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1. An integrated multi-omics approach identifies epigenetic alterations associated with Alzheimer’s disease

Author

Nancy M. Bonini, Greg Donahue, Shelley L. Berger, Li-San Wang, Benjamin A. Garcia, Alexandre Amlie-Wolf, Amit Berson, Raffaella Nativio, Xiaolong Cui, John Q. Trojanowski, Oksana Shcherbakova, Ananth R. Srinivasan, Ji Nie, Simone Sidoli, Chuan He, and Yemin Lan

Subjects
Transcriptional Activation, Proteome, Computational biology, Biology, Protein Aggregation, Pathological, Article, Transcriptome, Histones, 03 medical and health sciences, Histone H3, Epigenome, 0302 clinical medicine, Transcription (biology), Alzheimer Disease, Genetics, medicine, Humans, Epigenetics, 11 Medical and Health Sciences, 030304 developmental biology, Epigenomics, Histone Acetyltransferases, 0303 health sciences, Amyloid beta-Peptides, Neurodegeneration, Acetylation, 06 Biological Sciences, medicine.disease, Chromatin, Peptide Fragments, Histone Code, 030217 neurology & neurosurgery, Developmental Biology, Signal Transduction
Abstract

Protein aggregation is the hallmark of neurodegeneration, but the molecular mechanisms underlying late-onset Alzheimer's disease (AD) are unclear. Here we integrated transcriptomic, proteomic and epigenomic analyses of postmortem human brains to identify molecular pathways involved in AD. RNA sequencing analysis revealed upregulation of transcription- and chromatin-related genes, including the histone acetyltransferases for H3K27ac and H3K9ac. An unbiased proteomic screening singled out H3K27ac and H3K9ac as the main enrichments specific to AD. In turn, epigenomic profiling revealed gains in the histone H3 modifications H3K27ac and H3K9ac linked to transcription, chromatin and disease pathways in AD. Increasing genome-wide H3K27ac and H3K9ac in a fly model of AD exacerbated amyloid-β42-driven neurodegeneration. Together, these findings suggest that AD involves a reconfiguration of the epigenome, wherein H3K27ac and H3K9ac affect disease pathways by dysregulating transcription- and chromatin-gene feedback loops. The identification of this process highlights potential epigenetic strategies for early-stage disease treatment.

Published
2020

2. Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis

Author

Marla Gearing, David G. Clark, Steven L. Carroll, Marianne Johnstone, Darwin L. Conwell, Gregory A. Cote, Sandra Weintraub, Matthew P. Frosch, Stuart Sherman, Badri N. Vardarajan, Joshua A. Sonnen, Lindy E. Harrell, Peter B. Cotton, Lisa L. Barnes, Lawrence S. Honig, Carol A. Miller, Adam Slivka, Michelle A. Anderson, Nadine M. Melhem, David A. Bennett, Joel H. Kramer, Jill P. Smith, Michele D. Lewis, Mary Ganguli, Jean Paul Vonsatte, Thomas J. Montine, Lee-Way Jin, Kenneth B. Fallon, Marilyn S. Albert, Eliezer Masliah, John H. Growdon, Barry Reisberg, Chuanhai Cao, Patricia L. Kramer, Douglas J. Hartman, Allan I. Levey, Jennifer Williamson, Vivianna M. Van Deerlin, Wayne W. Poon, Alison Goate, Vijay P. Singh, Bernie Devlin, Christiane Reitz, Ann C. McKee, Amanda Smith, Neill R. Graff-Radford, Walter A. Kukul, John Baillie, Andres Gelrud, Ranjan Duara, Thomas D. Bird, Clinton B. Wright, Deborah Blacker, Chiao-Feng Lin, Ge Li, Ronald C. Kim, Deborah C. Mash, Debby W. Tsuang, John P. Neoptolemos, Timothy B. Gardner, Kathryn L. Lunetta, Steven G. Younkin, Kara L. Hamilton-Nelson, Ronald L. Hamilton, F. Yesim Demirci, Eric M. Reiman, Charles DeCarli, John M Olichney, Richard Mayeux, Gregory A. Jicha, Michael R. O'Connell, Matt Tector, Eileen H. Bigio, Jonathan D. Glass, M. Ilyas Kamboh, Randall E. Brand, Christopher Lawrence, Steven E. Arnold, Jessica LaRusch, Elaine R. Peskind, David H. Cribbs, M.-Marsel Mesulam, Constantine G. Lyketsos, Michelle L. Kienholz, Frank M. LaFerla, Duane Beekly, Kelley Faber, Salvatore Spina, Gyungah Jun, Thiruvengadam Muniraj, Erik D. Roberson, Anna Karydas, Steven H. Ferris, Bruce L. Miller, Randall L. Woltjer, Li-San Wang, Lon S. Schneider, John C. Morris, John Q. Trojanowski, Jeffrey Kaye, Joseph E. Parisi, Nilufer Ertekin-Taner, Harry V. Vinters, Lidiya Orlichenko, Robert Barber, Chris E. Forsmark, Mary Sano, Bimaljit S. Sandhu, Peter A. Banks, Martin R. Farlow, Bradley T. Hyman, Joseph F. Quinn, Gary W. Beecham, James A. DiSario, Hakon Hakonarson, Daniel C. Marson, Adam C. Naj, Frank Martiniuk, Oscar L. Lopez, Mary E. Money, Julia Mayerle, William Greenhalf, Kathryn Roeder, Adam L. Boxer, Christine M. Hulette, Gerard D. Schellenberg, Georgios I. Papachristou, Douglas Galasko, James R. Burke, Donna B. Stolz, Murray A. Raskind, Peter Simon, Linda J. Van Eldik, Robert A. Hawes, Chang En Yu, Tatiana Foroud, Jonathan L. Haines, Stephen R. Wisniewski, William W. Seeley, Dhiraj Yadav, James J. Lah, C. Mel Wilcox, Sid Gilman, Liana G. Apostolova, Howard J. Rosen, Clinton T. Baldwin, Robert S. Stern, Narcis O. Zarnescu, Dennis W. Dickson, Margaret A. Pericak-Vance, Ashok Raj, Stephen T. Amann, Joseph D. Buxbaum, Ronald C. Petersen, Robert C. Green, David C. Whitcomb, Rudolph E. Tanzi, Lindsay A. Farrer, Helena C. Chui, Laura B. Cantwell, Wendy J. Mack, Samer Alkaade, Nigel J. Cairns, Thomas G. Beach, Frank Ulrich Weiss, Alyssa M. Krasinskas, Elizabeth Head, Nalini M. Guda, Julie A. Schneider, Malcolm B. Dick, Roger N. Rosenberg, Jill R. Murrel, Otto Valladares, Andrew J. Saykin, Huntington Potter, John R. Gilbert, Neil W. Kowall, Joseph Romagnuolo, Markus M. Lerch, Aimee Pierce, Roger L. Albin, John M. Ringman, James B. Leverenz, Carlos Cruchaga, Joshua W. Miller, Lei Yu, M. Michael Barmada, Lambertus Klei, Andrew P. Lieberman, Bernardino Ghetti, Robert Sutton, Kathleen A. Welsh-Bohmer, Juan C. Troncoso, Edward H. Koo, Elizabeth Crocco, Eden R. Martin, Daniel H. Geschwind, and Regina M. Carney

Subjects
Male, Pancreatic disease, Pancreatitis, Alcoholic, Genome-wide association study, Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Sex Factors, Gene Frequency, Genotype, Genetics, medicine, PRSS2, Humans, Genetic Predisposition to Disease, Trypsin, Allele, Allele frequency, Homozygote, Genetic Variation, medicine.disease, 3. Good health, Hemizygote, 030220 oncology & carcinogenesis, Immunology, Claudins, Mutation, Trypsinogen, Pancreatitis, 030211 gastroenterology & hepatology, Female, Genome-Wide Association Study
Abstract

Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR and SPINK1 variants were associated with pancreatitis risk. We now report two associations at genome-wide significance identified and replicated at PRSS1-PRSS2 (P < 1 × 10(-12)) and X-linked CLDN2 (P < 1 × 10(-21)) through a two-stage genome-wide study (stage 1: 676 cases and 4,507 controls; stage 2: 910 cases and 4,170 controls). The PRSS1 variant likely affects disease susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous in males) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men (male hemizygote frequency is 0.26, whereas female homozygote frequency is 0.07).

Published
2012

3. Identification of common variants influencing risk of the tauopathy Progressive Supranuclear Palsy

Author

Marla Gearing, Jean Paul G. Vonsattel, Anna Karydas, Manuela Apfelbacher, Herbert Budka, Bernie Devlin, Alessandro Padovani, Wallace W. Tourtellotte, Andrew J. Lees, Karin Srulijes, Li-San Wang, Klaus Seppi, Gianni Pezzoli, Yvette Bordelon, Claudia Trenkwalder, Ryan J. Uitti, Peter Paul De Deyn, Nicole A. Finch, Roger L. Albin, Ranjan Duara, Gerard D. Schellenberg, Alberto Rábano, Kelly E. Lyons, Rosa Rademakers, Douglas Galasko, Giorgio Sacilotto, Dennis W. Dickson, Günter U. Höglinger, Silvana Tesei, John Hardy, Carlo Colosimo, Eliezer Masliah, Pia Winter, Joseph Jankovic, William W. Seeley, Claudio Mariani, David E. Riley, Matthew J. Farrer, Angelo Antonini, Jens Carsten Möller, Alex Rajput, Hans A. Kretzschmar, Nenad Bogdanovic, Nadine M. Melhem, Ulrich Müller, Steven E. Arnold, Wolfgang H. Oertel, Jorge L. Juncos, Rachel G. Gross, Daniela Berg, Rajesh Pahwa, Deborah A. Hall, Alexandra Durr, Chris Zarow, Lili-Naz Hazrati, Virginia M.-Y. Lee, Justo Garcãa De Yebenes, Donatella Ottaviani, John C. van Swieten, Tamas Revesz, John Q. Trojanowski, Zbigniew K. Wszolek, Sigrun Roeber, Werner Poewe, Matthias Höllerhage, Neill R. Graff-Radford, Laura B. Cantwell, Elena Alonso, Irene Litvan, Claire Troakes, Patrick M. A. Sleiman, Peter St George-Hyslop, Isabelle Leber, Lawrence I. Golbe, Chang En Yu, Allissa Dillman, Anna Zecchinelli, Stephen G. Reich, Stefano Goldwurm, Salvatore Spina, Eduardo Tolosa, Vivianna M. Van Deerlin, Charles L. White, Agnita J.W. Boon, Andrew B. Singleton, Huw R. Morris, Mi Ryung Han, Dena G. Hernandez, Carles Gaig, Matthew P. Frosch, Sebastiaan Engelborghs, Juan C. Troncoso, Roberto Cilia, Catriona McLean, Thomas Gasser, Robyn Flook, Barbara Borroni, Rohan de Silva, Murray Grossman, Martin N. Rossor, Bruce L. Miller, Sean S. O'Sullivan, Hakon Hakonarson, Walter Maetzler, Thomas D. Bird, David G. Standaert, Gesine Respondek, Marcel P. van der Brug, Sherry Beecher, Howard I. Hurtig, Gregor K. Wenning, J. Raphael Gibbs, Alexis Brice, Stuart Pickering-Brown, Jonathan D. Rohrer, Christopher Morris, Jana Vandrovcova, Giovanni Fabbrini, Jesús Avila, Owen A. Ross, Margherita Canesi, Lambertus Klei, Andrew P. Lieberman, Bernardino Ghetti, Laura Silveira-Moriyama, Peter Heutink, Pau Pastor, Nicoletta Meucci, Evan T. Geller, Luke A. Massey, Wang Zheng Chiu, Laura Donker Kaat, Maria Stamelou, Brit Mollenhauer, Mark R. Cookson, Thomas G. Beach, Novartis, Federal Ministry of Education and Research (Germany), Helmholtz Association, European Commission, Human genetics, NCA - Neurodegeneration, Neurology, Foundation for the National Institutes of Health, National Institute of Mental Health (US), German Genomics Initiative, German Research Foundation, Medical Research Council (UK), NIHR Biomedical Research Centre (UK), Harvard Brain Tissue Resource Center, Telethon Italia, Canadian Institutes of Health Research, Mayo Clinic, Nafarroako Gobernua, Fondazione Grigioni per il Morbo di Parkinson, De Deyn, Peter Paul, Engelborghs, Sebastiaan, and PSP Genetics Study Group

Subjects
pathology [Tauopathies], Genome-wide association study, Neurodegenerative, Medical and Health Sciences, Cohort Studies, 0302 clinical medicine, Degenerative disease, Risk Factors, Corticobasal degeneration, GWAS, 2.1 Biological and endogenous factors, Supranuclear Palsy, Chromosomes, Human, EIF2AK3, Aetiology, Genetics, Pediatric, 0303 health sciences, genetics [Supranuclear Palsy, Progressive], Single Nucleotide, Biological Sciences, Prognosis, 3. Good health, Frontotemporal Dementia (FTD), Tauopathies, Neurological, genetics [Polymorphism, Single Nucleotide], Tauopathy, Brain diseases, Supranuclear Palsy, Progressive, Palsy, Human, pathology [Supranuclear Palsy, Progressive], Single-nucleotide polymorphism, MAPT protein, human, tau Proteins, Neuropathology, Progressive Supranuclear Palsy, Biology, genetics [Chromosomes, Human], Polymorphism, Single Nucleotide, Chromosomes, Article, Progressive supranuclear palsy, PSP Genetics Study Group, 03 medical and health sciences, Rare Diseases, Progressive, ddc:570, medicine, Acquired Cognitive Impairment, Humans, Genetic Predisposition to Disease, Polymorphism, 030304 developmental biology, Cerebral Palsy, Prevention, Human Genome, genetics [Tauopathies], Neurosciences, Genetic Variation, Perinatal Period - Conditions Originating in Perinatal Period, medicine.disease, eye diseases, Brain Disorders, genetics [tau Proteins], Genetic Loci, Case-Control Studies, Dementia, Human medicine, 030217 neurology & neurosurgery, Developmental Biology, Genome-Wide Association Study
Abstract

Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common being Alzheimer’s disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 PSP cases and 3,247 controls (Stage 1) followed up by a second stage where 1,051 cases and 3,560 controls were genotyped for Stage 1 SNPs that yielded P ≤ 10−3. We found significant novel signals (P < 5 × 10−8) associated with PSP risk at STX6, EIF2AK3, and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response, and for a myelin structural component., T.G. serves as an editorial board member of Movement Disorders and Parkinsonism and Related Disorders and is funded by Novartis Pharma, the Federal Ministry of Education and Research (BMBF) (NGFN-Plus and ERA-Net NEURON), the Helmholtz Association (HelMA, Helmholtz Alliance for Health in an Ageing Society) and the European Community (MeFoPa, Medndelian Forms of Parkinsonism). T.G. received speakers honoraria from Novartis, Merck-Serono, Schwarz Pharma, Boehringer Ingelheim and Valeant Pharma and royalties for his consulting activities from Cefalon Pharma and Merck-Serono. T.G. holds a patent concerning the LRRK2 gene and neurodegenerative disorders. J.H. is consulting for Merck Serono and Eisai. I.Litvan is the founder of the Litvan Neurological Research Foundation, whose mission is to increase awareness, determine the cause/s and search for a cure for neurodegenerative disorders presenting with either parkinsonian or dementia symptoms (501c3).

Published
2011
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4. Common variants in MS4A4/MS4A6E, CD2uAP, CD33, and EPHA1 are associated with late-onset Alzheimer’s disease

Author

Bradley T. Hyman, Tatiana Foroud, James J. Lah, Roger N. Rosenberg, Philip L. De Jager, John M. Ringman, Thomas D. Bird, Ramon Diaz-Arrastia, Wayne W. Poon, Barry Reisberg, Juan C. Troncoso, Peter St George-Hyslop, Deborah Blacker, Ronald C. Kim, Adam L. Boxer, Gerard D. Schellenberg, Douglas Galasko, John Hardy, Erik D. Roberson, Minerva M. Carrasquillo, Richard Mayeux, Steven L. Carroll, Elaine R. Peskind, Walter A. Kukull, Marla Gearing, Lee-Way Jin, Paul K. Crane, James D. Bowen, Deborah C. Mash, Carol A. Miller, Eileen H. Bigio, Duane Beekly, Kenneth B. Fallon, Bruce L. Miller, Eliezer Masliah, Charles DeCarli, Gyungah Jun, Mary Ganguli, M. Ilyas Kamboh, Steven E. Arnold, Patricia L. Kramer, Gregory A. Jicha, David G. Clark, Lon S. Schneider, William G. Ellis, Anna Karydas, Alison Goate, Michael A. Slifer, Matthew P. Frosch, Steven G. Younkin, Steven T. DeKosky, F. Yesim Demirci, John Q. Trojanowski, Jeffrey Kaye, Sandra Weintraub, Jonathan D. Glass, Lindy E. Harrell, Adam C. Naj, Frank Martiniuk, Harry V. Vinters, Gail P. Jarvik, Ronald L. Hamilton, Ruchita Rajbhandary, Wayne C. McCormick, Neill R. Graff-Radford, Allan I. Levey, Jennifer Williamson, Daniel C. Marson, Andrew McDavid, John R. Gilbert, Thomas H. Beach, Christine M. Hulette, David A. Bennett, William P. Seeley, Christopher S. Carlson, Amanda J. Myers, Hakon Hakonarson, Debby W. Tsuang, Kathryn L. Lunetta, James R. Burke, Sid Gilman, John C. Morris, Bradley F. Boeve, Oscar L. Lopez, Nilufer Ertekin-Taner, Thomas J. Montine, Daniel P. Perl, Eric M. Reiman, Joseph F. Quinn, Susan M. McCurry, Paul Gallins, Murray A. Raskind, Badri N. Vardarajan, Joshua A. Sonnen, Robert S. Stern, Denis A. Evans, Lawrence S. Honig, Ekaterina Rogaeva, John H. Growdon, Michael L. Shelanski, Vivianna M. Van Deerlin, Joseph E. Parisi, Mary Sano, Dennis W. Dickson, Steven H. Ferris, Randall L. Woltjer, Li-San Wang, Jonathan L. Haines, Bruno Giordani, Martin R. Farlow, Jason J. Corneveaux, Gary W. Beecham, Clinton T. Baldwin, Ann C. McKee, Jean Paul Vonsattel, Julie A. Schneider, Malcolm B. Dick, Kelley Faber, John S. K. Kauwe, Neil W. Kowall, Wendy J. Mack, W Marsel Mesulam, Nigel J. Cairns, Nancy Johnson, Jacqueline L. Buros, Eric B. Larson, Ronald C. Petersen, Laura B. Cantwell, Margaret A. Pericak-Vance, Elizabeth Head, Petra Nowotny, Joseph D. Buxbaum, Andrew J. Saykin, Robert C. Green, Lindsay A. Farrer, Carlos Cruchaga, Joshua W. Miller, Matthew J. Huentelman, Rudolph E. Tanzi, Beth A. Dombroski, Andrew P. Lieberman, Daniel H. Geschwind, Robert W Barber, Jeffrey L. Cummings, Charles D. Smith, Bernardino Ghetti, Salvatore Spina, Regina M. Carney, Kathleen A. Welsh-Bohmer, Jason Karlawish, Edward H. Koo, Eden R. Martin, M. Michael Barmada, Carl W. Cotman, and Helena C. Chui

Subjects
Male, Sialic Acid Binding Ig-like Lectin 3, Antigens, Differentiation, Myelomonocytic, Late onset, Joint analysis, Biology, Polymorphism, Single Nucleotide, Article, Cohort Studies, 03 medical and health sciences, Disease susceptibility, 0302 clinical medicine, Alzheimer Disease, Antigens, CD, Databases, Genetic, Genetics, Humans, Genetic Predisposition to Disease, Age of Onset, 030304 developmental biology, Adaptor Proteins, Signal Transducing, Aged, Aged, 80 and over, 0303 health sciences, Receptor, EphA1, Genetic Variation, Membrane Proteins, Molecular biology, 3. Good health, Cytoskeletal Proteins, Multigene Family, Female, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.

Published
2011

5. Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions

Author

Paul G. Ince, James J. Lah, Roger N. Rosenberg, Daniel C. Marson, Glenda M. Halliday, Randall L. Woltjer, Li-San Wang, Isidro Ferrer, Howard Feldman, John B.J. Kwok, Harro Seelaar, Dennis W. Dickson, Ronald L. Hamilton, Charles L. White, Patrick M. A. Sleiman, Sid Gilman, Gerard D. Schellenberg, Albert Lladó, Jill R. Murrell, Douglas Galasko, Hans A. Kretzschmar, Manuela Neumann, Daniel P. Perl, Ann C. McKee, Claire Troakes, Eileen H. Bigio, William G. Ellis, Päivi Hartikainen, Neill R. Graff-Radford, Carl W. Cotman, Eliezer Masliah, Stefanie H. Freeman, Christine Van Broeckhoven, Helena C. Chui, Safa Al-Sarraj, John Hardy, Thomas G. Beach, M.-Marsel Mesulam, Steven T. DeKosky, Nigel J. Cairns, John R. Hodges, Richard Mayeux, Danielle Seilhean, David M. A. Mann, John C. Morris, M. Cristina Caballero Martínez, Andrew P. Lieberman, John H. Growdon, John Q. Trojanowski, Jeffrey Kaye, Peter Riederer, Christine M. Hulette, Bryan K. Woodruff, Bernardino Ghetti, Kathleen A. Welsh-Bohmer, Peter Heutink, Vivianna M. Van Deerlin, Allan I. Levey, Julie A. Schneider, Mary Sano, Jordan Grafman, Bruce L. Miller, Rosa Rademakers, Bradley F. Boeve, David G. Munoz, Samir Kumar-Singh, David A. Bennett, John C. van Swieten, Steven L. Carroll, Catriona McLean, Stuart Pickering-Brown, Maria Martinez-Lage, Ainhoa Alzualde, Jeffrey L. Cummings, Jonathan D. Rohrer, Maria Grazia Spillantini, Jillian J. Kril, Hakon Hakonarson, Pamela J. Shaw, Nenad Bogdanovic, Tammaryn Lashley, Ian R. A. Mackenzie, Julie van der Zee, Eric M. Reiman, Salvatore Spina, Harry V. Vinters, Adolfo López de Munain, Matthew P. Frosch, Irina Alafuzoff, Virginia M.-Y. Lee, Alice Chen-Plotkin, Juan C. Troncoso, Thomas D. Bird, Jean Paul G. Vonsattel, Murray Grossman, Marla Gearing, Carol A. Miller, M. Teresa Tũón, Charles DeCarli, Steven E. Arnold, Neurology, Obstetrics & Gynecology, Surgery, University of Zurich, Human genetics, and NCA - Neurodegeneration

Subjects
Linkage disequilibrium, Genome-wide association study, Neurodegenerative, Medical and Health Sciences, Linkage Disequilibrium, 0302 clinical medicine, Progranulins, Gene Frequency, 2.1 Biological and endogenous factors, Aetiology, Alzheimer's Disease Related Dementias (ADRD), Genetics, Inclusion Bodies, 0303 health sciences, Frontotemporal lobar degeneration, Single Nucleotide, Biological Sciences, DNA-Binding Proteins, Frontotemporal Dementia (FTD), Intercellular Signaling Peptides and Proteins, Pair 7, Chromosomes, Human, Pair 7, Human, Genotype, 10208 Institute of Neuropathology, Single-nucleotide polymorphism, 610 Medicine & health, Neuropathology, Biology, Polymorphism, Single Nucleotide, Article, Chromosomes, 03 medical and health sciences, Rare Diseases, 1311 Genetics, Clinical Research, mental disorders, medicine, Acquired Cognitive Impairment, SNP, Humans, Genetic Predisposition to Disease, Polymorphism, Allele frequency, 030304 developmental biology, Prevention, Human Genome, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Membrane Proteins, nutritional and metabolic diseases, medicine.disease, Brain Disorders, nervous system diseases, Minor allele frequency, Case-Control Studies, 570 Life sciences, biology, Dementia, Human medicine, Frontotemporal Lobar Degeneration, 030217 neurology & neurosurgery, Developmental Biology, Genome-Wide Association Study
Abstract

Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA-binding protein (TDP-43) inclusions (FTLD-TDP)1. FTLD-TDP is frequently familial, resulting from mutations in GRN (which encodes progranulin). We assembled an international collaboration to identify susceptibility loci for FTLD-TDP through a genome-wide association study of 515 individuals with FTLD-TDP. We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium block on 7p21 that contains TMEM106B. Three SNPs retained genome-wide significance following Bonferroni correction (top SNP rs1990622, P = 1.08 × 10−11; odds ratio, minor allele (C) 0.61, 95% CI 0.530.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 × 10−4). TMEM106B variants may confer risk of FTLD-TDP by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in individuals with mutations in GRN. Our data implicate variants in TMEM106B as a strong risk factor for FTLD-TDP, suggesting an underlying pathogenic mechanism. Abstract: Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA-binding protein (TDP-43) inclusions (FTLD-TDP) 1. FTLD-TDP is frequently familial, resulting from mutations in GRN (which encodes progranulin). We assembled an international collaboration to identify susceptibility loci for FTLD-TDP through a genome-wide association study of 515 individuals with FTLD-TDP. We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium block on 7p21 that contains TMEM106B. Three SNPs retained genome-wide significance following Bonferroni correction (top SNP rs1990622, P = 1.08 x 10(-11); odds ratio, minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 x 10(-4)). TMEM106B variants may confer risk of FTLD-TDP by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in individuals with mutations in GRN. Our data implicate variants in TMEM106B as a strong risk factor for FTLD-TDP, suggesting an underlying pathogenic mechanism.

Published
2010
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6. Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy.

Author

Höglinger, Günter U., Melhem, Nadine M., Dickson, Dennis W., Sleiman, Patrick M. A., Li-San Wang, Klei, Lambertus, Rademakers, Rosa, de Silva, Rohan, Litvan, Irene, Riley, David E., van Swieten, John C., Heutink, Peter, Wszolek, Zbigniew K., Uitti, Ryan J., Vandrovcova, Jana, Hurtig, Howard I., Gross, Rachel G., Maetzler, Walter, Goldwurm, Stefano, and Tolosa, Eduardo

Subjects
PROGRESSIVE supranuclear palsy, NEUROLOGICAL disorders, ALZHEIMER'S disease, GENOMES, MYELIN genes
Abstract

Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer's disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 individuals with PSP (cases) and 3,247 controls (stage 1) followed by a second stage in which we genotyped 1,051 cases and 3,560 controls for the stage 1 SNPs that yielded P ? 10?3. We found significant previously unidentified signals (P < 5 × 10?8) associated with PSP risk at STX6, EIF2AK3 and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response and for a myelin structural component. [ABSTRACT FROM AUTHOR]

Published
2011
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7. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease.

Author

Naj, Adam C., Gyungah Jun, Beecham, Gary W., Li-San Wang, Vardarajan, Badri Narayan, Buros, Jacqueline, Gallins, Paul J., Buxbaum, Joseph D., Jarvik, Gail P., Crane, Paul K., Larson, Eric B., Bird, Thomas D., Boeve, Bradley F., Graff-Radford, Neill R., De Jager, Philip L., Evans, Denis, Schneider, Julie A., Carrasquillo, Minerva M., Ertekin-Taner, Nilufer, and Younkin, Steven G.

Subjects
ALZHEIMER'S disease research, NEURODEGENERATION, DISEASES in older people, META-analysis, EXPERIMENTAL design
Abstract

The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (PM) = 1.7 × 10−9, joint analysis P (PJ) = 1.7 × 10−9; stages 1, 2 and 3, PM = 8.2 × 10−12), CD2AP (rs9349407; stages 1, 2 and 3, PM = 8.6 × 10−9), EPHA1 (rs11767557; stages 1, 2 and 3, PM = 6.0 × 10−10) and CD33 (rs3865444; stages 1, 2 and 3, PM = 1.6 × 10−9). We also replicated previous associations at CR1 (rs6701713; PM = 4.6 × 10−10, PJ = 5.2 × 10−11), CLU (rs1532278; PM = 8.3 × 10−8, PJ = 1.9 × 10−8), BIN1 (rs7561528; PM = 4.0 × 10−14, PJ = 5.2 × 10−14) and PICALM (rs561655; PM = 7.0 × 10−11, PJ = 1.0 × 10−10), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility. [ABSTRACT FROM AUTHOR]

Published
2011
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8. Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions.

Author

Van Deerlin, Vivianna M., Sleiman, Patrick M. A., Martinez-Lage, Maria, Chen-Plotkin, Alice, Li-San Wang, Graff-Radford, Neill R., Dickson, Dennis W., Rademakers, Rosa, Boeve, Bradley F., Grossman, Murray, Arnold, Steven E., Mann, David M. A., Pickering-Brown, Stuart M., Seelaar, Harro, Heutink, Peter, van Swieten, John C., Murrell, Jill R., Ghetti, Bernardino, Spina, Salvatore, and Grafman, Jordan

Subjects
FRONTOTEMPORAL dementia, DEGENERATION (Pathology), NEUROLOGICAL disorders, DNA-binding proteins, GENETIC mutation
Abstract

Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA-binding protein (TDP-43) inclusions (FTLD-TDP). FTLD-TDP is frequently familial, resulting from mutations in GRN (which encodes progranulin). We assembled an international collaboration to identify susceptibility loci for FTLD-TDP through a genome-wide association study of 515 individuals with FTLD-TDP. We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium block on 7p21 that contains TMEM106B. Three SNPs retained genome-wide significance following Bonferroni correction (top SNP rs1990622, P = 1.08 × 10−11; odds ratio, minor allele (C) 0.61, 95% CI 0.53–0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 × 10−4). TMEM106B variants may confer risk of FTLD-TDP by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in individuals with mutations in GRN. Our data implicate variants in TMEM106B as a strong risk factor for FTLD-TDP, suggesting an underlying pathogenic mechanism. [ABSTRACT FROM AUTHOR]

Published
2010
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