further studies will be needed to establish a causal link between increased baseline levels of Aβ40 and the development of the disease.

Published
2020
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2. Heritability and genetic variance of dementia with Lewy bodies

Author

Rita Guerreiro, Valentina Escott-Price, Dena G. Hernandez, Celia Kun-Rodrigues, Owen A. Ross, Tatiana Orme, Joao Luis Neto, Susana Carmona, Nadia Dehghani, John D. Eicher, Claire Shepherd, Laura Parkkinen, Lee Darwent, Michael G. Heckman, Sonja W. Scholz, Juan C. Troncoso, Olga Pletnikova, Ted Dawson, Liana Rosenthal, Olaf Ansorge, Jordi Clarimon, Alberto Lleo, Estrella Morenas-Rodriguez, Lorraine Clark, Lawrence S. Honig, Karen Marder, Afina Lemstra, Ekaterina Rogaeva, Peter St. George-Hyslop, Elisabet Londos, Henrik Zetterberg, Imelda Barber, Anne Braae, Kristelle Brown, Kevin Morgan, Claire Troakes, Safa Al-Sarraj, Tammaryn Lashley, Janice Holton, Yaroslau Compta, Vivianna Van Deerlin, Geidy E. Serrano, Thomas G. Beach, Suzanne Lesage, Douglas Galasko, Eliezer Masliah, Isabel Santana, Pau Pastor, Monica Diez-Fairen, Miquel Aguilar, Pentti J. Tienari, Liisa Myllykangas, Minna Oinas, Tamas Revesz, Andrew Lees, Brad F. Boeve, Ronald C. Petersen, Tanis J. Ferman, Neill Graff-Radford, Nigel J. Cairns, John C. Morris, Stuart Pickering-Brown, David Mann, Glenda M. Halliday, John Hardy, John Q. Trojanowski, Dennis W. Dickson, Andrew Singleton, David J. Stone, and Jose Bras

Subjects
Genetic variance, Dementia, Lewy bodies, Genetic correlation, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Recent large-scale genetic studies have allowed for the first glimpse of the effects of common genetic variability in dementia with Lewy bodies (DLB), identifying risk variants with appreciable effect sizes. However, it is currently well established that a substantial portion of the genetic heritable component of complex traits is not captured by genome-wide significant SNPs. To overcome this issue, we have estimated the proportion of phenotypic variance explained by genetic variability (SNP heritability) in DLB using a method that is unbiased by allele frequency or linkage disequilibrium properties of the underlying variants. This shows that the heritability of DLB is nearly twice as high as previous estimates based on common variants only (31% vs 59.9%). We also determine the amount of phenotypic variance in DLB that can be explained by recent polygenic risk scores from either Parkinson's disease (PD) or Alzheimer's disease (AD), and show that, despite being highly significant, they explain a low amount of variance. Additionally, to identify pleiotropic events that might improve our understanding of the disease, we performed genetic correlation analyses of DLB with over 200 diseases and biomedically relevant traits. Our data shows that DLB has a positive correlation with education phenotypes, which is opposite to what occurs in AD. Overall, our data suggests that novel genetic risk factors for DLB should be identified by larger GWAS and these are likely to be independent from known AD and PD risk variants.

Published
2019
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3. Penetrance estimation of Alzheimer disease in SORL1 loss-of-function variant carriers using a family-based strategy and stratification by APOE genotypes

Author

Schramm, Catherine, Charbonnier, Camille, Zaréa, Aline, Lacour, Morgane, Wallon, David, Boland, Anne, Deleuze, Jean-François, Olaso, Robert, Alarcon, Flora, Campion, Dominique, Nuel, Grégory, Nicolas, Gaël, Collaborators Daniela Andriuta, Pierre, Anthony, Sophie, Auriacombe, Anna-Chloé, Balageas, Guillaume, Ballan, Mélanie, Barbay, Emilie, Beaufils, Yannick, Béjot, Serge, Belliard, Marie, Benaiteau, Karim, Bennys, Frédéric, Blanc, Stéphanie, Bombois, Claire Boutoleau Bretonnière, Pierre, Branger, Jasmine, Carlier, Leslie, Cartz-Piver, Pascaline, Cassagnaud, Giovanni, Castelnovo, Christine, Champion, Annabelle, Chaussenot, Mathieu, Ceccaldi, Valérie, Chauviré, Yaohua, Chen, Julien, Cogez, Emmanuel, Cognat, Fabienne, Contegal-Callier, Lea, Corneille, Philippe, Couratier, Hélène, Courtemanche, Benjamin, Cretin, Charlotte, Crinquette, Bernard, Croisille, Benjamin, Dauriat, Sophie, Dautricourt, Vincent de la Sayette, Astrid De Liège, Marie De Verdal, Didier, Deffond, Benoit, Delpont, Florence, Demurger, Vincent, Deramecourt, Céline, Derollez, Mira, Didic, Giulia, Diemert, Elsa, Dionet, Philippe, Diraison, Aude, Doan, Martine Doco Fenzy, Boris, Dufournet, Julien, Dumurgier, Hélène, Durand, Anas, Dutray, Frédérique, Etcharry-Bouyx, Maté, Formaglio, Audrey, Gabelle, Anne, Gainche-Salmon, Jean-Claude, Getenet, Emmanuelle, Ginglinger, Olivier, Godefroy, Mathilde, Graber, Chloé, Gregoire, Stephan, Grimaldi, Julien, Gueniat, Claude, Gueriot, Sophie, Haffen, Lorraine, Hamelin, Didier, Hannequin, Cezara, Hanta, Clémence, Hardy, Geoffroy, Hautecloque, Camille, Heitz, Claire, Hourregue, Thérèse, Jonveaux, Snejana, Jurici, Catia, Khoumri, Lejla, Koric, Pierre, Krolak-Salmon, Pierre, Labauge, Morgane, Lacour, Julien, Lagarde, Hélène-Marie, Lanoiselée, Brice, Laurens, Isabelle Le Ber, Gwenaël Le Guyader, Amélie, Leblanc, Thibaud, Lebouvier, Anas, Lippi, Marie-Anne, Mackowiak, Eloi, Magnin, Cecilia, Marelli, Olivier, Martinaud, Aurélien, Maureille, Emilie, Milongo-Rigal, Sophie, Mohr, Hélène, Mollion, Olivier, Moreaud, Alexandre, Morin, Gaël, Nicolas, Julia, Nivelle, Camille, Noiray, Elisabeth, Ollagnon-Roman, Claire, Paquet, Jérémie, Pariente, Florence, Pasquier, Alexandre, Perron, Nathalie, Philippi, Virginie, Pichon, Vincent, Planche, Céline, Poirsier, Marie, Rafiq, Pauline, Rod-Olivieri, Adeline, Rollin-Sillaire, Carole, Roué-Jagot, Dario, Saracino, Marie, Sarazin, Mathilde, Sauvée, François, Sellal, Lila Sirven Villaros, Christel, Thauvin, Camille, Tisserand, Christophe, Tomasino, Cédric, Turpinat, Laurène Van Damme, Olivier, Vercruysse, Alice, Voilly, Nathalie, Wagemann, David, Wallon, Aline, Zarea, Shahzad, Ahmad, Philippe, Amouyel, Claudine, Berr, Anne, Boland, Paola, Bossu, Femke, Bouwman, Jose, Bras, Dominique, Campion, Camille, Charbonnier, Jordi, Clarimon, Antonio, Daniele, Jean-François, Dartigues, Stéphanie, Debette, Jean-François, Deleuze, Nicola, Denning, Oriol, Dols-Icardo, Nick, C Fox, Daniela, Galimberti, Emmanuelle, Génin, Hans, Gille, Benjamin, Grenier-Boley, Detelina, Grozeva, Rita, Guerreiro, John, J Hardy, Clive, Holmes, Henne, Holstege, Marc, Hulsman, Holger, Hummerich, M Arfan Ikram, M Kamran Ikram, Iris, Jansen, Amit, Kawalia, Robert, Kraaij, Jean-Charles, Lambert, Marc, Lathrop, Afina, W Lemstra, Alberto, Lleo, Lauren, Luckcuck, Marcel M A, M Mannens, Rachel, Marshall, Carlo, Masullo, Simon, Mead, Mecocci, Patrizia, Alun, Meggy, Merel, O Mol, Kevin, Morgan, Benedetta, Nacmias, Penny, J Norsworthy, Pau, Pastor, Olivier, Quenez, Alfredo, Ramirez, Rachel, Raybould, Richard, Redon, Marcel J, T Reinders, Anne-Claire, Richard, Steffi, G Riedel-Heller, Fernando, Rivadeneira, Stéphane, Rousseau, Natalie, S Ryan, Salha, Saad, Pascual, Sanchez-Juan, Philip, Scheltens, Jonathan, M Schott, Davide, Seripa, Daoud, Sie, Rebecca, Sims, Erik, Sistermans, Sandro, Sorbi, Resie van Spaendonk, Gianfranco, Spalleta, Nicćolo, Tesi, Betty, Tijms, André, G Uitterlinden, Wiesje, M van der Flier, Sven, J van der Lee, Cornelia, M van Duijn, Jeroen G, J van Rooij, John, C van Swieten, Pieter, J de Visser, Michael, Wagner, and Julie, Williams

Subjects
Genotype, Membrane Transport Proteins, Penetrance, Lifetime risk, Pedigree, Expectation-maximization algorithm, Settore MED/26 - NEUROLOGIA, Apolipoproteins E, Missing genotypes, Alzheimer Disease, Case-Control Studies, SORL1, Alzheimer, Genetics, Humans, Molecular Medicine, Molecular Biology, LDL-Receptor Related Proteins, APOE, Genetics (clinical)
Abstract

Background Alzheimer disease (AD) is a common complex disorder with a high genetic component. Loss-of-function (LoF) SORL1 variants are one of the strongest AD genetic risk factors. Estimating their age-related penetrance is essential before putative use for genetic counseling or preventive trials. However, relative rarity and co-occurrence with the main AD risk factor, APOE-ε4, make such estimations difficult. Methods We proposed to estimate the age-related penetrance of SORL1-LoF variants through a survival framework by estimating the conditional instantaneous risk combining (i) a baseline for non-carriers of SORL1-LoF variants, stratified by APOE-ε4, derived from the Rotterdam study (N = 12,255), and (ii) an age-dependent proportional hazard effect for SORL1-LoF variants estimated from 27 extended pedigrees (including 307 relatives ≥ 40 years old, 45 of them having genotyping information) recruited from the French reference center for young Alzheimer patients. We embedded this model into an expectation-maximization algorithm to accommodate for missing genotypes. To correct for ascertainment bias, proband phenotypes were omitted. Then, we assessed if our penetrance curves were concordant with age distributions of APOE-ε4-stratified SORL1-LoF variant carriers detected among sequencing data of 13,007 cases and 10,182 controls from European and American case-control study consortia. Results SORL1-LoF variants penetrance curves reached 100% (95% confidence interval [99–100%]) by age 70 among APOE-ε4ε4 carriers only, compared with 56% [40–72%] and 37% [26–51%] in ε4 heterozygous carriers and ε4 non-carriers, respectively. These estimates were fully consistent with observed age distributions of SORL1-LoF variant carriers in case-control study data. Conclusions We conclude that SORL1-LoF variants should be interpreted in light of APOE genotypes for future clinical applications.

Published
2022
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4. SLITRK2, an X-linked modifier of the age at onset in C9orf72 frontotemporal lobar degeneration

Author

Barbier, Mathieu, Camuzat, Agnès, Hachimi, Khalid El, Guegan, Justine, Rinaldi, Daisy, Lattante, Serena, Houot, Marion, Sánchez-Valle, Raquel, Sabatelli, Mario, Antonell, Anna, Molina-Porcel, Laura, Clot, Fabienne, Couratier, Philippe, van der Ende, Emma, van der Zee, Julie, Manzoni, Claudia, Camu, William, Cazeneuve, Cécile, Sellal, François, Didic, Mira, Golfier, Véronique, Pasquier, Florence, Duyckaerts, Charles, Rossi, Giacomina, Bruni, Amalia C, Alvarez, Victoria, Gómez-Tortosa, Estrella, de Mendonça, Alexandre, Graff, Caroline, Masellis, Mario, Nacmias, Benedetta, Oumoussa, Badreddine Mohand, Jornea, Ludmila, Forlani, Sylvie, Van Deerlin, Viviana, Rohrer, Jonathan D, Gelpi, Ellen, Rademakers, Rosa, Van Swieten, John, Le Guern, Eric, Van Broeckhoven, Christine, Ferrari, Raffaele, Génin, Emmanuelle, Brice, Alexis, Ber, Le, Isabelle Alexis Brice, Sophie, Auriacombe, Serge, Belliard, Anne, Bertrand, Anne, Bissery, Fre ́ de, ́ ric Blanc, Marie-Paule, Boncoeur, Ste, ́ phanie Bombois, Claire Boutoleau-Bretonnie` re, Agne`, s Camuzat, Mathieu, Ceccaldi, Marie, Chupin, Philippe, Couratier, Olivier, Colliot, Vincent, Deramecourt, Mira, Didic, Bruno, Dubois, Charles, Duyckaerts, Fre ́ de, ́ rique Etcharry-Bouyx, Aure, ́ lie Guignebert-Funkiewiez, Maı ̈te, ́ Formaglio, ́ ronique Golfier, Ve, Marie-Odile, Habert, Didier, Hannequin, Lucette, Lacomblez, Julien, Lagarde, ́ raldine Lautrette, Ge, Isabelle Le Ber, Benjamin Le Toullec, Richard, Levy, Marie-Anne, Mackowiak, Bernard-Franc ̧ois Michel, Florence, Pasquier, Thibaud, Lebouvier, Carole Roue, ́ -Jagot, Christel Thauvin- Robinet, Catherine, Thomas-Anterion, Je ́ re, ́ mie Pariente, Franc ̧ois Salachas, Sabrina, Sayah, Franc ̧ois Sellal, Assi-Herve, ́ Oya, Daisy, Rinaldi, Adeline, Rollin-Sillaire, Martine, Vercelletto, David, Wallon, Armelle, Rametti-Lacroux, Raffaele, Ferrari, Hernandez, Dena G., Nalls, Michael A., Rohrer, Jonathan D., Adaikalavan, Ramasamy, Kwok, John B. J., Carol Dobson- Stone, Brooks, William S., Schofield, Peter R., Halliday, Glenda M., Hodges, John R., Olivier, Piguet, Lauren, Bartley, Elizabeth, Thompson, Isabel Herna, ́ ndez, Agustı ́n Ruiz, Merce`, Boada, Barbara, Borroni, Alessandro, Padovani, Carlos, Cruchaga, Cairns, Nigel J., Luisa, Benussi, Giuliano, Binetti, Roberta, Ghidoni, Gianluigi, Forloni, Diego, Albani, Daniela, Galimberti, Chiara, Fenoglio, Maria, Serpente, Elio, Scarpini, ́ n, Jordi Clarimo, Alberto Lleo, ́, Rafael, Blesa, Maria Landqvist Waldo, ̈, Karin, Nilsson, Christer, Nilsson, Mackenzie, Ian R. A., Hsiung, Ging-Yuek R., Mann, David M. A., Jordan, Grafman, Morris, Christopher M., Johannes, Attems, Griffiths, Timothy D., Mckeith, Ian G., Thomas, Alan J., Pietro, Pietrini, Edward, Uey, Wassermann, Eric M., Atik, Baborie, Evelyn, Jaros, Tierney, Michael C., Pau, Pastor, Cristina, Razquin, Sara, Ortega-Cubero, Elena, Alonso, Robert, Perneczky, Janine, Diehl-Schmid, Panagiotis, Alexopoulos, Alexander, Kurz, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Ekaterina, Rogaeva, Peter St George-Hyslop, Giacomina, Rossi, Fabrizio, Tagliavini, Giorgio, Giaccone, Rowe, James B., Schlachetzki, Johannes C. M., James, Uphill, John, Collinge, Simon, Mead, Adrian, Danek, Van Deerlin, Vivianna M., Murray, Grossman, Trojanowski, John Q., Julie van der Zee, Christine Van Broeckhoven, Cappa, Stefano F., Isabelle, Leber, Alexis, Brice, Benedetta, Nacmias, Sandro, Sorbi, Silvia, Bagnoli, Irene, Piaceri, Nielsen, Jørgen E., Hjermind, Lena E., Matthias, Riemenschneider, Manuel, Mayhaus, Bernd, Ibach, Gilles, Gasparoni, Sabrina, Pichler, Wei, Gu, Rossor, Martin N., Fox, Nick C., Warren, Jason D., Maria Grazia Spillantini, Morris, Huw R., Patrizia, Rizzu, Peter, Heutink, Snowden, Julie S., Sara, Rollinson, Anna, Richardson, Alexander, Gerhard, Bruni, Amalia C., Raffaele, Maletta, Francesca, Frangipane, Chiara, Cupidi, Livia, Bernardi, Maria, Anfossi, Maura, Gallo, Maria Elena Conidi, Nicoletta, Smirne, Rosa, Rademakers, Matt, Baker, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., David, Knopman, Josephs, Keith A., Boeve, Bradley F., Parisi, Joseph E., Seeley, William W., Miller, Bruce L., Karydas, Anna M., Howard, Rosen, van Swieten, John C., Dopper, Elise G. P., Harro, Seelaar, Pijnenburg, Yolande A. L., Philip, Scheltens, Giancarlo, Logroscino, Rosa, Capozzo, Valeria, Novelli, Puca, Annibale A., Massimo, Franceschi, Alfredo, Postiglione, Graziella, Milan, Paolo, Sorrentino, Mark, Kristiansen, Huei-Hsin, Chiang, Caroline, Graff, Adeline, Rollin, Dimitrios, Kapogiannis, Luigi, Ferrucci, Stuart, Pickering-Brown, Singleton, Andrew B., John, Hardy, Parastoo, Momeni., Neurology, Amsterdam Neuroscience - Neurodegeneration, Institut du Cerveau = Paris Brain Institute (ICM), 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)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière] (CIC Paris-Est), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital Dupuytren [CHU Limoges], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Center for Molecular Neurology (VIB-UAntwerp), University of Antwerp (UA), University College of London [London] (UCL), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Neurologie [Hôpitaux Civils de Colmar], Hôpitaux Civils Colmar, Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurologie, maladies neuro-musculaires [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Institut de Neurosciences des Systèmes (INS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Yves le Foll, Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Regional Neurogenetic Centre [Lamezia Terme, Italy] (CRN - ASP Catanzaro), Hospital Central de Asturias, Institute of Health Research of Principado de Asturias (ISPA), Fundación Jiménez Díaz, Fundacion Jimenez Diaz [Madrid] (FJD), Faculdade de Medicina [Lisboa], Universidade de Lisboa = University of Lisbon (ULISBOA), Karolinska University Hospital [Stockholm], Sunnybrook Research Institute [Toronto] (SRI), Sunnybrook Health Sciences Centre, Università degli Studi di Firenze = University of Florence (UniFI), Fondazione Don Carlo Gnocchi, Plateforme Post-génomique de la Pitié-Salpêtrière (PASS-P3S), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hospital of the University of Pennsylvania (HUP), Perelman School of Medicine, University of Pennsylvania-University of Pennsylvania, Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerpen, Belgium, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), The French clinical and genetic Research network on FTLD/FTLD-ALS and PREVDEMALS, The International Frontotemporal Dementia Genomics Consortium, The European Early Onset Dementia (EU -EOD) Consortium, Brainbank Neuro-CEB Neuropathology Network, and Neurological Tissue Bank of the Biobank Hospital Clinic-IDIBAPS

Subjects
Adult, Male, TDP-43, C9orf72, SLITRK2, amyotrophic lateral sclerosis, frontotemporal dementia, Nerve Tissue Proteins, Settore MED/03 - GENETICA MEDICA, Polymorphism, Single Nucleotide, Cohort Studies, Genes, X-Linked, 80 and over, Medicine, Dementia, Humans, Allele, Age of Onset, Polymorphism, Aged, Aged, 80 and over, biology, C9orf72 Protein, business.industry, Membrane Proteins, MESH: Frontotemporal Lobar Degeneration / epidemiology, Frontotemporal Lobar, Degeneration / genetics, Genes, X-Linked / genetics, Genome-Wide Association Study / methods, Frontotemporal lobar degeneration, Single Nucleotide, Middle Aged, X-Linked, medicine.disease, Amyotrophic lateral sclerosis, Minor allele frequency, Genes, Immunology, Synaptophysin, biology.protein, Female, MESH: Adult, C9orf72 Protein / genetics, Frontotemporal Lobar Degeneration / diagnosis, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Human medicine, Neurology (clinical), MESH: Humans, Membrane Proteins / genetics, Nerve Tissue Proteins / genetics, Polymorphism, Single Nucleotide / genetics, Age of onset, Frontotemporal Lobar Degeneration, business, Frontotemporal dementia, Genome-Wide Association Study
Abstract

The G4C2-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or discordant age at onset. Linkage and association analyses provided converging evidence for a locus on chromosome Xq27.3. The minor allele A of rs1009776 was associated with an earlier onset (P = 1 × 10−5). The association with onset of dementia was replicated in an independent cohort of unrelated C9orf72 patients (P = 0.009). The protective major allele delayed the onset of dementia from 5 to 13 years on average depending on the cohort considered. The same trend was observed in an independent cohort of C9orf72 patients with extreme deviation of the age at onset (P = 0.055). No association of rs1009776 was detected in GRN patients, suggesting that the effect of rs1009776 was restricted to the onset of dementia due to C9orf72. The minor allele A is associated with a higher SLITRK2 expression based on both expression quantitative trait loci (eQTL) databases and in-house expression studies performed on C9orf72 brain tissues. SLITRK2 encodes for a post-synaptic adhesion protein. We further show that synaptic vesicle glycoprotein 2 and synaptophysin, two synaptic vesicle proteins, were decreased in frontal cortex of C9orf72 patients carrying the minor allele. Upregulation of SLITRK2 might be associated with synaptic dysfunctions and drives adverse effects in C9orf72 patients that could be modulated in those carrying the protective allele. How the modulation of SLITRK2 expression affects synaptic functions and influences the disease onset of dementia in C9orf72 carriers will require further investigations. In summary, this study describes an original approach to detect modifier genes in rare diseases and reinforces rising links between C9orf72 and synaptic dysfunctions that might directly influence the occurrence of first symptoms.

Published
2021
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5. Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease.

Author

Valentina Escott-Price, Céline Bellenguez, Li-San Wang, Seung-Hoan Choi, Denise Harold, Lesley Jones, Peter Holmans, Amy Gerrish, Alexey Vedernikov, Alexander Richards, Anita L DeStefano, Jean-Charles Lambert, Carla A Ibrahim-Verbaas, Adam C Naj, Rebecca Sims, Gyungah Jun, Joshua C Bis, Gary W Beecham, Benjamin Grenier-Boley, Giancarlo Russo, Tricia A Thornton-Wells, Nicola Denning, Albert V Smith, Vincent Chouraki, Charlene Thomas, M Arfan Ikram, Diana Zelenika, Badri N Vardarajan, Yoichiro Kamatani, Chiao-Feng Lin, Helena Schmidt, Brian Kunkle, Melanie L Dunstan, Maria Vronskaya, United Kingdom Brain Expression Consortium, Andrew D Johnson, Agustin Ruiz, Marie-Thérèse Bihoreau, Christiane Reitz, Florence Pasquier, Paul Hollingworth, Olivier Hanon, Annette L Fitzpatrick, Joseph D Buxbaum, Dominique Campion, Paul K Crane, Clinton Baldwin, Tim Becker, Vilmundur Gudnason, Carlos Cruchaga, David Craig, Najaf Amin, Claudine Berr, Oscar L Lopez, Philip L De Jager, Vincent Deramecourt, Janet A Johnston, Denis Evans, Simon Lovestone, Luc Letenneur, Isabel Hernández, David C Rubinsztein, Gudny Eiriksdottir, Kristel Sleegers, Alison M Goate, Nathalie Fiévet, Matthew J Huentelman, Michael Gill, Kristelle Brown, M Ilyas Kamboh, Lina Keller, Pascale Barberger-Gateau, Bernadette McGuinness, Eric B Larson, Amanda J Myers, Carole Dufouil, Stephen Todd, David Wallon, Seth Love, Ekaterina Rogaeva, John Gallacher, Peter St George-Hyslop, Jordi Clarimon, Alberto Lleo, Anthony Bayer, Debby W Tsuang, Lei Yu, Magda Tsolaki, Paola Bossù, Gianfranco Spalletta, Petra Proitsi, John Collinge, Sandro Sorbi, Florentino Sanchez Garcia, Nick C Fox, John Hardy, Maria Candida Deniz Naranjo, Paolo Bosco, Robert Clarke, Carol Brayne, Daniela Galimberti, Elio Scarpini, Ubaldo Bonuccelli, Michelangelo Mancuso, Gabriele Siciliano, Susanne Moebus, Patrizia Mecocci, Maria Del Zompo, Wolfgang Maier, Harald Hampel, Alberto Pilotto, Ana Frank-García, Francesco Panza, Vincenzo Solfrizzi, Paolo Caffarra, Benedetta Nacmias, William Perry, Manuel Mayhaus, Lars Lannfelt, Hakon Hakonarson, Sabrina Pichler, Minerva M Carrasquillo, Martin Ingelsson, Duane Beekly, Victoria Alvarez, Fanggeng Zou, Otto Valladares, Steven G Younkin, Eliecer Coto, Kara L Hamilton-Nelson, Wei Gu, Cristina Razquin, Pau Pastor, Ignacio Mateo, Michael J Owen, Kelley M Faber, Palmi V Jonsson, Onofre Combarros, Michael C O'Donovan, Laura B Cantwell, Hilkka Soininen, Deborah Blacker, Simon Mead, Thomas H Mosley, David A Bennett, Tamara B Harris, Laura Fratiglioni, Clive Holmes, Renee F A G de Bruijn, Peter Passmore, Thomas J Montine, Karolien Bettens, Jerome I Rotter, Alexis Brice, Kevin Morgan, Tatiana M Foroud, Walter A Kukull, Didier Hannequin, John F Powell, Michael A Nalls, Karen Ritchie, Kathryn L Lunetta, John S K Kauwe, Eric Boerwinkle, Matthias Riemenschneider, Mercè Boada, Mikko Hiltunen, Eden R Martin, Reinhold Schmidt, Dan Rujescu, Jean-François Dartigues, Richard Mayeux, Christophe Tzourio, Albert Hofman, Markus M Nöthen, Caroline Graff, Bruce M Psaty, Jonathan L Haines, Mark Lathrop, Margaret A Pericak-Vance, Lenore J Launer, Christine Van Broeckhoven, Lindsay A Farrer, Cornelia M van Duijn, Alfredo Ramirez, Sudha Seshadri, Gerard D Schellenberg, Philippe Amouyel, Julie Williams, and Cardiovascular Health Study (CHS)

Subjects
Medicine, Science
Abstract

BACKGROUND:Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. PRINCIPAL FINDINGS:In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci. SIGNIFICANCE:The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.

Published
2014
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6. The

Author

Yuetiva, Deming, Fabia, Filipello, Francesca, Cignarella, Claudia, Cantoni, Simon, Hsu, Robert, Mikesell, Zeran, Li, Jorge L, Del-Aguila, Umber, Dube, Fabiana Geraldo, Farias, Joseph, Bradley, John, Budde, Laura, Ibanez, Maria Victoria, Fernandez, Kaj, Blennow, Henrik, Zetterberg, Amanda, Heslegrave, Per M, Johansson, Johan, Svensson, Bengt, Nellgård, Alberto, Lleo, Daniel, Alcolea, Jordi, Clarimon, Lorena, Rami, José Luis, Molinuevo, Marc, Suárez-Calvet, Estrella, Morenas-Rodríguez, Gernot, Kleinberger, Michael, Ewers, Oscar, Harari, Christian, Haass, Thomas J, Brett, Bruno A, Benitez, Celeste M, Karch, Laura, Piccio, and Carlos, Cruchaga

Subjects
Male, Membrane Glycoproteins, Meta-Analysis as Topic, Alzheimer Disease, Macrophages, Multigene Family, Humans, Membrane Proteins, Female, Receptors, Immunologic, Article, Genome-Wide Association Study
Abstract

Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in the cerebrospinal fluid (CSF) has been associated with Alzheimer disease (AD). TREM2 plays a critical role in microglial activation, survival, and phagocytosis; however, the pathophysiological role of sTREM2 in AD is not well understood. Understanding the role of sTREM2 in AD may reveal novel pathological mechanisms underlying AD and identify distinct therapeutic targets. We performed a genome-wide association study (GWAS) to identify genetic modifiers of CSF sTREM2 obtained from the Alzheimer Disease Neuroimaging Initiative (ADNI, N = 813). Common variants in the membrane-spanning 4-domains subfamily A (MS4A) gene region were associated with CSF sTREM2 (rs1582763; P = 1.15×10(−15)) which replicated in independent datasets. The variants associated with increased CSF sTREM2 are associated with reduced AD risk and delayed age-at-onset. Rs1582763 modifies expression of MS4A4A and MS4A6A in multiple tissues, suggesting that one or both of these genes are important for modulating sTREM2. MS4A genes encode transmembrane proteins that are expressed in microglia. Using human macrophages to model the relationship between MS4A4A and TREM2, we found that MS4A4A and TREM2 colocalize on lipid rafts at the plasma membrane, that sTREM2 increases with MS4A4A overexpression, and that antibody-mediated targeting of MS4A4A reduces sTREM2 production. Thus, genetic, molecular, and cellular findings suggest that MS4A4A modulates sTREM2. These findings also provide a mechanistic explanation for the original GWAS signal in the MS4A locus for AD risk and indicate that TREM2 is involved in sporadic AD pathogenesis, not only in TREM2 risk-variant carriers.

Published
2018

7. LRP10 in α-synucleinopathies

Author

Rita Guerreiro, Tatiana Orme, João Luís Neto, Jose Bras, John Hardy, Celia Kun-Rodrigues, Lee Darwent, Joao Neto, Susana Carmona, Olaf Ansorge, Laura Parkkinen, Kevin Morgan, Kristelle Brown, Anne Braae, Imelda Barber, Claire Troakes, Safa Al-Sarraj, Tammaryn Lashley, Janice Holton, Yaroslau Compta, Tamas Revesz, Andrew Lees, Henrik Zetterberg, Valentina Escott-Price, Stuart Pickering-Brown, David Mann, Andrew Singleton, Dena Hernandez, Owen Ross, Dennis Dickson, Neill Graff-Radford, Tanis Ferman, Ronald Petersen, Brad Boeve, Michael Heckman, John Q. Trojanowski, Vivianna Van Deerlin, Nigel Cairns, John Morris, David A. Stone, John Eicher, Lorraine Clark, Lawrence Honig, Karen Marder, Geidy Serrano, Thomas Beach, Douglas Galasko, Eliezer Masliah, Ekaterina Rogaeva, Peter St. George-Hyslop, Jordi Clarimon, Alberto Lleo, Estrella Morenas-Rodriguez, Pau Pastor, Monica Diez-Fairen, Miquel Aquilar, Claire Shepherd, Glenda Halliday, Pentti Tienari, Liisa Myllykangas, Minna Oinas, Isabel Santana, Suzanne Lesage, Elisabet Londos, Afina Lemstra, Neurology, and Amsterdam Neuroscience - Neurodegeneration

Subjects
0301 basic medicine, Synucleinopathies, business.industry, MEDLINE, Computational biology, medicine.disease, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Text mining, Genetic linkage, Medicine, Dementia, Neurology (clinical), business, Lewy body disease, 030217 neurology & neurosurgery
Published
2018
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8. PLD3 in non-familial Alzheimer's disease

Author

André Lacour, Rafael Blesa, Maitee Rosende Roca, Markus M. Nöthen, Reinhard Heun, Juan Fortea, Michael Hüll, Wolfgang Maier, Stefanie Heilmann, Alfredo Ramirez, Holger Wagner, Frank Jessen, Alberto Lleo, Martin Scherer, Michael T. Heneka, Oliver Peters, Lutz Frölich, Dmitriy Drichel, Montserrat Alegret, Mercè Boada, Lluís Tárraga, Jens Wiltfang, Isabel Hernández, Eckart Rüther, Victoria Fernández, Tim Becker, Jordi Clarimón, Johannes Kornhuber, Ana Mauleón, Agustín Ruiz, Steffi G. Riedel-Heller, and Mathias Thelen

Subjects
Male, genotype, genetics [Alzheimer Disease], genetic analysis, Bioinformatics, Article, Text mining, Alzheimer Disease, genetic variability, Phospholipase D, Medicine, follow up, Humans, genetics, Genetic Predisposition to Disease, human, genetics [Genetic Predisposition to Disease], genetics [Phospholipase D], phospholipase D3, family history, Multidisciplinary, business.industry, Genetic Variation, German (citizen), genetics [Genetic Variation], unclassified drug, enzyme activity, genetic code, aged, female, disease incidence, priority journal, DNA polymorphism, Familial Alzheimer's disease, ddc:500, business, genetic predisposition
Abstract

[No abstract available]

Published
2015
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