263 results on '"Kauwe, John S. K."'
Search Results
2. The Polygenic Risk Score Knowledge Base offers a centralized online repository for calculating and contextualizing polygenic risk scores
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Page, Madeline L., Vance, Elizabeth L., Cloward, Matthew E., Ringger, Ed, Dayton, Louisa, Ebbert, Mark T. W., Miller, Justin B., and Kauwe, John S. K.
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- 2022
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3. Distinct clinicopathologic clusters of persons with TDP-43 proteinopathy
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Katsumata, Yuriko, Abner, Erin L., Karanth, Shama, Teylan, Merilee A., Mock, Charles N., Cykowski, Matthew D., Lee, Edward B., Boehme, Kevin L., Mukherjee, Shubhabrata, Kauwe, John S. K., Kryscio, Richard J., Schmitt, Frederick A., Fardo, David W., and Nelson, Peter T.
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- 2020
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4. A comprehensive analysis of the phylogenetic signal in ramp sequences in 211 vertebrates
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McKinnon, Lauren M., Miller, Justin B., Whiting, Michael F., Kauwe, John S. K., and Ridge, Perry G.
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- 2021
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5. Phylogeographic and nested clade analysis of the stonefly Pteronarcys californica (Plecoptera:Pteronarcyidae) in the western USA
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Kauwe, John S. K., Shiozawa, Dennis K., and Evans, R. Paul
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- 2004
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6. Atypical chemokine receptor ACKR2-V41A has decreased CCL2 binding, scavenging, and activation, supporting sustained inflammation and increased Alzheimer’s disease risk
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Murcia, Josue D. Gonzalez, Weinert, Allen, Freitas, Claudia M. Tellez, Arens, Daniel K., Ferrel, Meganne N., Grose, Julianne H., Ridge, Perry G., Wilson, Eric, Kauwe, John S. K., and Weber, K. Scott
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- 2020
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7. Mitochondria and Alzheimer’s Disease: the Role of Mitochondrial Genetic Variation
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Ridge, Perry G. and Kauwe, John S. K.
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- 2018
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8. Genome-wide, high-content siRNA screening identifies the Alzheimer’s genetic risk factor FERMT2 as a major modulator of APP metabolism
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Chapuis, Julien, Flaig, Amandine, Grenier-Boley, Benjamin, Eysert, Fanny, Pottiez, Virginie, Deloison, Gaspard, Vandeputte, Alexandre, Ayral, Anne-Marie, Mendes, Tiago, Desai, Shruti, Goate, Alison M., Kauwe, John S. K., Leroux, Florence, Herledan, Adrien, Demiautte, Florie, Bauer, Charlotte, Checler, Fréderic, Petersen, Ronald C., Blennow, Kaj, Zetterberg, Henrik, Minthon, Lennart, Van Deerlin, Vivianna M., Lee, Virginia Man-Yee, Shaw, Leslie M., Trojanowski, John Q., Albert, Marilyn, Moghekar, Abhay, O’Brien, Richard, Peskind, Elaine R., Malmanche, Nicolas, Schellenberg, Gerard D., Dourlen, Pierre, Song, Ok-Ryul, Cruchaga, Carlos, Amouyel, Philippe, Deprez, Benoit, Brodin, Priscille, Lambert, Jean-Charles, and ADGC, Alzheimer’s Disease Neuroimaging Initiative
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- 2017
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9. Genome-wide association study identifies four novel loci associated with Alzheimer’s endophenotypes and disease modifiers
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Deming, Yuetiva, Li, Zeran, Kapoor, Manav, Harari, Oscar, Del-Aguila, Jorge L., Black, Kathleen, Carrell, David, Cai, Yefei, Fernandez, Maria Victoria, Budde, John, Ma, Shengmei, Saef, Benjamin, Howells, Bill, Huang, Kuan-lin, Bertelsen, Sarah, Fagan, Anne M., Holtzman, David M., Morris, John C., Kim, Sungeun, Saykin, Andrew J., De Jager, Philip L., Albert, Marilyn, Moghekar, Abhay, O’Brien, Richard, Riemenschneider, Matthias, Petersen, Ronald C., Blennow, Kaj, Zetterberg, Henrik, Minthon, Lennart, Van Deerlin, Vivianna M., Lee, Virginia Man-Yee, Shaw, Leslie M., Trojanowski, John Q., Schellenberg, Gerard, Haines, Jonathan L., Mayeux, Richard, Pericak-Vance, Margaret A., Farrer, Lindsay A., Peskind, Elaine R., Li, Ge, Di Narzo, Antonio F., Kauwe, John S. K., Goate, Alison M., Cruchaga, Carlos, Alzheimer’s Disease Neuroimaging Initiative (ADNI), and The Alzheimer Disease Genetic Consortium (ADGC)
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- 2017
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10. Erratum to: “Sex Differences in Risk for Alzheimer’s Disease Related to Neurotrophin Gene Polymorphisms: The Cache County Memory Study”
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Matyi, Joshua, Tschanz, JoAnn T, Rattinger, Gail B, Sanders, Chelsea, Vernon, Elizabeth K, Corcoran, Chris, Kauwe, John S K, and Buhusi, Mona
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- 2018
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11. Author Correction: Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing
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Kunkle, Brian W., Grenier-Boley, Benjamin, Sims, Rebecca, Bis, Joshua C., Damotte, Vincent, Naj, Adam C., Boland, Anne, Vronskaya, Maria, van der Lee, Sven J., Amlie-Wolf, Alexandre, Bellenguez, Céline, Frizatti, Aura, Chouraki, Vincent, Martin, Eden R., Sleegers, Kristel, Badarinarayan, Nandini, Jakobsdottir, Johanna, Hamilton-Nelson, Kara L., Moreno-Grau, Sonia, Olaso, Robert, Raybould, Rachel, Chen, Yuning, Kuzma, Amanda B., Hiltunen, Mikko, Morgan, Taniesha, Ahmad, Shahzad, Vardarajan, Badri N., Epelbaum, Jacques, Hoffmann, Per, Boada, Merce, Beecham, Gary W., Garnier, Jean-Guillaume, Harold, Denise, Fitzpatrick, Annette L., Valladares, Otto, Moutet, Marie-Laure, Gerrish, Amy, Smith, Albert V., Qu, Liming, Bacq, Delphine, Denning, Nicola, Jian, Xueqiu, Zhao, Yi, Del Zompo, Maria, Fox, Nick C., Choi, Seung-Hoan, Mateo, Ignacio, Hughes, Joseph T., Adams, Hieab H., Malamon, John, Sanchez-Garcia, Florentino, Patel, Yogen, Brody, Jennifer A., Dombroski, Beth A., Naranjo, Maria Candida Deniz, Daniilidou, Makrina, Eiriksdottir, Gudny, Mukherjee, Shubhabrata, Wallon, David, Uphill, James, Aspelund, Thor, Cantwell, Laura B., Garzia, Fabienne, Galimberti, Daniela, Hofer, Edith, Butkiewicz, Mariusz, Fin, Bertrand, Scarpini, Elio, Sarnowski, Chloe, Bush, Will S., Meslage, Stéphane, Kornhuber, Johannes, White, Charles C., Song, Yuenjoo, Barber, Robert C., Engelborghs, Sebastiaan, Sordon, Sabrina, Voijnovic, Dina, Adams, Perrie M., Vandenberghe, Rik, Mayhaus, Manuel, Cupples, L. Adrienne, Albert, Marilyn S., De Deyn, Peter P., Gu, Wei, Himali, Jayanadra J., Beekly, Duane, Squassina, Alessio, Hartmann, Annette M., Orellana, Adelina, Blacker, Deborah, Rodriguez-Rodriguez, Eloy, Lovestone, Simon, Garcia, Melissa E., Doody, Rachelle S., Munoz-Fernadez, Carmen, Sussams, Rebecca, Lin, Honghuang, Fairchild, Thomas J., Benito, Yolanda A., Holmes, Clive, Karamujić-Čomić, Hata, Frosch, Matthew P., Thonberg, Hakan, Maier, Wolfgang, Roshchupkin, Gennady, Ghetti, Bernardino, Giedraitis, Vilmantas, Kawalia, Amit, Li, Shuo, Huebinger, Ryan M., Kilander, Lena, Moebus, Susanne, Hernández, Isabel, Kamboh, M. Ilyas, Brundin, RoseMarie, Turton, James, Yang, Qiong, Katz, Mindy J., Concari, Letizia, Lord, Jenny, Beiser, Alexa S., Keene, C. Dirk, Helisalmi, Seppo, Kloszewska, Iwona, Kukull, Walter A., Koivisto, Anne Maria, Lynch, Aoibhinn, Tarraga, Lluís, Larson, Eric B., Haapasalo, Annakaisa, Lawlor, Brian, Mosley, Thomas H., Lipton, Richard B., Solfrizzi, Vincenzo, Gill, Michael, Longstreth, Jr, W. T., Montine, Thomas J., Frisardi, Vincenza, Diez-Fairen, Monica, Rivadeneira, Fernando, Petersen, Ronald C., Deramecourt, Vincent, Alvarez, Ignacio, Salani, Francesca, Ciaramella, Antonio, Boerwinkle, Eric, Reiman, Eric M., Fievet, Nathalie, Rotter, Jerome I., Reisch, Joan S., Hanon, Olivier, Cupidi, Chiara, Uitterlinden, A. G. Andre, Royall, Donald R., Dufouil, Carole, Maletta, Raffaele Giovanni, de Rojas, Itziar, Sano, Mary, Brice, Alexis, Cecchetti, Roberta, George-Hyslop, Peter St, Ritchie, Karen, Tsolaki, Magda, Tsuang, Debby W., Dubois, Bruno, Craig, David, Wu, Chuang-Kuo, Soininen, Hilkka, Avramidou, Despoina, Albin, Roger L., Fratiglioni, Laura, Germanou, Antonia, Apostolova, Liana G., Keller, Lina, Koutroumani, Maria, Arnold, Steven E., Panza, Francesco, Gkatzima, Olymbia, Asthana, Sanjay, Hannequin, Didier, Whitehead, Patrice, Atwood, Craig S., Caffarra, Paolo, Hampel, Harald, Quintela, Inés, Carracedo, Ángel, Lannfelt, Lars, Rubinsztein, David C., Barnes, Lisa L., Pasquier, Florence, Frölich, Lutz, Barral, Sandra, McGuinness, Bernadette, Beach, Thomas G., Johnston, Janet A., Becker, James T., Passmore, Peter, Bigio, Eileen H., Schott, Jonathan M., Bird, Thomas D., Warren, Jason D., Boeve, Bradley F., Lupton, Michelle K., Bowen, James D., Proitsi, Petra, Boxer, Adam, Powell, John F., Burke, James R., Kauwe, John S. K., Burns, Jeffrey M., Mancuso, Michelangelo, Buxbaum, Joseph D., Bonuccelli, Ubaldo, Cairns, Nigel J., McQuillin, Andrew, Cao, Chuanhai, Livingston, Gill, Carlson, Chris S., Bass, Nicholas J., Carlsson, Cynthia M., Hardy, John, Carney, Regina M., Bras, Jose, Carrasquillo, Minerva M., Guerreiro, Rita, Allen, Mariet, Chui, Helena C., Fisher, Elizabeth, Masullo, Carlo, Crocco, Elizabeth A., DeCarli, Charles, Bisceglio, Gina, Dick, Malcolm, Ma, Li, Duara, Ranjan, Graff-Radford, Neill R., Evans, Denis A., Hodges, Angela, Faber, Kelley M., Scherer, Martin, Fallon, Kenneth B., Riemenschneider, Matthias, Fardo, David W., Heun, Reinhard, Farlow, Martin R., Kölsch, Heike, Ferris, Steven, Leber, Markus, Foroud, Tatiana M., Heuser, Isabella, Galasko, Douglas R., Giegling, Ina, Gearing, Marla, Hüll, Michael, Geschwind, Daniel H., Gilbert, John R., Morris, John, Green, Robert C., Mayo, Kevin, Growdon, John H., Feulner, Thomas, Hamilton, Ronald L., Harrell, Lindy E., Drichel, Dmitriy, Honig, Lawrence S., Cushion, Thomas D., Huentelman, Matthew J., Hollingworth, Paul, Hulette, Christine M., Hyman, Bradley T., Marshall, Rachel, Jarvik, Gail P., Meggy, Alun, Abner, Erin, Menzies, Georgina E., Jin, Lee-Way, Leonenko, Ganna, Real, Luis M., Jun, Gyungah R., Baldwin, Clinton T., Grozeva, Detelina, Karydas, Anna, Russo, Giancarlo, Kaye, Jeffrey A., Kim, Ronald, Jessen, Frank, Kowall, Neil W., Vellas, Bruno, Kramer, Joel H., Vardy, Emma, LaFerla, Frank M., Jöckel, Karl-Heinz, Lah, James J., Dichgans, Martin, Leverenz, James B., Mann, David, Levey, Allan I., Pickering-Brown, Stuart, Lieberman, Andrew P., Klopp, Norman, Lunetta, Kathryn L., Wichmann, H-Erich, Lyketsos, Constantine G., Morgan, Kevin, Marson, Daniel C., Brown, Kristelle, Martiniuk, Frank, Medway, Christopher, Mash, Deborah C., Nöthen, Markus M., Masliah, Eliezer, Hooper, Nigel M., McCormick, Wayne C., Daniele, Antonio, McCurry, Susan M., Bayer, Anthony, McDavid, Andrew N., Gallacher, John, McKee, Ann C., van den Bussche, Hendrik, Mesulam, Marsel, Brayne, Carol, Miller, Bruce L., Riedel-Heller, Steffi, Miller, Carol A., Miller, Joshua W., Al-Chalabi, Ammar, Morris, John C., Shaw, Christopher E., Myers, Amanda J., Wiltfang, Jens, O’Bryant, Sid, Olichney, John M., Alvarez, Victoria, Parisi, Joseph E., Singleton, Andrew B., Paulson, Henry L., Collinge, John, Perry, William R., Mead, Simon, Peskind, Elaine, Cribbs, David H., Rossor, Martin, Pierce, Aimee, Ryan, Natalie S., Poon, Wayne W., Nacmias, Benedetta, Potter, Huntington, Sorbi, Sandro, Quinn, Joseph F., Sacchinelli, Eleonora, Raj, Ashok, Spalletta, Gianfranco, Raskind, Murray, Caltagirone, Carlo, Bossù, Paola, Orfei, Maria Donata, Reisberg, Barry, Clarke, Robert, Reitz, Christiane, Smith, A David, Ringman, John M., Warden, Donald, Roberson, Erik D., Wilcock, Gordon, Rogaeva, Ekaterina, Bruni, Amalia Cecilia, Rosen, Howard J., Gallo, Maura, Rosenberg, Roger N., Ben-Shlomo, Yoav, Sager, Mark A., Mecocci, Patrizia, Saykin, Andrew J., Pastor, Pau, Cuccaro, Michael L., Vance, Jeffery M., Schneider, Julie A., Schneider, Lori S., Slifer, Susan, Seeley, William W., Smith, Amanda G., Sonnen, Joshua A., Spina, Salvatore, Stern, Robert A., Swerdlow, Russell H., Tang, Mitchell, Tanzi, Rudolph E., Trojanowski, John Q., Troncoso, Juan C., Van Deerlin, Vivianna M., Van Eldik, Linda J., Vinters, Harry V., Vonsattel, Jean Paul, Weintraub, Sandra, Welsh-Bohmer, Kathleen A., Wilhelmsen, Kirk C., Williamson, Jennifer, Wingo, Thomas S., Woltjer, Randall L., Wright, Clinton B., Yu, Chang-En, Yu, Lei, Saba, Yasaman, Alzheimer Disease Genetics Consortium (ADGC), The European Alzheimer’s Disease Initiative (EADI), Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE), Genetic and Environmental Risk in AD/Defining Genetic, Polygenic and Environmental Risk for Alzheimer’s Disease Consortium (GERAD/PERADES), Pilotto, Alberto, Bullido, Maria J., Peters, Oliver, Crane, Paul K., Bennett, David, Bosco, Paola, Coto, Eliecer, Boccardi, Virginia, De Jager, Phil L., Lleo, Alberto, Warner, Nick, Lopez, Oscar L., Ingelsson, Martin, Deloukas, Panagiotis, Cruchaga, Carlos, Graff, Caroline, Gwilliam, Rhian, Fornage, Myriam, Goate, Alison M., Sanchez-Juan, Pascual, Kehoe, Patrick G., Amin, Najaf, Ertekin-Taner, Nilifur, Berr, Claudine, Debette, Stéphanie, Love, Seth, Launer, Lenore J., Younkin, Steven G., Dartigues, Jean-Francois, Corcoran, Chris, Ikram, M. Arfan, Dickson, Dennis W., Nicolas, Gael, Campion, Dominique, Tschanz, JoAnn, Schmidt, Helena, Hakonarson, Hakon, Clarimon, Jordi, Munger, Ron, Schmidt, Reinhold, Farrer, Lindsay A., Van Broeckhoven, Christine, O’Donovan, Michael C., DeStefano, Anita L., Jones, Lesley, Haines, Jonathan L., Deleuze, Jean-Francois, Owen, Michael J., Gudnason, Vilmundur, Mayeux, Richard, Escott-Price, Valentina, Psaty, Bruce M., Ramirez, Alfredo, Wang, Li-San, Ruiz, Agustin, van Duijn, Cornelia M., Holmans, Peter A., Seshadri, Sudha, Williams, Julie, Amouyel, Phillippe, Schellenberg, Gerard D., Lambert, Jean-Charles, and Pericak-Vance, Margaret A.
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- 2019
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12. Locus specific endogenous retroviral expression associated with Alzheimer's disease.
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Dawson, Tyson, Rentia, Uzma, Sanford, Jessie, Cruchaga, Carlos, Kauwe, John S. K., and Crandall, Keith A.
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RNA analysis ,ALZHEIMER'S disease ,RETROVIRUS diseases ,GENE expression ,CELLULAR signal transduction ,RESEARCH funding ,DESCRIPTIVE statistics ,DATA analysis software ,DISEASE complications - Abstract
Introduction: Human endogenous retroviruses (HERVs) are transcriptionally-active remnants of ancient retroviral infections that may play a role in Alzheimer's disease. Methods: We combined two, publicly available RNA-Seq datasets with a third, novel dataset for a total cohort of 103 patients with Alzheimer's disease and 45 healthy controls. We use telescope to perform HERV quantification for these samples and simultaneously perform gene expression analysis. Results: We identify differentially expressed genes and differentially expressed HERVs in Alzheimer's disease patients. Differentially expressed HERVs are scattered throughout the genome; many of them are members of the HERVK superfamily. A number of HERVs are correlated with the expression of dysregulated genes in Alzheimer's and are physically proximal to genes which drive disease pathways. Discussion: Dysregulated expression of ancient retroviral insertions in the human genome are present in Alzheimer's disease and show localization patterns that may explain how these elements drive pathogenic gene expression. [ABSTRACT FROM AUTHOR]
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- 2023
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13. Genome-wide association study for variants that modulate relationships between cerebrospinal fluid amyloid-beta 42, tau, and p-tau levels
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Maxwell, Taylor J., Corcoran, Chris, del-Aguila, Jorge L., Budde, John P., Deming, Yuetiva, Cruchaga, Carlos, Goate, Alison M., Kauwe, John S. K., and Alzheimer’s Disease Neuroimaging Initiative
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- 2018
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14. Variation in MAPT Is Associated with Cerebrospinal Fluid Tau Levels in the Presence of Amyloid-Beta Deposition
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Kauwe, John S. K., Cruchaga, Carlos, Mayo, Kevin, Fenoglio, Chiara, Bertelsen, Sarah, Nowotny, Petra, Galimberti, Daniela, Scarpini, Elio, Morris, John C., Fagan, Anne M., Holtzman, David M., and Goate, Alison M.
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- 2008
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15. Pairwise Correlation Analysis of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) Dataset Reveals Significant Feature Correlation
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Huckvale, Erik D., Hodgman, Matthew W., Greenwood, Brianna B., Stucki, Devorah O., Ward, Katrisa M., Ebbert, Mark T. W., Kauwe, John S. K., Initiative, The Alzheimer’s Disease Neuroimaging Initiative The Alzheimer’s Disease Neuroimaging, Consortium, The Alzheimer’s Disease Metabolomics Consortium The Alzheimer’s Disease Metabolomics, and Miller, Justin B.
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Biometrics ,Computer science ,Datasets as Topic ,Neuroimaging ,QH426-470 ,Machine learning ,computer.software_genre ,Article ,Correlation ,symbols.namesake ,Feature correlation ,Alzheimer Disease ,Genetics ,ADNI ,Humans ,Generalizability theory ,Genetic Association Studies ,Genetics (clinical) ,feature reduction ,business.industry ,Magnetic Resonance Imaging ,Bonferroni correction ,machine learning ,Feature (computer vision) ,symbols ,Artificial intelligence ,pairwise feature correlation ,Transcriptome ,business ,computer ,Alzheimer’s disease ,Biomarkers ,Alzheimer's Disease Neuroimaging Initiative - Abstract
The Alzheimer’s Disease Neuroimaging Initiative (ADNI) contains extensive patient measurements (e.g., magnetic resonance imaging [MRI], biometrics, RNA expression, etc.) from Alzheimer’s disease (AD) cases and controls that have recently been used by machine learning algorithms to evaluate AD onset and progression. While using a variety of biomarkers is essential to AD research, highly correlated input features can significantly decrease machine learning model generalizability and performance. Additionally, redundant features unnecessarily increase computational time and resources necessary to train predictive models. Therefore, we used 49,288 biomarkers and 793,600 extracted MRI features to assess feature correlation within the ADNI dataset to determine the extent to which this issue might impact large scale analyses using these data. We found that 93.457% of biomarkers, 92.549% of the gene expression values, and 100% of MRI features were strongly correlated with at least one other feature in ADNI based on our Bonferroni corrected α (p-value ≤ 1.40754 × 10−13). We provide a comprehensive mapping of all ADNI biomarkers to highly correlated features within the dataset. Additionally, we show that significant correlation within the ADNI dataset should be resolved before performing bulk data analyses, and we provide recommendations to address these issues. We anticipate that these recommendations and resources will help guide researchers utilizing the ADNI dataset to increase model performance and reduce the cost and complexity of their analyses.
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- 2021
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16. Genetic analysis of quantitative phenotypes in AD and MCI: imaging, cognition and biomarkers
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Shen, Li, Thompson, Paul M., Potkin, Steven G., Bertram, Lars, Farrer, Lindsay A., Foroud, Tatiana M., Green, Robert C., Hu, Xiaolan, Huentelman, Matthew J., Kim, Sungeun, Kauwe, John S. K., Li, Qingqin, Liu, Enchi, Macciardi, Fabio, Moore, Jason H., Munsie, Leanne, Nho, Kwangsik, Ramanan, Vijay K., Risacher, Shannon L., Stone, David J., Swaminathan, Shanker, Toga, Arthur W., Weiner, Michael W., Saykin, Andrew J., and for the Alzheimer’s Disease Neuroimaging Initiative
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- 2014
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17. Genetic Discoveries in AD Using CSF Amyloid and Tau
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Cruchaga, Carlos, Ebbert, Mark T. W., and Kauwe, John S. K.
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- 2014
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18. Comorbidity and Cancer Disease Rates among Those at High-Risk for Alzheimer's Disease: A Population Database Analysis.
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Valentine, David, Teerlink, Craig C., Farnham, James M., Rowe, Kerry, Kaddas, Heydon, Tschanz, JoAnn, Kauwe, John S. K., and Cannon-Albright, Lisa A.
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- 2022
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19. Rarity of the Alzheimer Disease–Protective APP A673T Variant in the United States
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Wang, Li-San, Naj, Adam C., Graham, Robert R., Crane, Paul K., Kunkle, Brian W., Cruchaga, Carlos, Murcia, Josue D. Gonzalez, Cannon-Albright, Lisa, Baldwin, Clinton T., Zetterberg, Henrik, Blennow, Kaj, Kukull, Walter A., Faber, Kelley M., Schupf, Nicole, Norton, Maria C., Tschanz, JoAnn T., Munger, Ronald G., Corcoran, Christopher D., Rogaeva, Ekaterina, Lin, Chiao-Feng, Dombroski, Beth A., Cantwell, Laura B., Partch, Amanda, Valladares, Otto, Hakonarson, Hakon, St George-Hyslop, Peter, Green, Robert C., Goate, Alison M., Foroud, Tatiana M., Carney, Regina M., Larson, Eric B., Behrens, Timothy W., Kauwe, John S. K., Haines, Jonathan L., Farrer, Lindsay A., Pericak-Vance, Margaret A., Mayeux, Richard, Schellenberg, Gerard D., Albert, Marilyn S., Albin, Roger L., Apostolova, Liana G., Arnold, Steven E., Barber, Robert, Barmada, M. Michael, Barnes, Lisa L., Beach, Thomas G., Becker, James T., Beecham, Gary W., Beekly, Duane, Bennett, David A., Bigio, Eileen H., Bird, Thomas D., Blacker, Deborah, Boeve, Bradley F., Bowen, James D., Boxer, Adam, Burke, James R., Buxbaum, Joseph D., Cairns, Nigel J., Cao, Chuanhai, Carlson, Chris S., Carroll, Steven L., Chui, Helena C., Clark, David G., Cribbs, David H., Crocco, Elizabeth A., DeCarli, Charles, DeKosky, Steven T., Demirci, F. Yesim, Dick, Malcolm, Dickson, Dennis W., Duara, Ranjan, Ertekin-Taner, Nilufer, Fallon, Kenneth B., Farlow, Martin R., Ferris, Steven, Frosch, Matthew P., Galasko, Douglas R., Ganguli, Mary, Gearing, Marla, Geschwind, Daniel H., Ghetti, Bernardino, Gilbert, John R., Glass, Jonathan D., Graff-Radford, Neill R., Growdon, John H., Hamilton, Ronald L., Hamilton-Nelson, Kara L., Harrell, Lindy E., Head, Elizabeth, Honig, Lawrence S., Hulette, Christine M., Hyman, Bradley T., Jarvik, Gail P., Jicha, Gregory A., Jin, Lee-Way, Jun, Gyungah, Kamboh, M. Ilyas, Karydas, Anna, Kaye, Jeffrey A., Kim, Ronald, Koo, Edward H., Kowall, Neil W., Kramer, Joel H., Kramer, Patricia, LaFerla, Frank M., Lah, James J., Leverenz, James B., Levey, Allan I., Li, Ge, Lieberman, Andrew P., Lopez, Oscar L., Lunetta, Kathryn L., Lyketsos, Constantine G., Mack, Wendy J., Marson, Daniel C., Martin, Eden R., Martiniuk, Frank, Mash, Deborah C., Masliah, Eliezer, McCormick, Wayne C., McCurry, Susan M., McDavid, Andrew N., McKee, Ann C., Mesulam, M. Marsel, Miller, Bruce L., Miller, Carol A., Miller, Joshua W., Montine, Thomas J., Morris, John C., Murrell, Jill R., Olichney, John M., Parisi, Joseph E., Perry, William, Peskind, Elaine, Petersen, Ronald C., Pierce, Aimee, Poon, Wayne W., Potter, Huntington, Quinn, Joseph F., Raj, Ashok, Raskind, Murray, Reiman, Eric M., Reisberg, Barry, Reitz, Christiane, Ringman, John M., Roberson, Erik D., Rosen, Howard J., Rosenberg, Roger N., Sano, Mary, Saykin, Andrew J., Schneider, Julie A., Schneider, Lon S., Seeley, William W., Smith, Amanda G., Sonnen, Joshua A., Spina, Salvatore, Stern, Robert A., Tanzi, Rudolph E., Thornton-Wells, Tricia A., Trojanowski, John Q., Troncoso, Juan C., Tsuang, Debby W., Van Deerlin, Vivianna M., Van Eldik, Linda J., Vardarajan, Badri N., Vinters, Harry V., Vonsattel, Jean Paul, Weintraub, Sandra, Welsh-Bohmer, Kathleen A., Williamson, Jennifer, Wishnek, Sarah, Woltjer, Randall L., Wright, Clinton B., Younkin, Steven G., Yu, Chang-En, and Yu, Lei
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- 2015
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20. Web-Based Protein Interactions Calculator Identifies Likely Proteome Coevolution with Alzheimer's Disease-Associated Proteins.
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Ward, Katrisa M., Pickett, Brandon D., Ebbert, Mark T. W., Kauwe, John S. K., and Miller, Justin B.
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ALZHEIMER'S disease ,BACTERIAL proteins ,PROTEIN-protein interactions ,COEVOLUTION ,PROTEINS ,AMINO acid sequence - Abstract
Protein–protein functional interactions arise from either transitory or permanent biomolecular associations and often lead to the coevolution of the interacting residues. Although mutual information has traditionally been used to identify coevolving residues within the same protein, its application between coevolving proteins remains largely uncharacterized. Therefore, we developed the Protein Interactions Calculator (PIC) to efficiently identify coevolving residues between two protein sequences using mutual information. We verified the algorithm using 2102 known human protein interactions and 233 known bacterial protein interactions, with a respective 1975 and 252 non-interacting protein controls. The average PIC score for known human protein interactions was 4.5 times higher than non-interacting proteins (p = 1.03 × 10
−108 ) and 1.94 times higher in bacteria (p = 1.22 × 10−35 ). We then used the PIC scores to determine the probability that two proteins interact. Using those probabilities, we paired 37 Alzheimer's disease-associated proteins with 8608 other proteins and determined the likelihood that each pair interacts, which we report through a web interface. The PIC had significantly higher sensitivity and residue-specific resolution not available in other algorithms. Therefore, we propose that the PIC can be used to prioritize potential protein interactions, which can lead to a better understanding of biological processes and additional therapeutic targets belonging to protein interaction groups. [ABSTRACT FROM AUTHOR]- Published
- 2022
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21. Effects of Multiple Genetic Loci on Age at Onset in Late-Onset Alzheimer Disease: A Genome-Wide Association Study
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Naj, Adam C., Jun, Gyungah, Reitz, Christiane, Kunkle, Brian W., Perry, William, Park, Yo Son, Beecham, Gary W., Rajbhandary, Ruchita A., Hamilton-Nelson, Kara L., Wang, Li-San, Kauwe, John S. K., Huentelman, Matthew J., Myers, Amanda J., Bird, Thomas D., Boeve, Bradley F., Baldwin, Clinton T., Jarvik, Gail P., Crane, Paul K., Rogaeva, Ekaterina, Barmada, Michael M., Demirci, Yesim F., Cruchaga, Carlos, Kramer, Patricia L., Ertekin-Taner, Nilufer, Hardy, John, Graff-Radford, Neill R., Green, Robert C., Larson, Eric B., St. George-Hyslop, Peter H., Buxbaum, Joseph D., Evans, Denis A., Schneider, Julie A., Lunetta, Kathryn L., Kamboh, Ilyas M., Saykin, Andrew J., Reiman, Eric M., De Jager, Philip L., Bennett, David A., Morris, John C., Montine, Thomas J., Goate, Alison M., Blacker, Deborah, Tsuang, Debby W., Hakonarson, Hakon, Kukull, Walter A., Foroud, Tatiana M., Martin, Eden R., Haines, Jonathan L., Mayeux, Richard P., Farrer, Lindsay A., Schellenberg, Gerard D., Pericak-Vance, Margaret A., Albert, Marilyn S., Albin, Roger L., Apostolova, Liana G., Arnold, Steven E., Barber, Robert, Barnes, Lisa L., Beach, Thomas G., Becker, James T., Beekly, Duane, Bigio, Eileen H., Bowen, James D., Boxer, Adam, Burke, James R., Cairns, Nigel J., Cantwell, Laura B., Cao, Chuanhai, Carlson, Chris S., Carney, Regina M., Carrasquillo, Minerva M., Carroll, Steven L., Chui, Helena C., Clark, David G., Corneveaux, Jason, Cribbs, David H., Crocco, Elizabeth A., DeCarli, Charles, DeKosky, Steven T., Dick, Malcolm, Dickson, Dennis W., Duara, Ranjan, Faber, Kelley M., Fallon, Kenneth B., Farlow, Martin R., Ferris, Steven, Frosch, Matthew P., Galasko, Douglas R., Ganguli, Mary, Gearing, Marla, Geschwind, Daniel H., Ghetti, Bernardino, Gilbert, John R., Glass, Jonathan D., Growdon, John H., Hamilton, Ronald L., Harrell, Lindy E., Head, Elizabeth, Honig, Lawrence S., Hulette, Christine M., Hyman, Bradley T., Jicha, Gregory A., Jin, Lee-Way, Karydas, Anna, Kaye, Jeffrey A., Kim, Ronald, Koo, Edward H., Kowall, Neil W., Kramer, Joel H., LaFerla, Frank M., Lah, James J., Leverenz, James B., Levey, Allan I., Li, Ge, Lieberman, Andrew P., Lin, Chiao-Feng, Lopez, Oscar L., Lyketsos, Constantine G., Mack, Wendy J., Martiniuk, Frank, Mash, Deborah C., Masliah, Eliezer, McCormick, Wayne C., McCurry, Susan M., McDavid, Andrew N., McKee, Ann C., Mesulam, Marsel, Miller, Bruce L., Miller, Carol A., Miller, Joshua W., Murrell, Jill R., Olichney, John M., Pankratz, Vernon S., Parisi, Joseph E., Paulson, Henry L., Peskind, Elaine, Petersen, Ronald C., Pierce, Aimee, Poon, Wayne W., Potter, Huntington, Quinn, Joseph F., Raj, Ashok, Raskind, Murray, Reisberg, Barry, Ringman, John M., Roberson, Erik D., Rosen, Howard J., Rosenberg, Roger N., Sano, Mary, Schneider, Lon S., Seeley, William W., Smith, Amanda G., Sonnen, Joshua A., Spina, Salvatore, Stern, Robert A., Tanzi, Rudolph E., Thornton-Wells, Tricia A., Trojanowski, John Q., Troncoso, Juan C., Valladares, Otto, Van Deerlin, Vivianna M., Van Eldik, Linda J., Vardarajan, Badri N., Vinters, Harry V., Vonsattel, Jean Paul, Weintraub, Sandra, Welsh-Bohmer, Kathleen A., Williamson, Jennifer, Wishnek, Sarah, Woltjer, Randall L., Wright, Clinton B., Younkin, Steven G., Yu, Chang-En, and Yu, Lei
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- 2014
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22. Performances on the CogState and Standard Neuropsychological Batteries Among HIV Patients Without Dementia
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Overton, Edgar Turner, Kauwe, John S. K., Paul, Robert, Tashima, Karen, Tate, David F., Patel, Pragna, Carpenter, Charles C. J., Patty, David, Brooks, John T., and Clifford, David B.
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- 2011
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23. Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer’s disease
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Cruchaga, Carlos, Karch, Celeste M., Jin, Sheng Chih, Benitez, Bruno A., Cai, Yefei, Guerreiro, Rita, Harari, Oscar, Norton, Joanne, Budde, John, Bertelsen, Sarah, Jeng, Amanda T., Cooper, Breanna, Skorupa, Tara, Carrell, David, Levitch, Denise, Hsu, Simon, Choi, Jiyoon, Ryten, Mina, Trabzuni, Daniah, Weale, Michael E., Ramasamy, Adaikalavan, Smith, Colin, Sassi, Celeste, Bras, Jose, Gibbs, Raphael J., Hernandez, Dena G., Lupton, Michelle K., Powell, John, Forabosco, Paola, Ridge, Perry G., Corcoran, Christopher D., Tschanz, JoAnn T., Norton, Maria C., Munger, Ronald G., Schmutz, Cameron, Leary, Maegan, Demirci, Yesim F., Bamne, Mikhil N., Wang, Xingbin, Lopez, Oscar L., Ganguli, Mary, Medway, Christopher, Turton, James, Lord, Jenny, Braae, Anne, Barber, Imelda, Passmore, Peter, Craig, David, Johnston, Janet, McGuinness, Bernadette, Todd, Stephen, Heun, Reinhard, Kölsch, Heike, Kehoe, Patrick G., Hooper, Nigel M., Vardy, Emma R.L.C., Mann, David M., Pickering-Brown, Stuart, Brown, Kristelle, Kalsheker, Noor, Lowe, James, Morgan, Kevin, Smith, David A., Wilcock, Gordon, Warden, Donald, Holmes, Clive, Pastor, Pau, Lorenzo-Betancor, Oswaldo, Brkanac, Zoran, Scott, Erick, Topol, Eric, Rogaeva, Ekaterina, Singleton, Andrew B., Hardy, John, Kamboh, Ilyas M., St George-Hyslop, Peter, Cairns, Nigel, Morris, John C., Kauwe, John S. K., and Goate, Alison M.
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- 2014
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24. Alzheimer’s disease risk variants show association with cerebrospinal fluid amyloid beta
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Kauwe, John S. K., Wang, Jun, Mayo, Kevin, Morris, John C., Fagan, Anne M., Holtzman, David M., and Goate, Alison M.
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- 2009
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25. Ramp Atlas: facilitating tissue and cell-specific ramp sequence analyses through an intuitive web interface.
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Miller, Justin B, Meurs, Taylor E, Hodgman, Matthew W, Song, Benjamin, Miller, Kyle N, Ebbert, Mark T W, Kauwe, John S K, and Ridge, Perry G
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- 2022
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26. Fine-mapping of the human leukocyte antigen locus as a risk factor for Alzheimer disease: A case-control study
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Steele, Natasha Z. R., Carr, Jessie S., Bonham, Luke W., Geier, Ethan G., Damotte, Vincent, Miller, Zachary A., Desikan, Rahul S., Boehme, Kevin L., Mukherjee, Shubhabrata, Crane, Paul K., Kauwe, John S. K., Kramer, Joel H., Miller, Bruce L., Coppola, Giovanni, Hollenbach, Jill A., Huang, Yadong, and Yokoyama, Jennifer S.
- Subjects
Disease susceptibility -- Genetic aspects -- Risk factors ,Apolipoproteins -- Analysis -- Health aspects ,HLA antigens -- Analysis -- Health aspects ,Alzheimer's disease -- Genetic aspects -- Risk factors ,Biological sciences - Abstract
Background Alzheimer disease (AD) is a progressive disorder that affects cognitive function. There is increasing support for the role of neuroinflammation and aberrant immune regulation in the pathophysiology of AD. The immunoregulatory human leukocyte antigen (HLA) complex has been linked to susceptibility for a number of neurodegenerative diseases, including AD; however, studies to date have failed to consistently identify a risk HLA haplotype for AD. Contributing to this difficulty are the complex genetic organization of the HLA region, differences in sequencing and allelic imputation methods, and diversity across ethnic populations. Methods and findings Building on prior work linking the HLA to AD, we used a robust imputation method on two separate case-control cohorts to examine the relationship between HLA haplotypes and AD risk in 309 individuals (191 AD, 118 cognitively normal [CN] controls) from the San Francisco-based University of California, San Francisco (UCSF) Memory and Aging Center (collected between 1999-2015) and 11,381 individuals (5,728 AD, 5,653 CN controls) from the Alzheimer's Disease Genetics Consortium (ADGC), a National Institute on Aging (NIA)-funded national data repository (reflecting samples collected between 1984-2012). We also examined cerebrospinal fluid (CSF) biomarker measures for patients seen between 2005-2007 and longitudinal cognitive data from the Alzheimer's Disease Neuroimaging Initiative (n = 346, mean follow-up 3.15 ± 2.04 y in AD individuals) to assess the clinical relevance of identified risk haplotypes. The strongest association with AD risk occurred with major histocompatibility complex (MHC) haplotype A*03:01~B*07:02~DRB1*15:01~DQA1*01:02~DQB1*06:02 (p = 9.6 x 10.sup.-4, odds ratio [OR] [95% confidence interval] = 1.21 [1.08-1.37]) in the combined UCSF + ADGC cohort. Secondary analysis suggested that this effect may be driven primarily by individuals who are negative for the established AD genetic risk factor, apolipoprotein E (APOE) [epsilon]4. Separate analyses of class I and II haplotypes further supported the role of class I haplotype A*03:01~B*07:02 (p = 0.03, OR = 1.11 [1.01-1.23]) and class II haplotype DRB1*15:01- DQA1*01:02- DQB1*06:02 (DR15) (p = 0.03, OR = 1.08 [1.01-1.15]) as risk factors for AD. We followed up these findings in the clinical dataset representing the spectrum of cognitively normal controls, individuals with mild cognitive impairment, and individuals with AD to assess their relevance to disease. Carrying A*03:01~B*07:02 was associated with higher CSF amyloid levels (p = 0.03, [beta] ± standard error = 47.19 ± 21.78). We also found a dose-dependent association between the DR15 haplotype and greater rates of cognitive decline (greater impairment on the 11-item Alzheimer's Disease Assessment Scale cognitive subscale [ADAS11] over time [p = 0.03, [beta] ± standard error = 0.7 ± 0.3]; worse forgetting score on the Rey Auditory Verbal Learning Test (RAVLT) over time [p = 0.02, [beta] ± standard error = -0.2 ± 0.06]). In a subset of the same cohort, dose of DR15 was also associated with higher baseline levels of chemokine CC-4, a biomarker of inflammation (p = 0.005, [beta] ± standard error = 0.08 ± 0.03). The main study limitations are that the results represent only individuals of European-ancestry and clinically diagnosed individuals, and that our study used imputed genotypes for a subset of HLA genes. Conclusions We provide evidence that variation in the HLA locus-including risk haplotype DR15-contributes to AD risk. DR15 has also been associated with multiple sclerosis, and its component alleles have been implicated in Parkinson disease and narcolepsy. Our findings thus raise the possibility that DR15-associated mechanisms may contribute to pan-neuronal disease vulnerability., Author(s): Natasha Z. R. Steele 1,2, Jessie S. Carr 1,3, Luke W. Bonham 1,4, Ethan G. Geier 1, Vincent Damotte 1, Zachary A. Miller 1, Rahul S. Desikan 5, Kevin [...]
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- 2017
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27. Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting
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Chauhan, Ganesh, Adams, Hieab H H, Jian, Xueqiu, Sharma, Pankaj, Sudlow, Cathie L M, Rosand, Jonathan, Woo, Daniel, Cole, John W, Meschia, James F, Slowik, Agnieszka, Thijs, Vincent, Lindgren, Arne, Melander, Olle, Malik, Rainer, Grewal, Raji P, Rundek, Tatjana, Rexrode, Kathy, Rothwell, Peter M, Arnett, Donna K, Jern, Christina, Johnson, Julie A, Benavente, Oscar R, Wasssertheil-Smoller, Sylvia, Lee, Jin-Moo, Traylor, Matthew, Wong, Quenna, Mitchell, Braxton D, Rich, Stephen S, McArdle, Patrick F, Geerlings, Mirjam I, van der Graaf, Yolanda, de Bakker, Paul I W, Asselbergs, Folkert W, Srikanth, Velandai, Thomson, Russell, Pulit, Sara L, McWhirter, Rebekah, Moran, Chris, Callisaya, Michele, Phan, Thanh, Rutten-Jacobs, Loes C A, Bevan, Steve, Tzourio, Christophe, Mather, Karen A, Sachdev, Perminder S, van Duijn, Cornelia M, Amouyel, Philippe, Worrall, Bradford B, Dichgans, Martin, Kittner, Steven J, Markus, Hugh S, Ikram, Mohammad A, Fornage, Myriam, Launer, Lenore J, Seshadri, Sudha, Longstreth, W. T., Debette, Stéphanie, Mazoyer, Bernard, Network, Stroke Genetics, Almgren, Peter, Anderson, Christopher D, Attia, John, Ay, Hakan, Brown, Robert D, Bustamante, Mariana, Zhu, Yi-Cheng, Cheng, Yu-Ching, Cotlarciuc, Ioana, Cruchaga, Carlos, de Bakker, Paul Iw, Delavaran, Hossein, Engström, Gunnar, Kaffashian, Sara, Heitsch, Laura, Holliday, Elizabeth, Ibanez, Laure, Ilinca, Andreea, Irvin, Marguerite R, Jackson, Rebecca D, Jimenez-Conde, Jordi, Jood, Katarina, Schilling, Sabrina, Kissela, Brett M, Kleindorfer, Dawn O, Labovitz, Daniel, Laurie, Cathy C, Lemmens, Robin, Levi, Christopher, Li, Linxin, Lindgren, Arne G, Beecham, Gary W, Maguire, Jane, Müller-Nurasyid, Martina, Norrving, Bo, Peddareddygari, Leema Reddy, Pera, Joanna, Satizabal, Claudia L, Montine, Thomas J, Rexrode, Kathryn, Ribasés, Marta, Roquer, Jaume, Rost, Natalia S, Sacco, Ralph L, Schmidt, Reinhold, Schellenberg, Gerard D, Soriano-Tárraga, Carolina, Stanne, Tara, Stauch, Konstantin, Stine, O. C., Sudlow, Cathie Lm, Thijs, Vincent N S, Weir, David, Williams, Stephen R, Kjartansson, Olafur, Xu, Huichun, Hyacinth, Hyacinth I, Marini, Sandro, Nyquist, Paul, Lewis, Cathryn, Hansen, Bjorn, Guðnason, Vilmundur, Biffi, Alessandro, Kourkoulis, Christina, Anderson, Chris, Giese, Anne-Katrin, Sacco, Ralph, Chung, Jong-Won, Kim, Gyeong-Moon, Knopman, David S, Lubitz, Steven, Bourcier, Romain, Howson, Joanna, Granata, Alessandra, Drazyk, Anna, Markus, Hugh, Wardlaw, Joanna, Mitchell, Braxton, Cole, John, Hopewell, Jemma, Griswold, Michael E, Walters, Robin, Turnbull, Iain, Worrall, Bradford, Bis, Josh, Reiner, Alex, Dhar, Raj, Prasad, Kameshwar, Sarnowski, Chloé, Windham, B Gwen, Aparicio, Hugo Javier, Yang, Qiong, Chasman, Daniel, Phuah, Chia-Ling, Liu, Guiyou, Elkind, Mitchell, Lange, Leslie, Rost, Natalia, James, Michael, Gottesman, Rebecca F, Stewart, Jill, Vojinovic, Dina, Parati, Eugenio, Boncoraglio, Giorgio, Zand, Ramin, Bijlenga, Philippe, Selim, Magdy, Grond-Ginsbach, Caspar, Strbian, Daniel, Mosley, Thomas H, Tomppo, Liisa, Sallinen, Hanne, Pfeiffer, Dorothea, Torres, Nuria, Barboza, Miguel, Laarman, Melanie, Carriero, Roberta, Soriano, Carolina, Gill, Dipender, Debette, Stephanie, Mishra, Aniket, Wu, Jer-Yuarn, Ko, Tai-Ming, Bione, Silvia, Tatlisumak, Turgut, Holmegaard, Lukas, Yue, Suo, Bis, Joshua C, Saba, Yasaman, Bersano, Anna, Schlicht, Kristina, Ninomiya, Toshiharu, Oberstein, Saskia Lesnik, Lee, Tsong-Hai, Schmidt, Helena, Wasselius, Johan, Drake, Mattias, Stenman, Martin, Crawford, Katherine, Lena, Umme, Mateen, Farrah, Takeuchi, Fumihiko, Wu, Ona, Schirmer, Markus, Cramer, Steve, Golland, Polina, Brown, Robert, Meschia, James, Ross, Owen A, Pare, Guillaume, Chong, Mike, Yamaguchi, Shuhei, Gwinn, Katrina, Chen, Christopher, Koenig, Jim, Giralt, Eva, Saleheen, Danish, de Leeuw, Frank-Erik, Klijn, Karin, Kamatani, Yoichiro, Kubo, Michiaki, Nabika, Toru, Okada, Yukinori, Pedersen, Annie, Olsson, Maja, Martín, Juan José, Tan, Eng King, Frid, Petrea, Lee, Chaeyoung, Tregouet, David, Leung, Thomas, Kato, Norihiro, Choy, Richard, Loo, Keat Wei, Rinkel, Gabriel, Franca, Paulo, Cendes, Iscia, Carrera, Caty, Fernandez-Cadenas, Israel, Montaner, Joan, Kim, Helen, Rajan, Kumar B, Owolabi, Mayowa, Sofat, Reecha, Bakker, Mark, Ruigrok, Ynte, Hauer, Allard, van der Laan, Sander W, Irvin, Ryan, Sargurupremraj, Murali, Pezzini, Alessandro, Aggarwal, Neelum T, Abd-Allah, Foad, Liebeskind, David, Tan, Rhea, Danesh, John, Donatti, Amanda, Avelar, Wagner, Broderick, Joseph, Sudlow, Cathie, De Jager, Philip L, Rannikmae, Kristiina, McDonough, Caitrin Wheeler, van Agtmael, Tom, Walters, Matthew, Söderholm, Martin, Lorentzen, Erik, Olsson, Sandra, Olsson, Martina, Akinyemi, Rufus, Evans, Denis A, Cotlatciuc, Ioana, McArdle, Patrick, Dave, Tushar, Kittner, Steven, Faber, James E, Millwood, Iona, Márquez, Elsa Valdés, Mancuso, Michelangelo, Vibo, Riina, Teumer, Alexander, Psaty, Bruce M, Korv, Janika, Majersik, Jennifer, DeHavenon, Adam, Alexander, Matthew, Sale, Michele, Southerland, Andrew, Owens, Debra, Psaty, Bruce, Rotter, Jerome I, Wolfe, Stacey Quintero, Langefeld, Carl, Konrad, Jan, Sheth, Kevin, Falcone, Guido, Donahue, Kathleen, Simpkins, Alexis N, Liang Byorn, Tan Wei, Rice, Kenneth, Chan, Bernard, Clatworthy, Phil, Florez, Jose, Harshfield, Eric, Hozawa, Atsushi, Hsu, Chung, Hu, Chaur-Jong, Ihara, Masafumi, Lange, Marcos, Lopez, Oscar L, Lee, Soo Ji, Lee, I-Hui, Musolino, Patricia, Nakatomi, Hirofumi, Park, Kwang-Yeol, Riley, Chris, Sung, Joohon, Suzuki, Hideaki, Vo, Katie, Liao, Jiemin, Washida, Kazuo, Ibenez, Laura Garcia, Hofman, Albert, Algra, Ale, Reiner, Alex P, Doney, Alexander S F, Gschwendtner, Andreas, Vicente, Astrid M, Nordestgaard, Børge G, Carty, Cara L, Cheng, Ching-Yu, Palmer, Colin N A, Gamble, Dale M, Ringelstein, E Bernd, Valdimarsson, Einar, Davies, Gail, Wong, Tien Y, Pasterkamp, Gerard, Kuhlenbäumer, Gregor, Thorleifsson, Gudmar, Falcone, Guido J, Pare, Guillame, Ikram, Mohammad K, Aparicio, Hugo J, Deary, Ian, Hopewell, Jemma C, Liu, Jingmin, van der Lee, Sven J, Attia, John R, Ferro, Jose M, Bis, Joshua, Furie, Karen, Stefansson, Kari, Berger, Klaus, Kostulas, Konstantinos, Rannikmae, Kristina, Ikram, M Arfan, Sargurupremraj, Muralidharan, Amin, Najaf, Benn, Marianne, Farrall, Martin, Pandolfo, Massimo, Nalls, Mike, van Zuydam, Natalie R, Chouraki, Vincent, Abrantes, Patricia, Higgins, Peter, Lichtner, Peter, DeStefano, Anita L, Clarke, Robert, Abboud, Sherine, Oliveira, Sofia A, Gretarsdottir, Solveig, Mosley, Thomas, Battey, Thomas Wk, Thorsteinsdottir, Unnur, Thijs, Vincent Ns, Zhao, Wei, Chen, Wei-Min, Romero, Jose R, Albert, Marilyn S, Albin, Roger L, Apostolova, Liana G, Arnold, Steven E, Asthana, Sanjay, Atwood, Craig S, Baldwin, Clinton T, Barmada, M Michael, Barnes, Lisa L, Maillard, Pauline, Barral, Sandra, Beach, Thomas G, Becker, James T, Beekly, Duane, Bennett, David A, Bigio, Eileen H, Bird, Thomas D, Blacker, Deborah, Boeve, Bradley F, DeCarli, Charles, Boxer, Adam, Burke, James R, Burns, Jeffrey M, Buxbaum, Joseph D, Byrd, Goldie S, Cai, Guiqing, Cairns, Nigel J, Cantwell, Laura B, Cao, Chuanhai, Carlsson, Cynthia M, Wardlaw, Joanna M, Carney, Regina M, Carrasquillo, Minerva M, Carroll, Steven L, Chui, Helena C, Clark, David G, Cribbs, David H, Crocco, Elizabeth A, Hernández, Maria Del C Valdés, Demirci, F Yesim, Dick, Malcolm, Dickson, Dennis W, Duara, Ranjan, Ertekin-Taner, Nilufer, Faber, Kelley M, Fallin, M Daniele, Fallon, Kenneth B, Fardo, David W, Luciano, Michelle, Farlow, Martin R, Farrer, Lindsay A, Ferris, Steven, Foroud, Tatiana M, Frosch, Matthew P, Galasko, Douglas R, Gearing, Marla, Geschwind, Daniel H, Ghetti, Bernardino, Gilbert, John R, Hofer, Edith, Liewald, David, Go, Rodney C P, Goate, Alison M, Graff-Radford, Neill R, Green, Robert C, Griffith, Patrick, Growdon, John H, Haines, Jonathan L, Hakonarson, Hakon, Hamilton, Ronald L, Hamilton-Nelson, Kara L, Deary, Ian J, Haroutunian, Vahram, Harrell, Lindy E, Honig, Lawrence S, Huebinger, Ryan M, Hulette, Christine M, Hyman, Bradley T, Jicha, Gregory A, Jin, Lee-Way, Jun, Gyungah, Kamboh, M Ilyas, Starr, John M, Karydas, Anna, Kauwe, John S K, Kaye, Jeffrey A, Kim, Ronald, Kowall, Neil W, Kramer, Joel H, Kukull, Walter A, Kunkle, Brian W, LaFerla, Frank M, Lah, James J, Bastin, Mark E, Lang-Walker, Rosalyn, Larson, Eric B, Leverenz, James B, Levey, Allan I, Li, Ge, Lieberman, Andrew P, Logue, Mark W, Lunetta, Kathryn L, Lyketsos, Constantine G, Muñoz Maniega, Susana, Mack, Wendy J, Manly, Jennifer J, Marson, Daniel C, Martin, Eden R, Martiniuk, Frank, Mash, Deborah C, Masliah, Eliezer, Mayeux, Richard, McKee, Ann C, Mesulam, Marsel, Slagboom, P Eline, Miller, Bruce L, Miller, Carol A, Miller, Joshua W, Morris, John C, Murrell, Jill R, Naj, Adam C, Obisesan, Thomas O, Olichney, John M, Pankratz, Vernon S, Beekman, Marian, Parisi, Joseph E, Partch, Amanda, Paulson, Henry L, Pericak-Vance, Margaret A, Perry, William, Peskind, Elaine, Petersen, Ronald C, Pierce, Aimee, Poon, Wayne W, Potter, Huntington, Deelen, Joris, Quinn, Joseph F, Raj, Ashok, Raj, Towfique, Raskind, Murray, Reiman, Eric M, Reisberg, Barry, Reitz, Christiane, Ringman, John M, Roberson, Erik D, Rosen, Howard J, Uh, Hae-Won, Rosenberg, Roger N, Sager, Mark A, Sano, Mary, Saykin, Andrew J, Schneider, Julie A, Schneider, Lon S, Seeley, William W, Smith, Amanda G, Sonnen, Joshua A, Spina, Salvatore, Stern, Robert A, Swerdlow, Russell H, Tanzi, Rudolph E, Thornton-Wells, Tricia A, Trojanowski, John Q, Troncoso, Juan C, Tsuang, Debby W, Valladares, Otto, Van Deerlin, Vivianna M, Trompet, Stella, Brodaty, Henry, Van Eldik, Linda J, Vardarajan, Badri N, Vinters, Harry V, Vonsattel, Jean Paul, Wang, Li-San, Weintraub, Sandra, Welsh-Bohmer, Kathleen A, Williamson, Jennifer, Wingo, Thomas S, Wishnek, Sarah, Wright, Margaret J, Woltjer, Randall L, Wright, Clinton B, Younkin, Steven G, Yu, Chang-En, Yu, Lei, Chu, Audrey Y, Havulinna, Aki S, Ames, David, Smith, Albert Vernon, Choi, Seung Hoan, Garcia, Melissa E, Manichaikul, Ani, Gustafsson, Stefan, Bartz, Traci M, Boncoraglio, Giorgio B, Bellenguez, Céline, Vidal, Jean Sebastien, Wiggins, Kerri L, Xue, Flora, Ripatti, Samuli, Liu, Yongmei, Hoed, Marcel den, Heckbert, Susan R, Smith, Nicholas L, Buring, Julie E, Ridker, Paul M, Berr, Claudine, Dartigues, Jean-François, Beecham, Ashley H, Hamsten, Anders, Magnusson, Patrik K, Pedersen, Nancy L, Lannfelt, Lars, Lind, Lars, Lindgren, Cecilia M, Morris, Andrew P, Koudstaal, Peter J, Portegies, Marileen Lp, Blanton, Susan H, Uitterlinden, André G, de Craen, Anton Jm, Ford, Ian, Jukema, J Wouter, Stott, David J, Allen, Norrina B, Sale, Michele M, Johnson, Andrew D, White, Charles C, Paulista Markus, Marcello Ricardo, Nalls, Michael A, Beiser, Alexa, Vartiainen, Erkki, French, Curtis R, Kurth, Tobias, Harris, Tamara B, deStefano, Anita L, Schmidt, Carsten Oliver, Salomaa, Veikko, Wen, Wei, Ingelsson, Erik, Chasman, Daniel I, Verhaaren, Benjamin F J, Hilal, Saima, Thalamuthu, Anbupalam, Smith, Jennifer A, Ikram, M Kamran, Adams, Hieab H, Lopez, Lorna M, van Buchem, Mark A, Armstrong, Nicola J, van der Grond, Jeroen, Smith, Albert V, Hegenscheid, Katrin, de Andrade, Mariza, Atkinson, Elizabeth J, Beiser, Alexa S, Boerwinkle, Eric, Chong, Elizabeth, Brickman, Adam M, Bryan, R Nick, Chen, Christopher P L H, de Craen, Anton J M, Crivello, Fabrice, Schofield, Peter R, Dufouil, Carole, Elkind, Mitchell S V, Freudenberger, Paul, Habes, Mohamad, Heiss, Gerardo, Kwok, John B, Ibrahim-Verbaas, Carla A, Lewis, Cora E, Liewald, David C M, van der Lugt, Aad, Martinez, Oliver O, Nauck, Matthias, Niessen, Wiro J, Oostra, Ben A, Rice, Kenneth M, von Sarnowski, Bettina, Schreiner, Pamela J, Schuur, Maaike, Sidney, Stephen S, Sigurdsson, Sigurdur, Stott, David J M, van Swieten, John C, Töglhofer, Anna Maria, Turner, Stephen T, Vernooij, Meike W, Wang, Jing J, Wolf, Christiane, Zijdenbos, Alex, Kardia, Sharon L R, DeCarli, Charles C, Seshadri, Sudha S, Kavousi, Maryam, Franceschini, Nora, Isaacs, Aaron, Abecasis, Gonçalo R, Schminke, Ulf, Post, Wendy, Cupples, L Adrienne, Huffman, Jennifer E, Lehtimäki, Terho, Baumert, Jens, Münzel, Thomas, Dehghan, Abbas, North, Kari, Oostra, Ben, Stoegerer, Eva-Maria, Hayward, Caroline, Raitakari, Olli, Meisinger, Christa, Schillert, Arne, Sanna, Serena, Völzke, Henry, Thorsson, Bolli, Fox, Caroline S, Wittfeld, Katharina, Rivadeneira, Fernando, Nambi, Vijay, Halperin, Eran, Petrovic, Katja E, Peltonen, Leena, Wichmann, H Erich, Schnabel, Renate B, Dörr, Marcus, Parsa, Afshin, Aspelund, Thor, Grabe, Hans J, Demissie, Serkalem, Kathiresan, Sekar, Reilly, Muredach P, Taylor, Kent, Uitterlinden, Andre, Couper, David J, Sitzer, Matthias, Kähönen, Mika, Illig, Thomas, Wild, Philipp S, Hosten, Norbert, Orru, Marco, Lüdemann, Jan, Shuldiner, Alan R, Eiriksdottir, Gudny, Seissler, Jochen, Zeller, Tanja, Usala, Gianluca, Ernst, Florian, D'Agostino, Ralph B, O'Leary, Daniel H, Ballantyne, Christie, Thiery, Joachim, Ziegler, Andreas, Lakatta, Edward G, Chilukoti, Ravi Kumar, Völker, Uwe, Wolf, Philip A, Polak, Joseph F, Li, Xia, Rathmann, Wolfgang, Uda, Manuela, Klopp, Norman, Wilson, James F, Viikari, Jorma, Koenig, Wolfgang, Blankenberg, Stefan, Newman, Anne B, Witteman, Jacqueline, van Duijn, Cornelia, Scuteri, Angelo, Homuth, Georg, Gudnason, Vilmundur, O'Donnell, Christopher J, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lund University [Lund], Stroke Genetics Network (SiGN), METASTROKE, Alzheimer’s Disease Genetics Consortium (ADGC), Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, Peter Almgren, MSC, Christopher D. Anderson, MD, Donna K. Arnett, PhD, MSPH, John Attia, MD, PhD, FRACP, FRCPC, Hakan Ay, MD, Oscar R. Benavente, MD, Steve Bevan, PhD, Robert D. Brown, MD, Mariana Bustamante, PhD, Yu-Ching Cheng, PhD, John W. Cole, MD, MS, Ioana Cotlarciuc, PhD, Carlos Cruchaga, PhD, Paul IW. de Bakker, PhD, Hossein Delavaran, MD, PhD, Martin Dichgans, MD, Gunnar Engström, MD, PHD, PROF, Myriam Fornage, PhD, Raji P. Grewal, MD, Laura Heitsch, MD, Elizabeth Holliday, MSc, PhD, Laure Ibanez, PhD, Andreea Ilinca, MD, Marguerite R. Irvin, PhD, Rebecca D. Jackson, MD, Christina Jern, MD, PhD, Jordi Jimenez-Conde, MD, PhD, Julie A. Johnson, PharmD, Katarina Jood, MD, PhD, Brett M. Kissela, MD, MS, Steven J. Kittner, MD, Dawn O. Kleindorfer, MD, MS, Daniel Labovitz, MD, Cathy C. Laurie, PhD, Jin-Moo Lee, MD, PhD, Robin Lemmens, MD PhD, Christopher Levi, MBBS B Med Sci FRACP, Linxin Li, DPhil, Arne G. Lindgren, MD, PhD, Jane Maguire, PhD, Hugh S. Markus, FRCP, Patrick F. McArdle, PhD, Olle Melander, MD, PHD, PROF, James F. Meschia, MD, Braxton D. Mitchell, PhD, Martina Müller-Nurasyid, PhD, Bo Norrving, MD, PhD, Leema Reddy Peddareddygari, MD, Joanna Pera, MD, PhD, Sara L. Pulit, PhD, Kathryn Rexrode, MD, MPH, Marta Ribasés, PhD, BSc, Jaume Roquer, MD, PhD, Natalia S. Rost, MD, Peter M. Rothwell, FMedSci, Tatjana Rundek, MD PhD, Ralph L. Sacco, MD MS, Reinhold Schmidt, MD, Pankaj Sharma, MD PhD, Agnieszka Slowik, MD, PhD, Carolina Soriano-Tárraga, BSc, PhD, Tara Stanne, PhD, Konstantin Stauch, PhD, O C. Stine, PhD, Cathie LM. Sudlow, BMBCh, MSc, DPhil, FRCP (Ed), Vincent N.S. Thijs, MD, PhD, Sylvia Wasssertheil-Smoller, PhD, David Weir, PhD, Stephen R. Williams, PhD, Quenna Wong, PhD, Daniel Woo, MD, MS, Bradford B. Worrall, MD, MSc, Huichun Xu, MD, PhD, Sudha Seshadri, MD, Hyacinth I Hyacinth, MD, Sandro Marini, MD, Paul Nyquist, MD, PhD, Cathryn Lewis, PhD, Bjorn Hansen, MD, Bo Norrving, MD, PhD, Jonathan Rosand, MD, Alessandro Biffi, MD, Christina Kourkoulis, Bachelor, Chris Anderson, MD, MMSc, Anne-Katrin Giese, MD, Ralph Sacco, MD, MS, Pankaj Sharma, MD, PhD, Jong-Won Chung, MD, MSc, Gyeong-Moon Kim, MD, Steven Lubitz, MD, MPH, Romain Bourcier, MD, Joanna Howson, PhD, Alessandra Granata, PhD, Anna Drazyk, MRCPI, Hugh Markus, MD, Joanna Wardlaw, MD, Braxton Mitchell, MPH, PHD, John Cole, MD, MS, Jemma Hopewell, PhD, FESC, Robin Walters, MA, PhD, PgDip, Iain Turnbull, BA(Hons) MB BChir MRCP(UK) MRCGP, Bradford Worrall, MD, MSc, Josh Bis, PhD, Alex Reiner, MD, MSc, Raj Dhar, MD, Laura Heitsch, MD, Jin-Moo Lee, MD, PhD, Kameshwar Prasad, MD, DM, MMSc, FRCP(Edin), FAMS, Chloé Sarnowski, PhD, Hugo Javier Aparicio, MD, Qiong Yang, PhD, Daniel Chasman, PhD, Kathryn Rexrode, MD, MPH, Chia-Ling Phuah, MD, Guiyou Liu, PhD, Mitchell Elkind, MD, MSc, Leslie Lange, PhD, Natalia Rost, MD, Michael James, MD, Jill Stewart, PhD, Dina Vojinovic, MD, MS, Vincent Thijs, MD, PhD, Eugenio Parati, MD, Giorgio Boncoraglio, MD, Ramin Zand, MD, Philippe Bijlenga, MD, PhD, Magdy Selim, MD, PhD, Caspar Grond-Ginsbach, PhD, Daniel Strbian, MD, PhD, Liisa Tomppo, MD, Hanne Sallinen, MD, Dorothea Pfeiffer, MD, Nuria Torres, MSc, Miguel Barboza, MD, Melanie Laarman, PhD candidate, Roberta Carriero, PhD, Elizabeth Holliday, PhD, Jordi Jimenez-Conde, MD, PhD, Carolina Soriano, BSc, PhD, Dipender Gill, PhD, Stephanie Debette, MD, PhD, Aniket Mishra, PhD, Jer-Yuarn Wu, PhD, Tai-Ming Ko, PhD, Silvia Bione, PhD, Katarina Jood, MD, PhD, Turgut Tatlisumak, MD, PhD, Lukas Holmegaard, PhD, Suo Yue, system engineer, Anna bersano, MD, PhD, Joanna Pera, MD, PhD, Agnieszka Slowik, MD, PhD, Christopher Levi, MBBS B Med Sci FRACP, Kristina Schlicht, Dipl. Biol., Robin Lemmens, MD, PhD, Toshiharu Ninomiya, MD, PhD, Saskia Lesnik Oberstein, PhD, Tsong-Hai Lee, MD, PhD, Rainer Malik, PhD, Martin Dichgans, MD, Arne Lindgren, MD, PhD, Johan Wasselius, MD, PhD, Mattias Drake, student, Olle Melander, MD, PHD, Martin Stenman, MD, Andreea Ilinca, MD, Katherine Crawford, BS, Umme Lena, Bachelors of Arts, Farrah Mateen, MD, PhD, Hakan Ay, MD, Ona Wu, PhD, Markus Schirmer, PhD, Steve Cramer, MD, Polina Golland, PhD, Robert Brown, MD, MPH, James Meschia, MD, Owen A. Ross, PhD, Guillaume Pare, MD, MSc, FRCPC, Mike Chong, MSc, Tatjana Rundek, MD PhD, Katrina Gwinn, MD, Christopher Chen, BMBCh (Oxon), MRCP, FRCP, Jim Koenig, PhD, Eva Giralt, PhD, Danish Saleheen, MBBS, PhD, Frank-Erik de Leeuw, MD, PhD, Karin Klijn, MD, PhD, Yoichiro Kamatani, MD, PhD, Michiaki Kubo, MD, PhD, Yukinori Okada, MD, PhD, Annie Pedersen, MD, Maja Olsson, PhD, Juan José Martín, MD, Huichun Xu, MD, PhD, Eng King Tan, MD, Petrea Frid, MD, Chaeyoung Lee, PhD, David Tregouet, PhD, Thomas Leung, MB, ChB, MRCP, FHKCP, FHKAM, Richard Choy, BSc (Brad.), MSc(Med) (Birm.), PhD (CUHK), Christina Jern, MD, PhD, Keat Wei Loo, BSc, PhD, Gabriel Rinkel, MD, Paulo Franca, PhD, Iscia Cendes, MD, PhD, Caty Carrera, MD, Israel Fernandez-Cadenas, PhD, Joan Montaner, MD, PhD, Helen Kim, PhD, Mayowa Owolabi, MBBS, MSc, DrM, MWACP, FMCP, FAAN, FAS, Reecha Sofat, MD, Mark Bakker, PhD, Ynte Ruigrok, MD, PhD, Allard Hauer, PhD candidate, Sara L. Pulit, PhD, Sander W. van der Laan, PhD, Ryan Irvin, PhD, Murali Sargurupremraj, PhD, Alessandro Pezzini, MD, Foad Abd-Allah, MD, David Liebeskind, MD, Matthew Traylor, PhD, Rhea Tan, BSc (Hons), John Danesh, MD, DPhil, Loes Rutten-Jacobs, PhD, Amanda Donatti, PhD, student, Wagner Avelar, PhD, Joseph Broderick, MD, Daniel Woo, MD, MS, Cathie Sudlow, BMBCh, MSc, DPhil, FRCP, Kristiina Rannikmae, MD, Caitrin Wheeler McDonough, PhD, Tom van Agtmael, PhD, Matthew Walters, MD, MBChB, FRCP, Martin Söderholm, MD, PhD, Erik Lorentzen, Ph.Lic., Sandra Olsson, PhD, MSc, Tara Stanne, PhD, Martina Olsson, MSc, Rufus Akinyemi, PhD, MSc, MWACP, FMCP, Ioana Cotlatciuc, PhD, Patrick McArdle, PhD, Tushar Dave, MSc, Steven Kittner, MD, MPH, John Attia, MD, PhD, James E Faber, PhD, Iona Millwood, DPhil, Elsa Valdés Márquez, PhD, Michelangelo Mancuso, MD, PhD, Riina Vibo, MD, PhD, Janika Korv, MD, PhD, FESO, Jane Maguire, PhD, BN (Hons), BA, RN, Myriam Fornage, PhD, Jennifer Majersik, MD, Adam DeHavenon, MD, Matthew Alexander, MD, Michele Sale, PhD, Andrew Southerland, MD, MSc, Debra Owens, NNP, Bruce Psaty, MD, PhD, W. T. Longstreth, Jr, MD, MPH, Stacey Quintero Wolfe, MD, FAANS, Carl Langefeld, PhD, Carlos Cruchaga, PhD, Jan Konrad, administrative coordinator, Kevin Sheth, MD, Guido Falcone, MD, ScD, MPH, Kathleen Donahue, BS, Alexis N Simpkins, MD, PhD, Tan Wei Liang Byorn, MMBS, student, Bernard Chan, MD, Phil Clatworthy, MD, PhD, Jose Florez, MD, Eric Harshfield, PhD, Atsushi Hozawa, MD, Chung Hsu, MD, PhD, Chaur-Jong Hu, MD, PhD, Laure Ibanez, PhD, Masafumi Ihara, MD, PhD, FACP, Marcos Lange, PhD, Soo Ji Lee, PhD, MPH, I-Hui Lee, MD, PhD, Patricia Musolino, MD, PhD, Hirofumi Nakatomi, MD, PhD, Kwang-Yeol Park, MD, Stephen S Rich, PhD, Chris Riley, MBA, Joohon Sung, MD, PhD, Hideaki Suzuki, MD, PhD, Katie Vo, MD, Kazuo Washida, MD, PhD, Laura Garcia Ibenez, PhD, Agnieszka Slowik, MD, PhD, Albert Hofman, MD, PhD, Ale Algra, MD, MSc, Alex P Reiner, MD, MSc, Alexander S F Doney, PhD, Andreas Gschwendtner, MD, Andreea Ilinca, MD, Anne-Katrin Giese, MD, Arne Lindgren, MD, PhD, Astrid M Vicente, PhD, Bo Norrving, MD, PhD, Børge G Nordestgaard, MD, PhD, DMSc, Braxton D Mitchell, PhD, Bradford B Worrall, MD, MSc, Bruce M Psaty, MD, PhD, Cara L Carty, PhD, Cathie Sudlow, BMBCh, MSc, DPhil, FRCP, Christopher D Anderson, MD, Christopher Levi, MBBS B Med Sci FRACP, Claudia L Satizabal, PhD, Colin N A Palmer, PhD, Dale M Gamble, CCRP, Daniel Woo, MD, MS, Danish Saleheen, MBBS, PhD, E Bernd Ringelstein, MD, FAHA, Einar Valdimarsson, MD, Elizabeth Holliday, PhD, Gail Davies, PhD, Ganesh Chauhan, PhD, Gerard Pasterkamp, MD, PhD, Giorgio Boncoraglio, MD, Gregor Kuhlenbäumer, MD, PhD, Gudmar Thorleifsson, PhD, Guido J Falcone, MD, ScD, MPH, Guillame Pare, MD, MSc, FRCPC, Helena Schmidt, MD, PhD, Hossein Delavaran, MD, PhD, Hugh S Markus, MD, Hugo J Aparicio, MD, Ian Deary, PhD, Ioana Cotlarciuc, PhD, Israel Fernandez-Cadenas, PhD, James Meschia, MD, Jemma C Hopewell, PhD, FESC, Jingmin Liu, MSc, Joan Montaner, MD, PhD, Joanna Pera, MD, PhD, John Cole, MD, MS, John R Attia, MD, PhD, FRACP, FRCPC, Jonathan Rosand, MD, MSc, Jose M Ferro, MD, PhD, Joshua Bis, PhD, Karen Furie, MD, Kari Stefansson, MD, Klaus Berger, MD, PhD, Konstantinos Kostulas, MD, PhD, Kristina Rannikmae, MD, M Arfan Ikram, MD, PhD, Marianne Benn, MD, PhD, Martin Dichgans, MD, Martin Farrall, FRCPath, Massimo Pandolfo, MD, Matthew Traylor, PhD, Matthew Walters, MD, MBChB, FRCP, Michele Sale, PhD, Mike Nalls, PhD, Myriam Fornage, PhD, Natalie R van Zuydam, PhD, Pankaj Sharma, MD, PhD, Patricia Abrantes, PhD, Paul IW de Bakker, PhD, Peter Higgins, FRCP, Peter Lichtner, PhD, Peter M Rothwell, FMedSci, Philippe Amouyel, MD, PhD, Qiong Yang, PhD, Rainer Malik, PhD, Reinhold Schmidt, MD, Robert Clarke, MD, MRCP, FRCP, FFPH, Robin Lemmens, MD, PhD, Sander W van der Laan, PhD, Sara L Pulit, PhD, Sherine Abboud, MD, PhD, Sofia A Oliveira, PhD, Solveig Gretarsdottir, PhD, Stephanie Debette, MD, PhD, Stephen R Williams, PhD, Steve Bevan, BSc, PhD, Steven J Kittner, MD, Sudha Seshadri, MD, Thomas Mosley, PhD, Thomas WK Battey, BS, Turgut Tatlisumak, MD, PhD, Unnur Thorsteinsdottir, PhD, Vincent NS Thijs, MD, PhD, W T Longstreth, MD, Wei Zhao, MD, PhD, Wei-Min Chen, PhD, Yu-Ching Cheng, PhD, Marilyn S. Albert, PhD, Roger L. Albin, MD, Liana G. Apostolova, MD, Steven E. Arnold, MD, Sanjay Asthana, MD, Craig S. Atwood, PhD, Clinton T. Baldwin, PhD, M. Michael Barmada, PhD, Lisa L. Barnes, PhD, Sandra Barral, PhD, Thomas G. Beach, MD, PhD, James T. Becker, PhD, Gary W. Beecham, PhD, Duane Beekly, BS, David A. Bennett, MD, Eileen H. Bigio, MD, Thomas D. Bird, MD, Deborah Blacker, MD, ScD, Bradley F. Boeve, MD, Adam Boxer, MD, PhD, James R. Burke, MD, PhD, Jeffrey M. Burns, MD, MS, Joseph D. Buxbaum, PhD, Goldie S. Byrd, PhD, Guiqing Cai, MD, PhD, Nigel J. Cairns, PhD FRCPath, Laura B. Cantwell, MPH, Chuanhai Cao, PhD, Cynthia M. Carlsson, MD, MS, Regina M. Carney, MD, Minerva M. Carrasquillo, PhD, Steven L. Carroll, MD, PhD, Helena C. Chui, PhD, David G. Clark, MD, David H. Cribbs, PhD, Elizabeth A. Crocco, MD, Carlos Cruchaga, PhD, Philip L. De Jager, MD, PhD, Charles DeCarli, MD, F. Yesim Demirci, MD, Malcolm Dick, Dennis W. Dickson, MD, Ranjan Duara, Md, Nilufer Ertekin-Taner, MD, PhD, Denis A. Evans, MD, Kelley M. Faber, MS, M. Daniele Fallin, PhD, Kenneth B. Fallon, MD, David W. Fardo, PhD, Martin R. Farlow, MD, Lindsay A. Farrer, PhD, Steven Ferris, PhD, Tatiana M. Foroud, PhD, Matthew P. Frosch, MD, PhD, Douglas R. Galasko, MD, Marla Gearing, PhD, Daniel H. Geschwind, MD, PhD, Bernardino Ghetti, MD, John R. Gilbert, PhD, Rodney C.P. Go, PhD, Alison M. Goate, DPhil, Neill R. Graff-Radford, MD, Robert C. Green, MD, MPH, Patrick Griffith, MD, John H. Growdon, MD, Jonathan L. Haines, PhD, Hakon Hakonarson, MD, PhD, Ronald L. Hamilton, MD, Kara L. Hamilton-Nelson, MPH, Vahram Haroutunian, PhD, Lindy E. Harrell, MD, PhD, Lawrence S. Honig, MD, PhD, Ryan M. Huebinger, PhD, Christine M. Hulette, MD, Bradley T. Hyman, MD, PhD, Gregory A. Jicha, MD, PhD, Lee-Way Jin, MD, PhD, Gyungah Jun, PhD, M. Ilyas Kamboh, PhD, Anna Karydas, BA, John S.K. Kauwe, PhD, Jeffrey A. Kaye, MD, Ronald Kim, MD, Neil W. Kowall, MD, Joel H. Kramer, PsyD, Walter A. Kukull, PhD, Brian W. Kunkle, PhD, Frank M. LaFerla, PhD, James J. Lah, MD, PhD, Rosalyn Lang-Walker, PhD, Eric B. Larson, MD, MPH, James B. Leverenz, MD, Allan I. Levey, MD, PhD, Ge Li, MD, PhD, Andrew P. Lieberman, MD, PhD, Mark W. Logue, PhD, Oscar L. Lopez, MD, Kathryn L. Lunetta, PhD, Constantine G. Lyketsos, MD, Wendy J. Mack, PhD, Jennifer J. Manly, PhD, Daniel C. Marson, JD, PhD, Eden R. Martin, PhD, Frank Martiniuk, PhD, Deborah C. Mash, PhD, Eliezer Masliah, MD, Richard Mayeux, MD, Ann C. McKee, MD, Marsel Mesulam, MD, Bruce L. Miller, MD, Carol A. Miller, MD, Joshua W. Miller, PhD, Thomas J. Montine, MD, PhD, John C. Morris, MD, Jill R. Murrell, PhD, Adam C. Naj, PhD, Thomas O. Obisesan, MD, John M. Olichney, MD, Vernon S. Pankratz, PhD, Joseph E. Parisi, MD, Amanda Partch, MS, Henry L. Paulson, MD, PhD, Margaret A. Pericak-Vance, PhD, William Perry, BS, Elaine Peskind, MD, Ronald C. Petersen, MD, PhD, Aimee Pierce, MD, Wayne W. Poon, PhD, Huntington Potter, PhD, Joseph F. Quinn, MD, Ashok Raj, MD, Towfique Raj, PhD, Murray Raskind, MD, Eric M. Reiman, MD, Barry Reisberg, MD, Christiane Reitz, MD, PhD, John M. Ringman, MD, MS, Erik D. Roberson, MD, PhD, Howard J. Rosen, MD, Roger N. Rosenberg, MD, Mark A. Sager, MD, Mary Sano, PhD, Andrew J. Saykin, PsyD, Gerard D. Schellenberg, PhD, Julie A. Schneider, MD, MS, Lon S. Schneider, MD, MS, William W. Seeley, MD, Amanda G. Smith, MD, Joshua A. Sonnen, MD, Salvatore Spina, MD, Robert A. Stern, PhD, Russell H. Swerdlow, MD, Rudolph E. Tanzi, PhD, Tricia A. Thornton-Wells, PhD, John Q. Trojanowski, MD, PhD, Juan C. Troncoso, MD, Debby W. Tsuang, MD, Otto Valladares, MS, Vivianna M. Van Deerlin, MD, PhD, Linda J. Van Eldik, PhD, Badri N. Vardarajan, PhD, MS, Harry V. Vinters, MD, Jean Paul Vonsattel, MD, Li-San Wang, PhD, Sandra Weintraub, PhD, Kathleen A. Welsh-Bohmer, PhD, Jennifer Williamson, MS, MPH, Thomas S. Wingo, MD, Sarah Wishnek, MPH, Randall L. Woltjer, MD, PhD, Clinton B. Wright, MD, MS, Steven G. Younkin, MD, PhD, Chang-En Yu, PhD, Lei Yu, PhD, Ganesh Chauhan, PhD, Audrey Y. Chu, PhD, Myriam Fornage, PhD, Joshua C. Bis, PhD, Aki S. Havulinna, DSc, Muralidharan Sargurupremraj, PhD, Albert Vernon Smith, PhD, Hieab H.H. Adams, MSc, Seung Hoan Choi, MA, Stella Trompet, PhD, Melissa E. Garcia, MPH, Ani Manichaikul, PhD, Alexander Teumer, PhD, Stefan Gustafsson, PhD, Traci M. Bartz, MS, Céline Bellenguez, PhD, Jean Sebastien Vidal, MD, Xueqiu Jian, PhD, Olafur Kjartansson, MD, Kerri L. Wiggins, MS, Claudia L. Satizabal, PhD, Flora Xue, MS, Samuli Ripatti, PhD, Yongmei Liu, PhD, Joris Deelen, PhD, Marcel den Hoed, PhD, Susan R. Heckbert, MD, Kenneth Rice, PhD, Nicholas L. Smith, PhD, Quenna Wong, MS, Hugo J. Aparicio, MD, Julie E. Buring, ScD, Paul M Ridker, MD, Claudine Berr, MD, Jean-François Dartigues, MD, Anders Hamsten, MD, Patrik K. Magnusson, PhD, Nancy L. Pedersen, PhD, Lars Lannfelt, MD, Lars Lind, MD, Cecilia M. Lindgren, PhD, Andrew P. Morris, PhD, Albert Hofman, MD, Peter J. Koudstaal, MD, Marileen LP. Portegies, MD, André G. Uitterlinden, PhD, Anton JM de Craen, PhD, Ian Ford, MD, J. Wouter Jukema, MD, David J Stott, MD, Norrina B. Allen, PhD, Michele M. Sale, PhD, Andrew D Johnson, PhD, David A. Bennett, MD, Philip L. De Jager, MD, PhD, Charles C. White, PhD, Hans Jörgen Grabe, MD, Marcello Ricardo Paulista Markus, MD, Oscar L Lopez, MD, Jerome I. Rotter, MD, Michael A. Nalls, PhD, Rebecca F. Gottesman, MD, Michael E. Griswold, PhD, David S. Knopman, MD, B. Gwen Windham, MD, Alexa Beiser, PhD, Erkki Vartiainen, MD, Curtis R. French, PhD, Tobias Kurth, MD, Bruce M. Psaty, MD, Tamara B. Harris, MD, Stephen S Rich, PhD, Anita L. deStefano, PhD, Carsten Oliver Schmidt, PhD, Veikko Salomaa, MD, Thomas H. Mosley, PhD, Erik Ingelsson, MD, PhD, Cornelia M. van Duijn, PhD, Christophe Tzourio, MD, Lenore J Launer, PhD, M. Arfan Ikram, MD, Daniel I. Chasman, PhD, W. T. Longstreth, Jr, MD, MPH, Sudha Seshadri, MD, Stéphanie Debette, MD, Benjamin F.J. Verhaaren, MD, PhD, Stéphanie Debette, MD, PhD, Joshua C. Bis, PhD, Jennifer A. Smith, PhD, MPH, MA, M. Kamran Ikram, MD, PhD, Hieab H. Adams, MSc, Ashley H. Beecham, MSc, Kumar B. Rajan, PhD, Lorna M. Lopez, PhD, Sandra Barral, PhD, Mark A. van Buchem, MD, PhD, Jeroen van der Grond, PhD, Albert V. Smith, PhD, Katrin Hegenscheid, MD, Neelum T. Aggarwal, MD, Mariza de Andrade, PhD, Elizabeth J. Atkinson, PhD, Marian Beekman, PhD, Alexa S. Beiser, PhD, Susan H. Blanton, PhD, Eric Boerwinkle, PhD, Adam M. Brickman, PhD, R. Nick Bryan, MD, PhD, Ganesh Chauhan, PhD, Christopher P.L.H. Chen, FRCP, Vincent Chouraki, MD, PhD, Anton J.M. de Craen, PhD, Fabrice Crivello, PhD, Ian J. Deary, PhD, Joris Deelen, MSc, Philip L. De Jager, MD, PhD, Carole Dufouil, PhD, Mitchell S.V. Elkind, MD, MSc, Denis A. Evans, MD, Paul Freudenberger, MSc, Rebecca F. Gottesman, MD, PhD, Vilmundur Guðnason, MD, PhD, Mohamad Habes, PhD, Susan R. Heckbert, MD, PhD, Gerardo Heiss, MD, Saima Hilal, MBBS, Edith Hofer, PhD, Albert Hofman, MD, PhD, Carla A. Ibrahim-Verbaas, MD, David S. Knopman, MD, Cora E. Lewis, MD, MSPH, Jiemin Liao, MSc, David C.M. Liewald, BSc, Michelle Luciano, PhD, Aad van der Lugt, MD, PhD, Oliver O. Martinez, PhD, Richard Mayeux, MD, MSc, Bernard Mazoyer, MD, PhD, Mike Nalls, PhD, Matthias Nauck, MD, Wiro J. Niessen, PhD, Ben A. Oostra, PhD, Bruce M. Psaty, MD, PhD, Kenneth M. Rice, PhD, Jerome I. Rotter, MD, Bettina von Sarnowski, MD, Helena Schmidt, MD, PhD, Pamela J. Schreiner, PhD, Maaike Schuur, MD, PhD, Stephen S. Sidney, MD, MPH, Sigurdur Sigurdsson, MSc, P. Eline Slagboom, PhD, David J.M. Stott, MD, John C. van Swieten, MD, PhD, Alexander Teumer, PhD, Anna Maria Töglhofer, MSc, Matthew Traylor, PhD, Stella Trompet, PhD, Stephen T. Turner, MD, Christophe Tzourio, MD, PhD, Hae-Won Uh, PhD, André G. Uitterlinden, PhD, Meike W. Vernooij, MD, PhD, Jing J. Wang, PhD, Tien Y. Wong, MD, PhD, Joanna M. Wardlaw, MD, B. Gwen Windham, MD, Katharina Wittfeld, MS, Christiane Wolf, PhD, Clinton B. Wright, MD, Qiong Yang, PhD, Wei Zhao, MD, PhD, Alex Zijdenbos, PhD, J. Wouter Jukema, MD, PhD, Ralph L. Sacco, MD, Sharon L.R. Kardia, PhD, Philippe Amouyel, MD, PhD, Thomas H. Mosley, PhD, W. T. Longstreth, Jr, MD, MPH, Charles C. DeCarli, MD, Cornelia M. van Duijn, PhD, Reinhold Schmidt, MD, Lenore J. Launer, PhD, Hans J. Grabe, MD, Sudha S. Seshadri, MD, M. Arfan Ikram, MD, PhD, Myriam Fornage, PhD, Joshua C. Bis, PhD, Maryam Kavousi, MD, MSc, Nora Franceschini, MD, MPH, Aaron Isaacs, PhD, Gonçalo R Abecasis, PhD, Ulf Schminke, MD, Wendy Post, MD, Albert V. Smith, PhD, L. Adrienne Cupples, PhD, Hugh S Markus, MD, Reinhold Schmidt, MD, Jennifer E. Huffman, MSc, Terho Lehtimäki, MD, PhD, Jens Baumert, PhD, Thomas Münzel, MD, Susan R. Heckbert, MD, PhD, Abbas Dehghan, MD, PhD, Kari North, PhD, Ben Oostra, PhD, Steve Bevan, PhD, Eva-Maria Stoegerer, MD, Caroline Hayward, PhD, Olli Raitakari, MD, PhD, Christa Meisinger, MD, MPH, Arne Schillert, PhD, Serena Sanna, PhD, Henry Völzke, MD, Yu-Ching Cheng, PhD, Bolli Thorsson, MD, Caroline S. Fox, MD, MS, Kenneth Rice, PhD, Fernando Rivadeneira, MD, PhD, Vijay Nambi, MD, Eran Halperin, PhD, Katja E. Petrovic, MSc, Leena Peltonen, MD, PhD, H. Erich Wichmann, MD, PhD, Renate B. Schnabel, MD, MSc, Marcus Dörr, MD, Afshin Parsa, MD, MPH, Thor Aspelund, PhD, Serkalem Demissie, PhD, Sekar Kathiresan, MD, Muredach P. Reilly, MBBCH, MSCE, Kent Taylor, PhD, Andre Uitterlinden, PhD, David J. Couper, PhD, Matthias Sitzer, MD, Mika Kähönen, MD, PhD, Thomas Illig, PhD, Philipp S. Wild, MD, Marco Orru, MD, Jan Lüdemann, PhD, Alan R. Shuldiner, MD, Gudny Eiriksdottir, MSc, Charles C. White, MPH, Jerome I. Rotter, MD, Albert Hofman, MD, PhD, Jochen Seissler, MD, Tanja Zeller, PhD, Gianluca Usala, PhD, Florian Ernst, PhD, Lenore J. Launer, PhD, Ralph B. D'Agostino, Sr, PhD, Daniel H. O'Leary, MD, Christie Ballantyne, MD, Joachim Thiery, MD, MBA, Andreas Ziegler, Dr. rer. nat. habil., Edward G. Lakatta, MD, Ravi Kumar Chilukoti, MSc, Tamara B. Harris, MD, PhD, Philip A. Wolf, MD, Bruce M. Psaty, MD, PhD, Joseph F Polak, MD, MPH, Xia Li, MD, MPH, Wolfgang Rathmann, MD, MSPH, Manuela Uda, PhD, Eric Boerwinkle, PhD, Norman Klopp, PhD, Helena Schmidt, MD PhD, James F Wilson, DPhil, Jorma Viikari, MD, PhD, Wolfgang Koenig, MD, Stefan Blankenberg, Prof Dr med, Anne B. Newman, MD, MPH, Jacqueline Witteman, PhD, Gerardo Heiss, MD, PhD, Cornelia van Duijn, PhD, Angelo Scuteri, MD, PhD, Georg Homuth, PhD, Braxton D. Mitchell, PhD, Vilmundur Gudnason, MD, PhD, and Christopher J. O’Donnell, MD, MPH, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, and Berr, Claudine
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Neurology & Neurosurgery ,[SDV]Life Sciences [q-bio] ,Heilaskaði ,Clinical Neurology ,Stroke Genetics Network (SiGN), the International Stroke Genetics Consortium (ISGC), METASTROKE, Alzheimer's Disease Genetics Consortium (ADGC), and the Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium ,R1 ,Article ,[SDV] Life Sciences [q-bio] ,Taugasjúkdómar ,[SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie ,Meta-analyses ,Brain infarcts ,GWAS ,[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie ,ddc:610 ,Erfðarannsóknir ,MRI - Abstract
Publisher's version (útgefin grein), Objective: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. Methods We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n=20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI. Results: The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 × 10-8; and LINC00539/ZDHHC20, p = 5.82 × 10-9. Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p[BI] = 9.38 × 10-25; p [SSBI] = 5.23 × 10-14 for hypertension), smoking (p[BI]= 4.4 × 10-10; p [SSBI] = 1.2 × 10 -4), diabetes (p[BI] = 1.7 × 10 -8; p [SSBI] = 2.8 × 10 -3), previous cardiovascular disease (p [BI] = 1.0 × 10-18; p [SSBI] = 2.3 × 10-7), stroke (p [BI] = 3.9 × 10-69; p [SSBI] = 3.2 × 10 -24), and MRI-defined white matter hyperintensity burden (p [BI]=1.43 × 10-157; p [SSBI] = 3.16 × 10-106), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p ≤ 0.0022), without indication of directional pleiotropy. Conclusion: In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI., CHAP: R01-AG-11101, R01-AG-030146, NIRP-14-302587. SMART: This study was supported by a grant from the Netherlands Organization for Scientific Research–Medical Sciences (project no. 904-65–095). LBC: The authors thank the LBC1936 participants and the members of the LBC1936 research team who collected and collated the phenotypic and genotypic data. The LBC1936 is supported by Age UK (Disconnected Mind Programme grant). The work was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross-council Lifelong Health and Wellbeing Initiative (MR/K026992/1). The brain imaging was performed in the Brain Research Imaging Centre (https://www.ed.ac.uk/clinical-sciences/edinburgh-imaging), a center in the SINAPSE Collaboration (sinapse.ac.uk) supported by the Scottish Funding Council and Chief Scientist Office. Funding from the UK Biotechnology and Biological Sciences Research Council (BBSRC) and the UK Medical Research Council is acknowledged. Genotyping was supported by a grant from the BBSRC (ref. BB/F019394/1). PROSPER: The PROSPER study was supported by an investigator-initiated grant obtained from Bristol-Myers Squibb. Prof. Dr. J.W. Jukema is an Established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Support for genotyping was provided by the seventh framework program of the European commission (grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging grant 050-060-810). SCES and SiMES: National Medical Research Council Singapore Centre Grant NMRC/CG/013/2013. C.-Y.C. is supported by the National Medical Research Council, Singapore (CSA/033/2012), Singapore Translational Research Award (STaR) 2013. Dr. Kamran Ikram received additional funding from the Singapore Ministry of Health's National Medical Research Council (NMRC/CSA/038/2013). SHIP: SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs, as well as the Social Ministry of the Federal State of Mecklenburg–West Pomerania, and the network “Greifswald Approach to Individualized Medicine (GANI_MED)” funded by the Federal Ministry of Education and Research (grant 03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthineers, Erlangen, Germany, and the Federal State of Mecklenburg–West Pomerania. Whole-body MRI was supported by a joint grant from Siemens Healthineers, Erlangen, Germany, and the Federal State of Mecklenburg–West Pomerania. The University of Greifswald is a member of the Caché Campus program of the InterSystems GmbH. OATS (Older Australian Twins Study): OATS was supported by an Australian National Health and Medical Research Council (NHRMC)/Australian Research Council (ARC) Strategic Award (ID401162) and by a NHMRC grant (ID1045325). OATS was facilitated via access to the Australian Twin Registry, which is supported by the NHMRC Enabling Grant 310667. The OATS genotyping was partly supported by a Commonwealth Scientific and Industrial Research Organisation Flagship Collaboration Fund Grant. NOMAS: The Northern Manhattan Study is funded by the NIH grant “Stroke Incidence and Risk Factors in a Tri-Ethnic Region” (NINDS R01NS 29993). TASCOG: NHMRC and Heart Foundation. AGES: The study was funded by the National Institute on Aging (NIA) (N01-AG-12100), Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament), with contributions from the Intramural Research Programs at the NIA, the National Heart, Lung, and Blood Institute (NHLBI), and the National Institute of Neurological Disorders and Stroke (NINDS) (Z01 HL004607-08 CE). ERF: The ERF study as a part of European Special Populations Research Network (EUROSPAN) was supported by European Commission FP6 STRP grant no. 018947 (LSHG-CT-2006-01947) and also received funding from the European Community's Seventh Framework Programme (FP7/2007–2013)/grant agreement HEALTH-F4-2007-201413 by the European Commission under the programme “Quality of Life and Management of the Living Resources” of 5th Framework Programme (no. QLG2-CT-2002-01254). High-throughput analysis of the ERF data was supported by a joint grant from Netherlands Organization for Scientific Research and the Russian Foundation for Basic Research (NWO-RFBR 047.017.043). Exome sequencing analysis in ERF was supported by the ZonMw grant (project 91111025). Najaf Amin is supported by the Netherlands Brain Foundation (project no. F2013[1]-28). ARIC: The Atherosclerosis Risk in Communities study was performed as a collaborative study supported by NHLBI contracts (HHSN268201100005C, HSN268201100006C, HSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL70825, R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and NIH contract HHSN268200625226C. Infrastructure was partly supported by grant no. UL1RR025005, a component of the NIH and NIH Roadmap for Medical Research. This project was also supported by NIH R01 grant NS087541 to M.F. FHS: This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (contracts no. N01-HC-25195 and no. HHSN268201500001I), and its contract with Affymetrix, Inc. for genotyping services (contract no. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. This study was also supported by grants from the NIA (R01s AG033040, AG033193, AG054076, AG049607, AG008122, and U01-AG049505) and the NINDS (R01-NS017950, UH2 NS100605). Dr. DeCarli is supported by the Alzheimer's Disease Center (P30 AG 010129). ASPS: The research reported in this article was funded by the Austrian Science Fund (FWF) grant nos. P20545-P05, P13180, and P20545-B05, by the Austrian National Bank Anniversary Fund, P15435, and the Austrian Ministry of Science under the aegis of the EU Joint Programme–Neurodegenerative Disease Research (JPND) (jpnd.eu). LLS: The Leiden Longevity Study has received funding from the European Union's Seventh Framework Programme (FP7/2007–2011) under grant agreement no. 259679. This study was supported by a grant from the Innovation-Oriented Research Program on Genomics (SenterNovem IGE05007), the Centre for Medical Systems Biology, and the Netherlands Consortium for Healthy Ageing (grant 050-060-810), all in the framework of the Netherlands Genomics Initiative, Netherlands Organization for Scientific Research (NWO), UnileverColworth, and by BBMRI-NL, a Research Infrastructure financed by the Dutch government (NWO 184.021.007). CHS: This CHS research was supported by contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, N01HC15103, and HHSN268200960009C and grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, R01HL085251, and R01HL130114 from the NHLBI with additional contribution from NINDS. Additional support was provided through R01AG023629 from the NIA. A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Rotterdam Study: The generation and management of GWAS genotype data for the Rotterdam Study is supported by the Netherlands Organisation of Scientific Research (NWO) Investments (no. 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/NWO project no. 050-060-810. The Rotterdam Study is funded by Erasmus MC Medical Center and Erasmus MC University, Rotterdam, Netherlands Organization for Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. M.A.I. is supported by an NWO Veni grant (916.13.054). The 3-City Study: The 3-City Study is conducted under a partnership agreement among the Institut National de la Santé et de la Recherche Médicale (INSERM), the University of Bordeaux, and Sanofi-Aventis. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study is also supported by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, Mutuelle Générale de l’Education Nationale (MGEN), Institut de la Longévité, Conseils Régionaux of Aquitaine and Bourgogne, Fondation de France, and Ministry of Research–INSERM Programme “Cohortes et collections de données biologiques.” C.T. and S.D. have received investigator-initiated research funding from the French National Research Agency (ANR) and from the Fondation Leducq. S.D. is supported by a starting grant from the European Research Council (SEGWAY), a grant from the Joint Programme of Neurodegenerative Disease research (BRIDGET), from the European Union's Horizon 2020 research and innovation programme under grant agreements No 643417 & No 640643, and by the Initiative of Excellence of Bordeaux University. Part of the computations were performed at the Bordeaux Bioinformatics Center (CBiB), University of Bordeaux. This work was supported by the National Foundation for Alzheimer's Disease and Related Disorders, the Institut Pasteur de Lille, the Labex DISTALZ, and the Centre National de Génotypage. ADGC: The Alzheimer Disease Genetics Consortium is supported by NIH. NIH-NIA supported this work through the following grants: ADGC, U01 AG032984, RC2 AG036528; NACC, U01 AG016976; NCRAD, U24 AG021886; NIA LOAD, U24 AG026395, U24 AG026390; Banner Sun Health Research Institute, P30 AG019610; Boston University, P30 AG013846, U01 AG10483, R01 CA129769, R01 MH080295, R01 AG017173, R01 AG025259, R01AG33193; Columbia University, P50 AG008702, R37 AG015473; Duke University, P30 AG028377, AG05128; Emory University, AG025688; Group Health Research Institute, UO1 AG06781, UO1 HG004610; Indiana University, P30 AG10133; Johns Hopkins University, P50 AG005146, R01 AG020688; Massachusetts General Hospital, P50 AG005134; Mayo Clinic, P50 AG016574; Mount Sinai School of Medicine, P50 AG005138, P01 AG002219; New York University, P30 AG08051, MO1RR00096, UL1 RR029893, 5R01AG012101, 5R01AG022374, 5R01AG013616, 1RC2AG036502, 1R01AG035137; Northwestern University, P30 AG013854; Oregon Health & Science University, P30 AG008017, R01 AG026916; Rush University, P30 AG010161, R01 AG019085, R01 AG15819, R01 AG17917, R01 AG30146; TGen, R01 NS059873; University of Alabama at Birmingham, P50 AG016582, UL1RR02777; University of Arizona, R01 AG031581; University of California, Davis, P30 AG010129; University of California, Irvine, P50 AG016573, P50, P50 AG016575, P50 AG016576, P50 AG016577; University of California, Los Angeles, P50 AG016570; University of California, San Diego, P50 AG005131; University of California, San Francisco, P50 AG023501, P01 AG019724; University of Kentucky, P30 AG028383, AG05144; University of Michigan, P50 AG008671; University of Pennsylvania, P30 AG010124; University of Pittsburgh, P50 AG005133, AG030653; University of Southern California, P50 AG005142; University of Texas Southwestern, P30 AG012300; University of Miami, R01 AG027944, AG010491, AG027944, AG021547, AG019757; University of Washington, P50 AG005136; Vanderbilt University, R01 AG019085; and Washington University, P50 AG005681, P01 AG03991. The Kathleen Price Bryan Brain Bank at Duke University Medical Center is funded by NINDS grant NS39764, NIMH MH60451, and by GlaxoSmithKline. Genotyping of the TGEN2 cohort was supported by Kronos Science. The TGen series was also funded by NIA grant AG041232, the Banner Alzheimer's Foundation, The Johnnie B. Byrd Sr. Alzheimer's Institute, the Medical Research Council, and the state of Arizona and also includes samples from the following sites: Newcastle Brain Tissue Resource (funding via the Medical Research Council [MRC], local NHS trusts, and Newcastle University), MRC London Brain Bank for Neurodegenerative Diseases (funding via the Medical Research Council), South West Dementia Brain Bank (funding via numerous sources including the Higher Education Funding Council for England [HEFCE], Alzheimer's Research Trust [ART], BRACE, as well as North Bristol NHS Trust Research and Innovation Department and DeNDRoN), The Netherlands Brain Bank (funding via numerous sources including Stichting MS Research, Brain Net Europe, Hersenstichting Nederland Breinbrekend Werk, International Parkinson Fonds, Internationale Stiching Alzheimer Onderzoek), Institut de Neuropatologia, Servei Anatomia Patologica, and Universitat de Barcelona). ADNI: Funding for ADNI is through the Northern California Institute for Research and Education by grants from Abbott, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare, GlaxoSmithKline, Innogenetics, Johnson & Johnson, Eli Lilly and Co., Medpace, Inc., Merck and Co., Inc., Novartis AG, Pfizer Inc, F. Hoffman-La Roche, Schering-Plough, Synarc, Inc., Alzheimer's Association, Alzheimer's Drug Discovery Foundation, the Dana Foundation, and the National Institute of Biomedical Imaging and Bioengineering and NIA grants U01 AG024904, RC2 AG036535, and K01 AG030514. Support was also provided by the Alzheimer's Association (LAF, IIRG-08-89720; MAP-V, IIRG-05-14147) and the US Department of Veterans Affairs Administration, Office of Research and Development, Biomedical Laboratory Research Program. SiGN: Stroke Genetic Network (SiGN) was supported in part by award nos. U01NS069208 and R01NS100178 from NINDS. Genetics of Early-Onset Stroke (GEOS) Study was supported by the NIH Genes, Environment and Health Initiative (GEI) grant U01 HG004436, as part of the GENEVA consortium under GEI, with additional support provided by the Mid-Atlantic Nutrition and Obesity Research Center (P30 DK072488); and the Office of Research and Development, Medical Research Service, and the Baltimore Geriatrics Research, Education, and Clinical Center of the Department of Veterans Affairs. Genotyping services were provided by the Johns Hopkins University Center for Inherited Disease Research (CIDR), which is fully funded through a federal contract from the NIH to Johns Hopkins University (contract no. HHSN268200782096C). Assistance with data cleaning was provided by the GENEVA Coordinating Center (U01 HG 004446; PI Bruce S. Weir). Study recruitment and assembly of datasets were supported by a Cooperative Agreement with the Division of Adult and Community Health, Centers for Disease Control and Prevention, and by grants from NINDS and the NIH Office of Research on Women's Health (R01 NS45012, U01 NS069208-01). METASTROKE: ASGC: Australian population control data were derived from the Hunter Community Study. This research was funded by grants from the Australian National and Medical Health Research Council (NHMRC Project Grant ID: 569257), the Australian National Heart Foundation (NHF Project Grant ID: G 04S 1623), the University of Newcastle, the Gladys M Brawn Fellowship scheme, and the Vincent Fairfax Family Foundation in Australia. E.G.H. was supported by a Fellowship from the NHF and National Stroke Foundation of Australia (ID: 100071). J.M. was supported by an Australian Postgraduate Award. BRAINS: Bio-Repository of DNA in Stroke (BRAINS) is partly funded by a Senior Fellowship from the Department of Health (UK) to P.S., the Henry Smith Charity, and the UK-India Education Research Institutive (UKIERI) from the British Council. GEOS: Genetics of Early Onset Stroke (GEOS) Study, Baltimore, was supported by GEI Grant U01 HG004436, as part of the GENEVA consortium under GEI, with additional support provided by the Mid-Atlantic Nutrition and Obesity Research Center (P30 DK072488), and the Office of Research and Development, Medical Research Service, and the Baltimore Geriatrics Research, Education, and Clinical Center of the Department of Veterans Affairs. Genotyping services were provided by the Johns Hopkins University Center for Inherited Disease Research (CIDR), which is fully funded through a federal contract from the NIH to the Johns Hopkins University (contract no. HHSN268200782096C). Assistance with data cleaning was provided by the GENEVA Coordinating Center (U01 HG 004446; PI Bruce S. Weir). Study recruitment and assembly of datasets were supported by a Cooperative Agreement with the Division of Adult and Community Health, Centers for Disease Control and Prevention, and by grants from NINDS and the NIH Office of Research on Women's Health (R01 NS45012, U01 NS069208-01). HPS: Heart Protection Study (HPS) (ISRCTN48489393) was supported by the UK MRC, British Heart Foundation, Merck and Co. (manufacturers of simvastatin), and Roche Vitamins Ltd. (manufacturers of vitamins). Genotyping was supported by a grant to Oxford University and CNG from Merck and Co. J.C.H. acknowledges support from the British Heart Foundation (FS/14/55/30806). ISGS: Ischemic Stroke Genetics Study (ISGS)/Siblings With Ischemic Stroke Study (SWISS) was supported in part by the Intramural Research Program of the NIA, NIH project Z01 AG-000954-06. ISGS/SWISS used samples and clinical data from the NIH-NINDS Human Genetics Resource Center DNA and Cell Line Repository (ccr.coriell.org/ninds), human subjects protocol nos. 2003-081 and 2004-147. ISGS/SWISS used stroke-free participants from the Baltimore Longitudinal Study of Aging (BLSA) as controls. The inclusion of BLSA samples was supported in part by the Intramural Research Program of the NIA, NIH project Z01 AG-000015-50, human subjects protocol no. 2003-078. The ISGS study was funded by NIH-NINDS Grant R01 NS-42733 (J.F.M.). The SWISS study was funded by NIH-NINDS Grant R01 NS-39987 (J.F.M.). This study used the high-performance computational capabilities of the Biowulf Linux cluster at the NIH (biowulf.nih.gov). MGH-GASROS: MGH Genes Affecting Stroke Risk and Outcome Study (MGH-GASROS) was supported by NINDS (U01 NS069208), the American Heart Association/Bugher Foundation Centers for Stroke Prevention Research 0775010N, the NIH and NHLBI's STAMPEED genomics research program (R01 HL087676), and a grant from the National Center for Research Resources. The Broad Institute Center for Genotyping and Analysis is supported by grant U54 RR020278 from the National Center for Research resources. Milan: Milano–Besta Stroke Register Collection and genotyping of the Milan cases within CEDIR were supported by the Italian Ministry of Health (grant nos.: RC 2007/LR6, RC 2008/LR6; RC 2009/LR8; RC 2010/LR8; GR-2011-02347041), FP6 LSHM-CT-2007-037273 for the PROCARDIS control samples. WTCCC2: Wellcome Trust Case-Control Consortium 2 (WTCCC2) was principally funded by the Wellcome Trust, as part of the Wellcome Trust Case Control Consortium 2 project (085475/B/08/Z and 085475/Z/08/Z and WT084724MA). The Stroke Association provided additional support for collection of some of the St George's, London cases. The Oxford cases were collected as part of the Oxford Vascular Study, which is funded by the MRC, Stroke Association, Dunhill Medical Trust, National Institute of Health Research (NIHR), and the NIHR Biomedical Research Centre, Oxford. The Edinburgh Stroke Study was supported by the Wellcome Trust (clinician scientist award to C.L.M.S.) and the Binks Trust. Sample processing occurred in the Genetics Core Laboratory of the Wellcome Trust Clinical Research Facility, Western General Hospital, Edinburgh. Much of the neuroimaging occurred in the Scottish Funding Council Brain Imaging Research Centre (https://www.ed.ac.uk/clinical-sciences/edinburgh-imaging), Division of Clinical Neurosciences, University of Edinburgh, a core area of the Wellcome Trust Clinical Research Facility, and part of the SINAPSE (Scottish Imaging Network: A Platform for Scientific Excellence) collaboration (sinapse.ac.uk), funded by the Scottish Funding Council and the Chief Scientist Office. Collection of the Munich cases and data analysis was supported by the Vascular Dementia Research Foundation. This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreements no. 666881, SVDs@target (to M.D.) and no. 667375, CoSTREAM (to M.D.); the DFG as part of the Munich Cluster for Systems Neurology (EXC 1010 SyNergy) and the CRC 1123 (B3) (to M.D.); the Corona Foundation (to M.D.); the Fondation Leducq (Transatlantic Network of Excellence on the Pathogenesis of Small Vessel Disease of the Brain) (to M.D.); the e:Med program (e:AtheroSysMed) (to M.D.) and the FP7/2007-2103 European Union project CVgenes@target (grant agreement no. Health-F2-2013-601456) (to M.D.). M.F. and A.H. acknowledge support from the BHF Centre of Research Excellence in Oxford and the Wellcome Trust core award (090532/Z/09/Z). VISP: The GWAS component of the Vitamin Intervention for Stroke Prevention (VISP) study was supported by the US National Human Genome Research Institute (NHGRI), grant U01 HG005160 (PI Michèle Sale and Bradford Worrall), as part of the Genomics and Randomized Trials Network (GARNET). Genotyping services were provided by the Johns Hopkins University Center for Inherited Disease Research (CIDR), which is fully funded through a federal contract from the NIH to Johns Hopkins University. Assistance with data cleaning was provided by the GARNET Coordinating Center (U01 HG005157; PI Bruce S. Weir). Study recruitment and collection of datasets for the VISP clinical trial were supported by an investigator-initiated research grant (R01 NS34447; PI James Toole) from the US Public Health Service, NINDS, Bethesda, MD. Control data obtained through the database of genotypes and phenotypes (dbGAP) maintained and supported by the United States National Center for Biotechnology Information, US National Library of Medicine. WHI: Funding support for WHI-GARNET was provided through the NHGRI GARNET (grant no. U01 HG005152). Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GARNET Coordinating Center (U01 HG005157). Funding support for genotyping, which was performed at the Broad Institute of MIT and Harvard, was provided by the GEI (U01 HG004424). R.L. is a senior clinical investigator of FWO Flanders. F.W.A. is supported by a Dekker scholarship-Junior Staff Member 2014T001–Netherlands Heart Foundation and UCL Hospitals NIHR Biomedical Research Centre.
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- 2019
28. Analysis of genes (TMEM106B, GRN, ABCC9, KCNMB2, and APOE) implicated in risk for LATE-NC and hippocampal sclerosis provides pathogenetic insights: a retrospective genetic association study.
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Dugan, Adam J., Nelson, Peter T., Katsumata, Yuriko, Shade, Lincoln M. P., Boehme, Kevin L., Teylan, Merilee A., Cykowski, Matthew D., Mukherjee, Shubhabrata, Kauwe, John S. K., Hohman, Timothy J., Schneider, Julie A., and Fardo, David W.
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SINGLE nucleotide polymorphisms ,GENETIC variation ,GENOME-wide association studies ,HIPPOCAMPAL sclerosis ,GENES ,EXOMES ,PHENOTYPES - Abstract
Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is the most prevalent subtype of TDP-43 proteinopathy, affecting up to 1/3rd of aged persons. LATE-NC often co-occurs with hippocampal sclerosis (HS) pathology. It is currently unknown why some individuals with LATE-NC develop HS while others do not, but genetics may play a role. Previous studies found associations between LATE-NC phenotypes and specific genes: TMEM106B, GRN, ABCC9, KCNMB2, and APOE. Data from research participants with genomic and autopsy measures from the National Alzheimer's Coordinating Center (NACC; n = 631 subjects included) and the Religious Orders Study and Memory and the Rush Aging Project (ROSMAP; n = 780 included) were analyzed in the current study. Our goals were to reevaluate disease-associated genetic variants using newly collected data and to query whether the specific genotype/phenotype associations could provide new insights into disease-driving pathways. Research subjects included in prior LATE/HS genome-wide association studies (GWAS) were excluded. Single nucleotide variants (SNVs) within 10 kb of TMEM106B, GRN, ABCC9, KCNMB2, and APOE were tested for association with HS and LATE-NC, and separately for Alzheimer's pathologies, i.e. amyloid plaques and neurofibrillary tangles. Significantly associated SNVs were identified. When results were meta-analyzed, TMEM106B, GRN, and APOE had significant gene-based associations with both LATE and HS, whereas ABCC9 had significant associations with HS only. In a sensitivity analysis limited to LATE-NC + cases, ABCC9 variants were again associated with HS. By contrast, the associations of TMEM106B, GRN, and APOE with HS were attenuated when adjusting for TDP-43 proteinopathy, indicating that these genes may be associated primarily with TDP-43 proteinopathy. None of these genes except APOE appeared to be associated with Alzheimer's-type pathology. In summary, using data not included in prior studies of LATE or HS genomics, we replicated several previously reported gene-based associations and found novel evidence that specific risk alleles can differentially affect LATE-NC and HS. [ABSTRACT FROM AUTHOR]
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- 2021
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29. Alzheimer's disease alters oligodendrocytic glycolytic and ketolytic gene expression.
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Saito, Erin R., Miller, Justin B., Harari, Oscar, Cruchaga, Carlos, Mihindukulasuriya, Kathie A., Kauwe, John S. K., and Bikman, Benjamin T.
- Abstract
Introduction: Sporadic Alzheimer's disease (AD) is strongly correlated with impaired brain glucose metabolism, which may affect AD onset and progression. Ketolysis has been suggested as an alternative pathway to fuel the brain. Methods: RNA‐seq profiles of post mortem AD brains were used to determine whether dysfunctional AD brain metabolism can be determined by impairments in glycolytic and ketolytic gene expression. Data were obtained from the Knight Alzheimer's Disease Research Center (62 cases; 13 controls), Mount Sinai Brain Bank (110 cases; 44 controls), and the Mayo Clinic Brain Bank (80 cases; 76 controls), and were normalized to cell type: astrocytes, microglia, neurons, oligodendrocytes. Results: In oligodendrocytes, both glycolytic and ketolytic pathways were significantly impaired in AD brains. Ketolytic gene expression was not significantly altered in neurons, astrocytes, and microglia. Discussion: Oligodendrocytes may contribute to brain hypometabolism observed in AD. These results are suggestive of a potential link between hypometabolism and dysmyelination in disease physiology. Additionally, ketones may be therapeutic in AD due to their ability to fuel neurons despite impaired glycolytic metabolism. [ABSTRACT FROM AUTHOR]
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- 2021
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30. Analysis of shared heritability in common disorders of the brain
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Anttila, Verneri, Bulik-Sullivan, Brendan, Finucane, Hilary K., Walters, Raymond K., Bras, Jose, Duncan, Laramie, Escott-Price, Valentina, Falcone, Guido J., Gormley, Padhraig, Malik, Rainer, Patsopoulos, Nikolaos A., Ripke, Stephan, Wei, Zhi, Yu, Dongmei, Lee, Phil H., Turley, Patrick, Grenier-Boley, Benjamin, Chouraki, Vincent, Kamatani, Yoichiro, Berr, Claudine, Letenneur, Luc, Hannequin, Didier, Amouyel, Philippe, Boland, Anne, Deleuze, Jean-Francois, Duron, Emmanuelle, Vardarajan, Badri N., Reitz, Christiane, Goate, Alison M., Huentelman, Matthew J., Kamboh, M. Ilyas, Larson, Eric B., Rogaeva, Ekaterina, St George-Hyslop, Peter, Hakonarson, Hakon, Kukull, Walter A., Farrer, Lindsay A., Barnes, Lisa L., Beach, Thomas G., Demirci, F. Yesim, Head, Elizabeth, Hulette, Christine M., Jicha, Gregory A., Kauwe, John S. K., Kaye, Jeffrey A., Leverenz, James B., Levey, Allan I., Lieberman, Andrew P., Pankratz, Vernon S., Poon, Wayne W., Lesch, Klaus-Peter, van Os, Jim, Corvin, Aiden, Neale, Benjamin M., Psychiatrie & Neuropsychologie, RS: MHeNs - R3 - Neuroscience, RS: MHeNs - R2 - Mental Health, MUMC+: MA Psychiatrie (3), and MUMC+: Hersen en Zenuw Centrum (3)
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MAJOR DEPRESSIVE DISORDER ,Brain Diseases/classification ,ANOREXIA-NERVOSA ,DEFICIT HYPERACTIVITY DISORDER ,LONG-TERM SURVIVAL ,Genetic Variation ,BIPOLAR DISORDER ,POPULATION-BASED TWIN ,BODY-MASS INDEX ,ALZHEIMERS-DISEASE ,Quantitative Trait, Heritable ,Phenotype ,Risk Factors ,Mental Disorders/classification ,Humans ,GENOME-WIDE ASSOCIATION ,GENETIC CORRELATIONS ,Genome-Wide Association Study - Abstract
Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.
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- 2018
31. CUBAP: an interactive web portal for analyzing codon usage biases across populations.
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Hodgman, Matthew W, Miller, Justin B, Meurs, Taylor E, and Kauwe, John S K
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- 2020
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32. Interaction Between Physical Activity and Genes Related to Neurotrophin Signaling in Late-Life Cognitive Performance: The Cache County Study.
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Sanders, Chelsea L, Rattinger, Gail B, Deberard, M Scott, Hammond, Alexandra G, Wengreen, Heidi, Kauwe, John S K, Buhusi, Mona, and Tschanz, Joann T
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PHYSICAL activity ,BRAIN-derived neurotrophic factor ,SINGLE nucleotide polymorphisms ,COGNITION disorders ,OLDER people ,NERVE growth factor ,RESEARCH ,NERVE tissue proteins ,RESEARCH methodology ,GENETIC polymorphisms ,EVALUATION research ,MEDICAL cooperation ,SEX distribution ,CELLULAR signal transduction ,COMPARATIVE studies ,NEUROPSYCHOLOGICAL tests ,EXERCISE ,RESEARCH funding ,GENETIC techniques ,LONGITUDINAL method - Abstract
Research indicates that lifestyle and genetic factors influence the course of cognitive impairment in aging, but their interactions have not been well-examined. This study examined the relationship between physical activity and genotypes related to brain-derived neurotrophic factor (BDNF) in predicting cognitive performance in a sample of older adults with up to 12 years of follow-up. Physical activity levels (sedentary, light, and moderate/vigorous) were determined for the sample of 3,591 participants (57% female) without dementia. The genotypes examined included BDNF gene single nucleotide polymorphisms (SNPs) (rs6265 and rs56164415) and receptor gene SNPs (NTRK2 rs2289656 and NGFR rs2072446). Cognition was assessed triennially using the Modified Mini-Mental State Exam. Unadjusted linear mixed models indicated that sedentary (β = -5.05) and light (β = -2.41) groups performed worse than moderate-vigorous (p < .001). Addition of interaction effects showed significant differences in rate of decline between activity levels, particularly among males (p = .006). A three-way interaction with sex, NGFR SNP rs2072446, and physical activity suggested that the C/C allele was associated with better cognitive performance among males engaging in light activity only (p = .004). Physical activity and sex, but not BDNF-related SNPs, predicted rate of cognitive decline in older adults, while NGFR rs2072446 may modify main effects. [ABSTRACT FROM AUTHOR]
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- 2020
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33. Lingering Taxonomic Challenges Hinder Conservation and Management of Global Bonefishes.
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Pickett, Brandon D., Wallace, Elizabeth M., Ridge, Perry G., and Kauwe, John S. K.
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- 2020
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34. Codon Pairs are Phylogenetically Conserved: A comprehensive analysis of codon pairing conservation across the Tree of Life.
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Miller, Justin B., McKinnon, Lauren M., Whiting, Michael F., Kauwe, John S. K., and Ridge, Perry G.
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RIBOSOMES ,TRANSFER RNA ,GENETIC code ,AMINO acids ,TREES ,PARSIMONIOUS models - Abstract
Identical codon pairing and co-tRNA codon pairing increase translational efficiency within genes when two codons that encode the same amino acid are translated by the same tRNA before it diffuses from the ribosome. We examine the phylogenetic signal in both identical and co-tRNA codon pairing across 23 428 species using alignment-free and parsimony methods. We determined that conserved codon pairing typically has a smaller window size than the length of a ribosome, and codon pairing tracks phylogenies across various taxonomic groups. We report a comprehensive analysis of codon pairing, including the extent to which each codon pairs. Our parsimony method generally recovers phylogenies that are more congruent with the established phylogenies than our alignment-free method. However, four of the ten taxonomic groups did not have sufficient orthologous codon pairings and were therefore analyzed using only the alignment-free methods. Since the recovered phylogenies using only codon pairing largely match phylogenies from the Open Tree of Life and the NCBI taxonomy, and are comparable to trees recovered by other algorithms, we propose that codon pairing biases are phylogenetically conserved and should be considered in conjunction with other phylogenomic techniques. [ABSTRACT FROM AUTHOR]
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- 2020
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35. Influence of Coding Variability in APP-Aβ Metabolism Genes in Sporadic Alzheimer’s Disease
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Sassi, Celeste, Ridge, Perry G., Nalls, Michael A., Gibbs, Raphael, Ding, Jinhui, Lupton, Michelle K, Troakes, Claire, Lunnon, Katie, Al-Sarraj, Safa, Brown, Kristelle S, Medway, Christopher, Lord, Jenny, Turton, James, Morgan, Kevin, Powell, John F, Kauwe, John S K, Cruchaga, Carlos, Bras, Jose, Goate, Alison M, Singleton, Andrew B, Guerreiro, Rita, Hardy, John, Passmore, Peter, Craig, David, Johnston, Janet, McGuinness, Bernadette, Todd, Stephen, Heun, Reinhard, Kölsch, Heike, Kehoe, Patrick G, Hooper, Nigel M, Vardy, Emma R L C, Mann, David M., Lowe, James, David Smith, A., Wilcock, Gordon, Warden, Donald, and Holmes, Clive
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Medicine(all) ,Agricultural and Biological Sciences(all) ,Biochemistry, Genetics and Molecular Biology(all) - Abstract
The cerebral deposition of Aβ42, a neurotoxic proteolytic derivate of amyloid precursor protein (APP), is a central event in Alzheimer's disease (AD)(Amyloid hypothesis). Given the key role of APP-Aβ metabolism in ADpathogenesis, we selected29 genes involved in APP processing, Aβ degradation and clearance. We then used exome and genome sequencing to investigate the single independent (single-variant association test) and cumulative (gene-based association test) effect of coding variants in these genes as potential susceptibility factors for AD, in a cohort composed of 332 sporadic and mainly late-onset ADcases and 676 elderly controls from North America and the UK. Our study shows that common coding variability in these genes does not play a major role for the disease development. In the single-variant association analysis, the main hits, none of which statistically significant after multiple testing correction (1.9e-4-3
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- 2016
36. Shared genetic contribution to ischemic stroke and Alzheimer's disease
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Traylor, Matthew, Adib Samii, Poneh, Harold, Denise, Dichgans, Martin, Williams, Julie, Lewis, Cathryn M., Markus, Hugh S., Fornage, Myriam, Holliday, Elizabeth G., Sharma, Pankaj, Bis, Joshua C., Psaty, Bruce M., Seshadri, Sudha, Nalls, Mike A., Devan, William J., Boncoraglio, Giorgio, Malik, Rainer, Mitchell, Braxton D., Kittner, Steven J., Ikram, M. Arfan, Clarke, Robert, Rosand, Jonathan, Meschia, James F., Sudlow, Cathie, Rothwell, Peter M., Levi, Christopher, Bevan, Steve, Kilarski, Laura L., Walters, Matthew, Thijs, Vincent, Slowik, Agnieszka, Lindgren, Arne, De Bakker, Paul I. W., Lambert, Jean Charles, Ibrahim Verbaas, Carla A., Naj, Adam C., Sims, Rebecca, Bellenguez, Céline, Jun, Gyungah, Destefano, Anita L., Beecham, Gary W., Grenier Boley, Benjamin, Russo, Giancarlo, Thornton Wells, Tricia A., Jones, Nicola, Smith, Albert V., Chouraki, Vincent, Thomas, Charlene, Zelenika, Diana, Vardarajan, Badri N., Kamatani, Yoichiro, Lin, Chiao Feng, Gerrish, Amy, Schmidt, Helena, Kunkle, Brian, Dunstan, Melanie L., Ruiz, Agustin, Bihoreau, Marie Thçrèse, Choi, Seung Hoan, Reitz, Christiane, Pasquier, Florence, Hollingworth, Paul, Ramirez, Alfredo, Hanon, Olivier, Fitzpatrick, Annette L, Buxbaum, Joseph D, Campion, Dominique, Crane, Paul K, Baldwin, Clinton, Becker, Tim, Gudnason, Vilmundur, Cruchaga, Carlos, Craig, David, Amin, Najaf, Berr, Claudine, Lopez, Oscar L, De Jager, Philip L, Deramecourt, Vincent, Johnston, Janet A, Evans, Denis, Lovestone, Simon, Letenneur, Luc, Morón, Francisco J, Rubinsztein, David C, Eiriksdottir, Gudny, Sleegers, Kristel, Goate, Alison M, Fiçvet, Nathalie, Huentelman, Matthew J, Gill, Michael, Brown, Kristelle, Kamboh, M. Ilyas, Keller, Lina, Barberger Gateau, Pascale, Mcguinness, Bernadette, Larson, Eric B, Green, Robert, Myers, Amanda J, Dufouil, Carole, Todd, Stephen, Wallon, David, Love, Seth, Rogaeva, Ekaterina, Gallacher, John, St George Hyslop, Peter, Clarimon, Jordi, Lleo, Alberto, Bayer, Anthony, Tsuang, Debby W, Lei, Yu, Tsolaki, Magda, Bossù, Paola, Spalletta, Gianfranco, Proitsi, Petroula, Collinge, John, Sorbi, Sandro, Sanchez Garcia, Florentino, Fox, Nick C, Hardy, John, Deniz Naranjo, Maria Candida, Bosco, Paolo, Brayne, Carol, Galimberti, Daniela, Mancuso, Michelangelo, Matthews, Fiona, Moebus, Susanne, Mecocci, Patrizia, DEL ZOMPO, MARIA RITA, Maier, Wolfgang, Hampel, Harald, Pilotto, Alberto, Bullido, Maria, Panza, Francesco, Caffarra, Paolo, Nacmias, Benedetta, Gilbert, John R, Mayhaus, Manuel, Lannfelt, Lars, Hakonarson, Hakon, Pichler, Sabrina, Carrasquillo, Minerva M, Ingelsson, Martin, Beekly, Duane, Alvarez, Victoria, Zou, Fanggeng, Valladares, Otto, Younkin, Steven G, Coto, Eliecer, Hamilton Nelson, Kara L, Wei, Gu, Razquin, Cristina, Pastor, Pau, Mateo, Ignacio, Owen, Michael J, Faber, Kelley M, Jonsson, Palmi V, Combarros, Onofre, O'Donovan, Michael C, Cantwell, Laura B, Soininen, Hilkka, Blacker, Deborah, Mead, Simon, Mosley, Thomas H, Bennett, David A, Harris, Tamara B, Fratiglioni, Laura, Holmes, Clive, De Bruijn, Renee F. A. G, Passmore, Peter, Montine, Thomas J, Bettens, Karolien, Rotter, Jerome I, Brice, Alexis, Morgan, Kevin, Foroud, Tatiana M, Kukull, Walter A, Hannequin, Didier, Powell, John F, Nalls, Michael A, Ritchie, Karen, Lunetta, Kathryn L, Kauwe, John S. K, Boerwinkle, Eric, Riemenschneider, Matthias, Boada, Mercè, Hiltunen, Mikko, Martin, Eden R, Schmidt, Reinhold, Rujescu, Dan, Wang, Li San, Dartigues, Jean François, Mayeux, Richard, Tzourio, Christophe, Hofman, Albert, Nöthen, Markus M, Graff, Caroline, Jones, Lesley, Haines, Jonathan L, Holmans, Peter A, Lathrop, Mark, Pericak Vance, Margaret A, Launer, Lenore J, Farrer, Lindsay A, Van Duijn, Cornelia M, Van Broeckhoven, Christine, Moskvina, Valentina, Schellenberg, Gerard D, and Amouyel, Philippe
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Neurology ,Neurology (clinical) ,Research Articles ,Research Article - Abstract
Objective Increasing evidence suggests epidemiological and pathological links between Alzheimer's disease (AD) and ischemic stroke (IS). We investigated the evidence that shared genetic factors underpin the two diseases. Methods Using genome‐wide association study (GWAS) data from METASTROKE + (15,916 IS cases and 68,826 controls) and the International Genomics of Alzheimer's Project (IGAP; 17,008 AD cases and 37,154 controls), we evaluated known associations with AD and IS. On the subset of data for which we could obtain compatible genotype‐level data (4,610 IS cases, 1,281 AD cases, and 14,320 controls), we estimated the genome‐wide genetic correlation (rG) between AD and IS, and the three subtypes (cardioembolic, small vessel, and large vessel), using genome‐wide single‐nucleotide polymorphism (SNP) data. We then performed a meta‐analysis and pathway analysis in the combined AD and small vessel stroke data sets to identify the SNPs and molecular pathways through which disease risk may be conferred. Results We found evidence of a shared genetic contribution between AD and small vessel stroke (rG [standard error] = 0.37 [0.17]; p = 0.011). Conversely, there was no evidence to support shared genetic factors in AD and IS overall or with the other stroke subtypes. Of the known GWAS associations with IS or AD, none reached significance for association with the other trait (or stroke subtypes). A meta‐analysis of AD IGAP and METASTROKE + small vessel stroke GWAS data highlighted a region (ATP5H/KCTD2/ICT1) associated with both diseases (p = 1.8 × 10−8). A pathway analysis identified four associated pathways involving cholesterol transport and immune response. Interpretation Our findings indicate shared genetic susceptibility to AD and small vessel stroke and highlight potential causal pathways and loci. Ann Neurol 2016;79:739–747
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- 2016
37. Quantitative interaction proteomics of neurodegenerative disease proteins
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Hosp, Fabian, Vossfeldt, Hannes, Heinig, Matthias, Vasiljevic, Djordje, Arumughan, Anup, Wyler, Emanuel, Landthaler, Markus, Hubner, Norbert, Wanker, Erich E., Lannfelt, Lars, Ingelsson, Martin, Lalowski, Maciej, Voigt, Aaron, Selbach, Matthias, Harold, Denise, Abraham, Richard, Hollingworth, Paul, Sims, Rebecca, Gerrish, Amy, Chapman, Jade, Russo, Giancarlo, Hamshere, Marian, Singh Pahwa, Jaspreet, Escott-Price, Valentina, Dowzell, Kimberley, Williams, Amy, Jones, Nicola, Thomas, Charlene, Stretton, Alexandra, Morgan, Angharad, Lovestone, Simon, Powell, John, Proitsi, Petroula, Lupton, Michelle K., Brayne, Carol, Rubinsztein, David C., Gill, Michael, Lawlor, Brian, Lynch, Aoibhinn, Morgan, Kevin, Brown, Kristelle, Passmore, Peter, Craig, David, McGuinness, Bernadette, Todd, Stephen, Johnston, Janet, Holmes, Clive, Mann, David, David Smith, A., Love, Seth, Kehoe, Patrick G., Hardy, John, Mead, Simon, Fox, Nick, Rossor, Martin, Collinge, John, Maier, Wolfgang, Jessen, Frank, Heun, Reiner, Schürmann, Britta, Ramirez, Alfredo, Becker, Tim, Herold, Christine, Lacour, André, Drichel, Dmitriy, van den Bussche, Hendrik, Heuser, Isabella, Kornhuber, Johannes, Wiltfang, Jens, Dichgans, Martin, Frölich, Lutz, Hampel, Harald, Hüll, Michael, Rujescu, Dan, Goate, Alison, Kauwe, John S. K., Cruchaga, Carlos, Nowotny, Petra, Morris, John C., Mayo, Kevin, Livingston, Gill, Bass, Nicholas J., Gurling, Hugh, McQuillin, Andrew, Gwilliam, Rhian, Deloukas, Panagiotis, Al-Chalabi, Ammar, Shaw, Christopher E., Singleton, Andrew B., Guerreiro, Rita, Mühleisen, Thomas W., Nöthen, Markus M., Moebus, Susanne, Jöckel, Karl-Heinz, Klopp, Norman, Wichmann, H.-Erich, Carrasquillo, Minerva M., Shane Pankratz, V., Younkin, Steven G., Holmans, Peter, O’Donovan, Michael, Owen, Michael J., and Williams, Julie
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mental disorders ,Medizin ,nervous system diseases - Abstract
Several proteins have been linked to neurodegenerative disorders (NDDs), but their molecular function isnot completely understood. Here, we used quantitative interaction proteomics to identify binding partners of Amyloid beta precursor protein (APP) and Presenilin-1 (PSEN1) for Alzheimer’s disease (AD), Huntingtin (HTT) for Huntington’s disease, Parkin(PARK2) for Parkinson’s disease, and Ataxin-1 (ATXN1) for spinocerebellar ataxia type 1. Our network reveals common signatures of protein degradation and misfolding and recapitulates known biology. Toxicity modifier screens and comparison to genome-wide association studies show that interaction partners are significantly linked to disease phenotypes invivo. Direct comparison of wild-type proteins and disease-associated variants identified binders involved in pathogenesis, highlighting the value of differential interactome mapping. Finally, we show that the mitochondrial protein LRPPRC interacts preferentially with an early-onset AD variant of APP. This interaction appears to induce mitochondrial dysfunction, which is an early phenotype of AD.
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- 2015
38. Bridging the Gap between Statistical and Biological Epistasis in Alzheimer’s Disease
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Ebbert, Mark T. W., Ridge, Perry G., and Kauwe, John S. K.
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Article Subject - Abstract
Alzheimer’s disease affects millions of people worldwide and incidence is expected to rise as the population ages, but no effective therapies exist despite decades of research and more than 20 known disease markers. Research has shown that Alzheimer’s disease’s missing heritability remains extensive with an estimated 25% of phenotypic variance unexplained by known variants. The missing heritability may be explained by missing variants or by epistasis. Researchers often focus on individual loci rather than epistatic interactions, which is likely an oversimplification of the underlying biology since most phenotypes are affected by multiple genes. Focusing research efforts on epistasis will be critical to resolving Alzheimer’s disease etiology, and a major key to identifying and properly interpreting key epistatic interactions will be bridging the gap between statistical and biological epistasis. This review covers the current state of epistasis research in Alzheimer’s disease and how researchers can bridge the gap between statistical and biological epistasis to help resolve Alzheimer’s disease etiology.
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- 2015
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39. Effects of Multiple Genetic Loci on Age at Onset in Late-Onset Alzheimer Disease
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Naj, Adam C, Jun, Gyungah, Reitz, Christiane, Kunkle, Brian W, Perry, William, Park, Yo Son, Beecham, Gary W, Rajbhandary, Ruchita A, Hamilton-Nelson, Kara L, Wang, Li-San, Kauwe, John S. K, Huentelman, Matthew J, Myers, Amanda J, Bird, Thomas D, Boeve, Bradley F, Baldwin, Clinton T, Jarvik, Gail P, Crane, Paul K, Rogaeva, Ekaterina, Barmada, M. Michael, Demirci, F. Yesim, Cruchaga, Carlos, Kramer, Patricia L, Ertekin-Taner, Nilufer, Hardy, John, Graff-Radford, Neill R, Green, Robert C, Larson, Eric B, St. George-Hyslop, Peter H, Buxbaum, Joseph D, Evans, Denis A, Schneider, Julie A, Lunetta, Kathryn L, Kamboh, M. Ilyas, Saykin, Andrew J, Reiman, Eric M, De Jager, Philip L, Bennett, David A, Morris, John C, Montine, Thomas J, Goate, Alison M, Blacker, Deborah, Tsuang, Debby W, Hakonarson, Hakon, Kukull, Walter A, Foroud, Tatiana M, Martin, Eden R, Haines, Jonathan L, Mayeux, Richard P, Farrer, Lindsay A, Schellenberg, Gerard D, Pericak-Vance, Margaret A, Albert, Marilyn S, Albin, Roger L, Apostolova, Liana G, Arnold, Steven E, Barber, Robert, Barnes, Lisa L, Beach, Thomas G, Becker, James T, Beekly, Duane, Bigio, Eileen H, Bowen, James D, Boxer, Adam, Burke, James R, Cairns, Nigel J, Cantwell, Laura B, Cao, Chuanhai, Carlson, Chris S, Carney, Regina M, Carrasquillo, Minerva M, Carroll, Steven L, Chui, Helena C, Clark, David G, Corneveaux, Jason, Cribbs, David H, Crocco, Elizabeth A, DeCarli, Charles, DeKosky, Steven T, Dick, Malcolm, Dickson, Dennis W, Duara, Ranjan, Faber, Kelley M, Fallon, Kenneth B, Farlow, Martin R, Ferris, Steven, Frosch, Matthew P, Galasko, Douglas R, Ganguli, Mary, Gearing, Marla, Geschwind, Daniel H, Ghetti, Bernardino, Gilbert, John R, Glass, Jonathan D, Growdon, John H, Hamilton, Ronald L, Harrell, Lindy E, Head, Elizabeth, Honig, Lawrence S, Hulette, Christine M, Hyman, Bradley T, Jicha, Gregory A, Jin, Lee-Way, Karydas, Anna, Kaye, Jeffrey A, Kim, Ronald, Koo, Edward H, Kowall, Neil W, Kramer, Joel H, LaFerla, Frank M, Lah, James J, Leverenz, James B, Levey, Allan I, Li, Ge, Lieberman, Andrew P, Lin, Chiao-Feng, Lopez, Oscar L, Lyketsos, Constantine G, Mack, Wendy J, Martiniuk, Frank, Mash, Deborah C, Masliah, Eliezer, McCormick, Wayne C, McCurry, Susan M, McDavid, Andrew N, McKee, Ann C, Mesulam, Marsel, Miller, Bruce L, Miller, Carol A, Miller, Joshua W, Murrell, Jill R, Olichney, John M, Pankratz, Vernon S, Parisi, Joseph E, Paulson, Henry L, Peskind, Elaine, Petersen, Ronald C, Pierce, Aimee, Poon, Wayne W, Potter, Huntington, Quinn, Joseph F, Raj, Ashok, Raskind, Murray, Reisberg, Barry, Ringman, John M, Roberson, Erik D, Rosen, Howard J, Rosenberg, Roger N, Sano, Mary, Schneider, Lon S, Seeley, William W, Smith, Amanda G, Sonnen, Joshua A, Spina, Salvatore, Stern, Robert A, Tanzi, Rudolph E, Thornton-Wells, Tricia A, Trojanowski, John Q, Troncoso, Juan C, Valladares, Otto, Van Deerlin, Vivianna M, Van Eldik, Linda J, Vardarajan, Badri N, Vinters, Harry V, Vonsattel, Jean Paul, Weintraub, Sandra, Welsh-Bohmer, Kathleen A, Williamson, Jennifer, Wishnek, Sarah, Woltjer, Randall L, Wright, Clinton B, Younkin, Steven G, Yu, Chang-En, and Yu, Lei
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Medicine and Health Sciences - Published
- 2014
40. Population-based analysis of CETP identifies association between I405V and cognitive decline: The Cache County Study
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Munger, Caitlin, Perkes, Ammon, Peterson, Michael, Schmutz, Cameron, Leary, Maegan, Ebbert, Mark T. W., Ridge, Perry G., Norton, Maria C., Tschanz, JoAnn T., Munger, Ronald G., Corcoran, Christopher D., and Kauwe, John S. K.
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Aged, 80 and over ,Male ,Risk ,Genetic Variation ,Article ,United States ,Cholesterol Ester Transfer Proteins ,carbohydrates (lipids) ,Cognition ,Alzheimer Disease ,Disease Progression ,Humans ,lipids (amino acids, peptides, and proteins) ,Female ,Aged - Abstract
Cholesterol has been implicated in the pathogenesis of Late-onset Alzheimer's disease (LOAD) and the Cholesteryl Ester Transfer Protein (CETP) is critical to cholesterol regulation within the cell, making CETP an Alzheimer’s disease candidate gene. Several studies have suggested that CETP I405V (rs5882) is associated with cognitive function and LOAD risk, but findings vary and most studies have been conducted using relatively small numbers of samples. To test whether this variant is involved in cognitive function and LOAD progression, we genotyped 4486 subjects with up to twelve years of longitudinal cognitive assessment. Analyses revealed an average 0.6-point decrease per year in the rate of cognitive decline for each additional valine (p < 0.011). We failed to detect association between CETP I405V and LOAD status (p < 0.28). We conclude that CETP I405V is associated with preserved cognition over time but is not associated with LOAD status.
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- 2014
41. Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease
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Escott-Price, Valentina, Bellenguez, Céline, DeStefano, Anita L, Galimberti, Daniela, Scarpini, Elio, Bonuccelli, Ubaldo, Mancuso, Michelangelo, Siciliano, Gabriele, Moebus, Susanne, Mecocci, Patrizia, Zompo, Maria Del, Maier, Wolfgang, Hampel, Harald, Lambert, Jean-Charles, Pilotto, Alberto, Frank-García, Ana, Panza, Francesco, Solfrizzi, Vincenzo, Caffarra, Paolo, Nacmias, Benedetta, Perry, William, Mayhaus, Manuel, Lannfelt, Lars, Hakonarson, Hakon, Ibrahim-Verbaas, Carla A, Pichler, Sabrina, Carrasquillo, Minerva M, Ingelsson, Martin, Beekly, Duane, Alvarez, Victoria, Zou, Fanggeng, Valladares, Otto, Younkin, Steven G, Coto, Eliecer, Hamilton-Nelson, Kara L, Naj, Adam C, Gu, Wei, Razquin, Cristina, Pastor, Pau, Mateo, Ignacio, Owen, Michael J, Faber, Kelley M, Jonsson, Palmi V, Combarros, Onofre, O'Donovan, Michael C, Cantwell, Laura B, Sims, Rebecca, Soininen, Hilkka, Blacker, Deborah, Mead, Simon, Mosley, Thomas H, Bennett, David A, Harris, Tamara B, Fratiglioni, Laura, Holmes, Clive, de Bruijn, Renee F A G, Passmore, Peter, Jun, Gyungah, Montine, Thomas J, Bettens, Karolien, Rotter, Jerome I, Brice, Alexis, Morgan, Kevin, Foroud, Tatiana M, Kukull, Walter A, Hannequin, Didier, Powell, John F, Nalls, Michael A, Bis, Joshua C, Ritchie, Karen, Lunetta, Kathryn L, Kauwe, John S K, Boerwinkle, Eric, Riemenschneider, Matthias, Boada, Mercè, Hiltunen, Mikko, Martin, Eden R, Schmidt, Reinhold, Rujescu, Dan, Beecham, Gary W, Dartigues, Jean-François, Mayeux, Richard, Tzourio, Christophe, Hofman, Albert, Nöthen, Markus M, Graff, Caroline, Psaty, Bruce M, Haines, Jonathan L, Lathrop, Mark, Pericak-Vance, Margaret A, Grenier-Boley, Benjamin, Launer, Lenore J, Van Broeckhoven, Christine, Farrer, Lindsay A, van Duijn, Cornelia M, Ramirez, Alfredo, Seshadri, Sudha, Schellenberg, Gerard D, Amouyel, Philippe, Williams, Julie, Study, Cardiovascular Health, Russo, Giancarlo, Olson, Jean, Kronmal, Richard, Arnold, Alice M, Robbins, John, Carlson, Michelle, Burke, Gregory, Kuller, Lewis H, Tracy, Russell, Gottdiener, John, Prineas, Ronald, Wang, Li-San, Thornton-Wells, Tricia A, Becker, James T, Enright, Paul, Klein, Ronald, O'Leary, Daniel H, Denning, Nicola, Smith, Albert V, Chouraki, Vincent, Thomas, Charlene, Ikram, M Arfan, Zelenika, Diana, Vardarajan, Badri N, Kamatani, Yoichiro, Lin, Chiao-Feng, Choi, Seung-Hoan, Schmidt, Helena, Kunkle, Brian, Dunstan, Melanie L, Vronskaya, Maria, Consortium, United Kingdom Brain Expression, Johnson, Andrew D, Ruiz, Agustin, Bihoreau, Marie-Thérèse, Reitz, Christiane, Pasquier, Florence, Harold, Denise, Hollingworth, Paul, Hanon, Olivier, Fitzpatrick, Annette L, Buxbaum, Joseph D, Campion, Dominique, Crane, Paul K, Baldwin, Clinton, Becker, Tim, Gudnason, Vilmundur, Cruchaga, Carlos, Jones, Lesley, Craig, David, Amin, Najaf, Berr, Claudine, Lopez, Oscar L, De Jager, Philip L, Deramecourt, Vincent, Johnston, Janet A, Evans, Denis, Lovestone, Simon, Letenneur, Luc, Holmans, Peter, Hernández, Isabel, Rubinsztein, David C, Eiriksdottir, Gudny, Sleegers, Kristel, Goate, Alison M, Fiévet, Nathalie, Huentelman, Matthew J, Gill, Michael, Brown, Kristelle, Kamboh, M Ilyas, Gerrish, Amy, Keller, Lina, Barberger-Gateau, Pascale, McGuinness, Bernadette, Larson, Eric B, Myers, Amanda J, Dufouil, Carole, Todd, Stephen, Wallon, David, Love, Seth, Rogaeva, Ekaterina, Vedernikov, Alexey, Gallacher, John, George-Hyslop, Peter St, Clarimon, Jordi, Lleo, Alberto, Bayer, Anthony, Tsuang, Debby W, Yu, Lei, Tsolaki, Magda, Bossù, Paola, Spalletta, Gianfranco, Richards, Alexander, Proitsi, Petra, Collinge, John, Sorbi, Sandro, Garcia, Florentino Sanchez, Fox, Nick C, Hardy, John, Naranjo, Maria Candida Deniz, Bosco, Paolo, Clarke, Robert, Brayne, Carol, Neurology, Radiology & Nuclear Medicine, Epidemiology, UAM. Departamento de Medicina, Universidad de Cantabria, and United Kingdom Brain Expression
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Genetics and Molecular Biology (all) ,Alzheimer Disease ,Carrier Proteins ,Case-Control Studies ,Genome-Wide Association Study ,Heat-Shock Proteins ,Humans ,Polymorphism, Single Nucleotide ,Receptors, Antigen, B-Cell ,Agricultural and Biological Sciences (all) ,Biochemistry, Genetics and Molecular Biology (all) ,Medicine (all) ,genotype ,Medizin ,lcsh:Medicine ,genetics [Alzheimer Disease] ,Genome-wide association study ,Genomics--Data processing ,Disease ,genetics [Carrier Proteins] ,Biochemistry ,Alzheimer's disease ,0302 clinical medicine ,genetics [Heat-Shock Proteins] ,genetics [Receptors, Antigen, B-Cell] ,Disease susceptibility--Genetic aspects ,Receptors ,Pathology ,Medicine and Health Sciences ,lcsh:Science ,Genetics ,0303 health sciences ,Multidisciplinary ,pathogenesis ,Genomics ,Single Nucleotide ,Neurology ,Antigen ,Physical Sciences ,protein degradation ,Alzheimer disease ,Engineering sciences. Technology ,Statistics (Mathematics) ,Research Article ,medicine.medical_specialty ,Medicina ,Geriatrik ,Late onset ,Biostatistics ,Biology ,Medical sciences ,03 medical and health sciences ,Molecular genetics ,Mental Health and Psychiatry ,Genome-Wide Association Studies ,medicine ,chromosome 8 ,Dementia ,ddc:610 ,Polymorphism ,QH426 ,Genetic Association Studies ,030304 developmental biology ,TP53INP1 protein, human ,lcsh:R ,Case-control study ,B-Cell ,Biology and Life Sciences ,Computational Biology ,Human Genetics ,Genome Analysis ,medicine.disease ,R1 ,Human genetics ,immune system ,Geriatrics ,FOS: Biological sciences ,Alzheimer's disease--Genetic aspects ,RC0321 ,lcsh:Q ,Mathematics ,030217 neurology & neurosurgery - 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, The i-Select chips was funded by the French National Foundation on Alzheimer's disease and related disorders. The French National Fondation on Alzheimer's disease and related disorders supported several I-GAP meetings and communications. Data management involved the Centre National de Génotypage,and was supported by the Institut Pasteur de Lille, Inserm, FRC (fondation pour la recherche sur le cerveau) and Rotary. This work has been developed and supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease) and by the LABEX GENMED grant (Medical Genomics). The French National Foundation on Alzheimer's disease and related disorders and the Alzheimer's Association (Chicago, Illinois) grant supported IGAP in-person meetings, communication and the Alzheimer's Association (Chicago, Illinois) grant provided some funds to each consortium for analyses. EADI The authors thank Dr. Anne Boland (CNG) for her technical help in preparing the DNA samples for analyses. This work was supported by the National Foundation for Alzheimer's disease and related disorders, the Institut Pasteur de Lille and the Centre National de Génotypage. The Three-City Study was performed as part of a collaboration between the Institut National de la Santé et de la Recherche Médicale (Inserm), the Victor Segalen Bordeaux II University and Sanofi-Synthélabo. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study was also funded by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, MGEN, Institut de la Longévité, Agence Française de Sécurité Sanitaire des Produits de Santé, the Aquitaine and Bourgogne Regional Councils, Agence Nationale de la Recherche, ANR supported the COGINUT and COVADIS projects. Fondation de France and the joint French Ministry of Research/INSERM «Cohortes et collections de données biologiques» programme. Lille Génopôle received an unconditional grant from Eisai. The Three-city biological bank was developed and maintained by the laboratory for genomic analysis LAG-BRC - Institut Pasteur de Lille. Belgium sample collection: The patients were clinically and pathological characterized by the neurologists Sebastiaan Engelborghs, Rik Vandenberghe and Peter P. De Deyn, and in part genetically by Caroline Van Cauwenberghe, Karolien Bettens and Kristel Sleegers. Research at the Antwerp site is funded in part by the Belgian Science Policy Office Interuniversity Attraction Poles program, the Foundation Alzheimer Research (SAO-FRA), the Flemish Government initiated Methusalem Excellence Program, the Research Foundation Flanders (FWO) and the University of Antwerp Research Fund, Belgium. Karolien Bettens is a postdoctoral fellow of the FWO. The Antwerp site authors thank the personnel of the VIB Genetic Service Facility, the Biobank of the Institute Born-Bunge and the Departments of Neurology and Memory Clinics at the Hospital Network Antwerp and the University Hospitals Leuven. Finish sample collection: Financial support for this project was provided by the Health Research Council of the Academy of Finland, EVO grant 5772708 of Kuopio University Hospital, and the Nordic Centre of Excellence in Neurodegeneration. Italian sample collections: the Bologna site (FL) obtained funds from the Italian Ministry of research and University as well as Carimonte Foundation. The Florence site was supported by grant RF-2010-2319722, grant from the the Cassa di Risparmio di Pistoia e Pescia (Grant 2012) and the Cassa di Risparmio di Firenze (Grant 2012). The Milan site was supported by a grant from the «fondazione Monzino». The authors thank the expert contribution of Mr. Carmelo Romano. The Roma site received financial support from Italian Ministry of Health, Grant RF07-08 and RC08-09-10-11-12. The Pisa site is grateful to Dr. Annalisa LoGerfo for her technical assistance in the DNA purification studies. Spanish sample collection: the Madrid site (MB) was supported by grants of the Ministerio de Educación y Ciencia and the Ministerio de Sanidad y Consumo (Instituto de Salud Carlos III), and an institutional grant of the Fundación Ramón Areces to the CBMSO. The authors thank I. Sastre and Dr. A. Martínez-García for the preparation and control of the DNA collection, and Drs. P. Gil and P. Coria for their cooperation in the cases/controls recruitment. The authors are grateful to the Asociación de Familiares de Alzheimer de Madrid (AFAL) for continuous encouragement and help. Swedish sample collection: Financially supported in part by the Swedish Brain Power network, the Marianne and Marcus Wallenberg Foundation, the Swedish Research Council (521-2010-3134), the King Gustaf V and Queen Victoria's Foundation of Freemasons, the Regional Agreement on Medical Training and Clinical Research (ALF) between Stockholm County Council and the Karolinska Institutet, the Swedish Brain Foundation and the Swedish Alzheimer Foundation. CHARGE AGES: The AGES-Reykjavik Study is funded by National Institutes of Health (NIH) contract N01-AG-12100 (National Institute on Aging (NIA) with contributions from the National Eye Institute, National Institute on Deafness and Other Communication Disorders and National Heart, Lung, and Blood Institute (NHLBI)), the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). ASPS/PRODEM: The Austrian Stroke Prevention Study and The Prospective Dementia Register of the Austrian Alzheimer Society was supported by The Austrian Science Fond (FWF) grant number P20545-P05 (H. Schmidt) and P13180; The Austrian Alzheimer Society; The Medical University of Graz. Cardiovascular Health Study (CHS): This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and HHSN268200960009C; and NHLBI grants HL080295, HL087652, HL105756 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through AG023629, AG15928, AG20098, AG027058 and AG033193 (Seshadri) from the NIA. A full list of CHS investigators and institutions can be found at http://www.chs-nhlbi.org/pi. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Framingham Heart Study (FHS): This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195) and its contract with A_ymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. This study as also supported by grants from the National Institute on Aging: AG08122 and AG033193 (Seshadri). Drs. Seshadri and DeStefano were also supported by additional grants from the National Institute on Aging: (R01 AG16495; AG031287, AG033040), the National Institute of Neurological Disorders and Stroke (R01 NS17950), and the National Heart, Lung and Blood Institute (U01 HL096917, HL093029 and K24HL038444, RC2-HL102419 and UC2 HL103010. Fundació ACE would like to thank patients and controls who participated in this project. This work has been funded by the Fundación Alzheimur (Murcia), the Ministerio de Educación y Ciencia (PCT-010000-2007-18), (DEX-580000-2008-4), (Gobierno de España), Corporación Tecnológica de Andalucía (08/211) and Agencia IDEA (841318) (Consejería de Innovación, Junta de Andalucía). The authors thank to Ms. Trinitat Port-Carbó and her family for their generous support of Fundació ACE research programs. The Rotterdam Study: The Rotterdam Study was funded by Erasmus Medical Center and Erasmus University, Rotterdam; the Netherlands Organization for Health Research and Development; the Research Institute for Diseases in the Elderly; the Ministry of Education, Culture and Science; the Ministry for Health, Welfare and Sports; the European Commission;and the Municipality of Rotterdam; by grants from the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), Internationale Stichting Alzheimer Onderzoek, Hersenstichting Nederland, the Netherlands Genomics Initiative–Netherlands Organization for Scientific Research (Center for Medical Systems Biology and the Netherlands Consortium for Healthy Aging), the Seventh Framework Program (FP7/2007-2013), the ENGAGE project (grant agreement HEALTH-F4-2007-201413), MRACE-grant from the Erasmus Medical Center, the Netherlands Organization for Health Research and Development (ZonMW Veni-grant no. 916.13.054). ARIC: The Atherosclerosis Risk in Communities Study (ARIC) is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01- HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022 and grants R01-HL087641, RC2-HL102419 (Boerwinkle, CHARGE-S), UC2 HL103010, U01-HL096917 (Mosley) and R01-HL093029; NHGRI contract U01- HG004402; and NIH contract HHSN268200625226C and NIA: R01 AG033193 (Seshadri). Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. GERAD Cardiff University was supported by the Wellcome Trust, Medical Research Council (MRC), Alzheimer's Research United Kingdom (ARUK) and the Welsh Government. ARUK supported sample collections at the Kings College London, the South West Dementia Bank, Universities of Cambridge, Nottingham, Manchester and Belfast. The Belfast group acknowledges support from the Alzheimer's Society, Ulster Garden Villages, N. Ireland R & D Office and the Royal College of Physicians/Dunhill Medical Trust. The MRC and Mercer's Institute for Research on Ageing supported the Trinity College group. DCR is a Wellcome Trust Principal Research fellow. The South West Dementia Brain Bank acknowledges support from Bristol Research into Alzheimer's and Care of the Elderly. The Charles Wolfson Charitable Trust supported the OPTIMA group. Washington University was funded by NIH grants, Barnes Jewish Foundation and the Charles and Joanne Knight Alzheimer's Research Initiative. Patient recruitment for the MRC Prion Unit/UCL Department of Neurodegenerative Disease collection was supported by the UCLH/UCL Biomedical Centre and their work was supported by the NIHR Queen Square Dementia BRU. LASER-AD was funded by Lundbeck SA. The Bonn group would like to thank Dr. Heike Koelsch for her scientific support. The Bonn group was funded by the German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) grant number 01GI0102, 01GI0711, 01GI0420. The AgeCoDe study group was supported by the German Federal Ministry for Education and Research grants 01 GI 0710, 01 GI 0712, 01 GI 0713, 01 GI 0714, 01 GI 0715, 01 GI 0716, 01 GI 0717. The Homburg group was funded by the German Federal Ministry of Education and Research (BMBF): German National Genome Research Network (NGFN); Alzheimer's disease Integrated Genome Research Network; AD-IG: 01GS0465. Genotyping of the Bonn case-control sample was funded by the German centre for Neurodegenerative Diseases (DZNE), Germany. The GERAD Consortium also used samples ascertained by the NIMH AD Genetics Initiative. Harald Hampel was supported by a grant of the Katharina-Hardt-Foundation, Bad Homburg vor der Höhe, Germany. The KORA F4 studies were financed by Helmholtz Zentrum München; German Research Center for Environmental Health; BMBF; German National Genome Research Network and the Munich Center of Health Sciences. The Heinz Nixdorf Recall cohort was funded by the Heinz Nixdorf Foundation (Dr. Jur. G.Schmidt, Chairman) and BMBF. Coriell Cell Repositories is supported by NINDS and the Intramural Research Program of the National Institute on Aging. The authors acknowledge use of genotype data from the 1958 Birth Cohort collection, funded by the MRC and the Wellcome Trust which was genotyped by the Wellcome Trust Case Control Consortium and the Type-1 Diabetes Genetics Consortium, sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Allergy and Infectious Diseases, National Human Genome Research Institute, National Institute of Child Health and Human Development and Juvenile Diabetes Research Foundation International. The Nottingham Group (KM) are supported by the Big Lottery. MRC CFAS is part of the consortium and data will be included in future analyses. ADGC The National Institutes of Health, National Institute on Aging (NIH-NIA) supported this work through the following grants: ADGC, U01 AG032984, RC2 AG036528; NACC, U01 AG016976; NCRAD, U24 AG021886; NIA LOAD, U24 AG026395, R01 AG041797; MIRAGE R01 AG025259; Banner Sun Health Research Institute P30 AG019610; Boston University, P30 AG013846, U01 AG10483, R01 CA129769, R01 MH080295, R01 AG017173, R01AG33193; Columbia University, P50 AG008702, R37 AG015473; Duke University, P30 AG028377, AG05128; Emory University, AG025688; Group Health Research Institute, UO1 AG06781, UO1 HG004610; Indiana University, P30 AG10133; Johns Hopkins University, P50 AG005146, R01 AG020688; Massachusetts General Hospital, P50 AG005134; Mayo Clinic, P50 AG016574; Mount Sinai School of Medicine, P50 AG005138, P01 AG002219; New York University, P30 AG08051, MO1RR00096, and UL1 RR029893; Northwestern University, P30 AG013854; Oregon Health & Science University, P30 AG008017, R01 AG026916; Rush University, P30 AG010161, R01 AG019085, R01 AG15819, R01 AG17917, R01 AG30146; TGen, R01 NS059873; University of Alabama at Birmingham, P50 AG016582, UL1RR02777; University of Arizona, R01 AG031581; University of California, Davis, P30 AG010129; University of California, Irvine, P50 AG016573, P50, P50 AG016575, P50 AG016576, P50 AG016577; University of California, Los Angeles, P50 AG016570; University of California, San Diego, P50 AG005131; University of California, San Francisco, P50 AG023501, P01 AG019724; University of Kentucky, P30 AG028383; University of Michigan, P50 AG008671; University of Pennsylvania, P30 AG010124; University of Pittsburgh, P50 AG005133, AG030653, AG041718; University of Southern California, P50 AG005142; University of Texas Southwestern, P30 AG012300; University of Miami, R01 AG027944, AG010491, AG027944, AG021547, AG019757; University of Washington, P50 AG005136; Vanderbilt University, R01 AG019085; and Washington University, P50 AG005681, P01 AG03991. The Kathleen Price Bryan Brain Bank at Duke University Medical Center is funded by NINDS grant # NS39764, NIMH MH60451 and by Glaxo Smith Kline. Genotyping of the TGEN2 cohort was supported by Kronos Science. The TGen series was also funded by NIA grant AG034504 to AJM, The Banner Alzheimer's Foundation, The Johnnie B. Byrd Sr. Alzheimer's Institute, the Medical Research Council, and the state of Arizona and also includes samples from the following sites: Newcastle Brain Tissue Resource (funding via the Medical Research Council, local NHS trusts and Newcastle University), MRC London Brain Bank for Neurodegenerative Diseases (funding via the Medical Research Council), South West Dementia Brain Bank (funding via numerous sources including the Higher Education Funding Council for England (HEFCE), Alzheimer's Research Trust (ART), BRACE as well as North Bristol NHS Trust Research and Innovation Department and DeNDRoN), The Netherlands Brain Bank (funding via numerous sources including Stichting MS Research, Brain Net Europe, Hersenstichting Nederland Breinbrekend Werk, International Parkinson Fonds, Internationale Stiching Alzheimer Onderzoek), Institut de Neuropatologia, Servei Anatomia Patologica, Universitat de Barcelona. Marcelle Morrison-Bogorad, PhD., Tony Phelps, PhD and Walter Kukull PhD are thanked for helping to co-ordinate this collection. ADNI Funding for ADNI is through the Northern California Institute for Research and Education by grants from Abbott, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare, Glaxo-SmithKline, Innogenetics, Johnson and Johnson, Eli Lilly and Co., Medpace, Inc., Merck and Co., Inc., Novartis AG, Pfizer Inc, F. Hoffman-La Roche, Schering-Plough, Synarc, Inc., Alzheimer's Association, Alzheimer's Drug Discovery Foundation, the Dana Foundation, and by the National Institute of Biomedical Imaging and Bioengineering and NIA grants U01 AG024904, RC2 AG036535, K01 AG030514. Data collection and sharing for this project was funded by the ADNI (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Alzheimer's Association; Alzheimer's Drug Discovery Foundation; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants P30 AG010129 and K01 AG030514. The authors thank Drs. D. Stephen Snyder and Marilyn Miller from NIA who are ex-o_cio ADGC members. Support was also from the Alzheimer's Association (LAF, IIRG-08-89720; MP-V, IIRG-05-14147) and the United States Department of Veterans Affairs Administration, Office of Research and Development, Biomedical Laboratory Research Program. Peter St George-Hyslop is supported by Wellcome Trust, Howard Hughes Medical Institute, and the Canadian Institute of Health
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- 2014
42. Genetic predisposition to increased blood cholesterol and triglyceride lipid levels and risk of Alzheimer disease: a Mendelian randomization analysis
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Proitsi, Petroula, Lupton, Michelle K, Velayudhan, Latha, Newhouse, Stephen, Fogh, Isabella, Tsolaki, Magda, Daniilidou, Makrina, Pritchard, Megan, Kloszewska, Iwona, Soininen, Hilkka, Mecocci, Patrizia, Vellas, Bruno, Williams, Julie, Harold, Denise, Sims, Rebecca, Gerrish, Amy, Chapman, Jade, Escott-Price, Valentina, Abraham, Richard, Hollingworth, Paul, Hamshere, Marian, Singh Pahwa, Jaspreet, Dowzell, Kimberley, Williams, Amy, Jones, Nicola, Thomas, Charlene, Stretton, Alexandra, Morgan, Angharad R, Williams, Kate, Lovestone, Simon, Powell, John F, Brayne, Carol, Rubinsztein, David C, Gill, Michael, Lawlor, Brian, Lynch, Aoibhinn, Morgan, Kevin, Brown, Kristelle S, Passmore, Peter, Craig, David, Mcguinness, Bernadette, Johnston, Janet A., Todd, Stephen, Holmes, Clive, Mann, David, Smith, A David, Love, Seth, Kehoe, Patrick G, Hardy, John, Guerreiro, Rita, Singleton, Andrew B, Mead, Simon, Fox, Nick, Rossor, Martin, Collinge, John, Maier, Wolfgang, Jessen, Frank, Heun, Reiner, Schürmann, Britta, Ramirez, Alfredo, Becker, Tim, Herold, Christine, Lacour, André, Drichel, Dmitriy, van den Bussche, Hendrik, Heuser, Isabella, Kornhuber, Johannes, Wiltfang, Jens, Dichgans, Martin, Frölich, Lutz, Hampel, Harald, Hüll, Michael, Rujescu, Dan, Goate, Alison M, Kauwe, John S K, Cruchaga, Carlos, Nowotny, Petra, Morris, John C, Mayo, Kevin, Livingston, Gill, Bass, Nicholas J, Gurling, Hugh, McQuillin, Andrew, Gwilliam, Rhian, Deloukas, Panagiotis, Nöthen, Markus M, Holmans, Peter A, O'Donovan, Michael C, Owen, Michael J, Stewart, Robert C, Sham, Pak, Proitsi, Petroula [0000-0002-2553-6974], Velayudhan, Latha [0000-0002-7712-930X], Newhouse, Stephen [0000-0002-1843-9842], Fogh, Isabella [0000-0002-6266-8933], Tsolaki, Magda [0000-0002-2072-8010], Pritchard, Megan [0000-0001-8872-3614], Mecocci, Patrizia [0000-0003-0729-5246], Williams, Julie [0000-0002-4069-0259], Stewart, Robert [0000-0002-4435-6397], Lovestone, Simon [0000-0003-0473-4565], and Apollo - University of Cambridge Repository
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Male ,Epidemiology ,genetics [Triglycerides] ,Blood lipids ,Physiology ,Genome-wide association study ,genetics [Alzheimer Disease] ,genetics [Cholesterol] ,Bioinformatics ,methods [Genome-Wide Association Study] ,Biochemistry ,methods [Mendelian Randomization Analysis] ,Risk Factors ,Medicine and Health Sciences ,Longitudinal Studies ,genetics [Genetic Predisposition to Disease] ,blood [Cholesterol] ,Aged, 80 and over ,education.field_of_study ,Research Support, Non-U.S. Gov't ,diagnosis [Alzheimer Disease] ,Mendelian Randomization Analysis ,General Medicine ,3. Good health ,Cholesterol ,genetics [Polymorphism, Single Nucleotide] ,Medicine ,Female ,Biotechnology ,Research Article ,Population ,Biology ,Polymorphism, Single Nucleotide ,blood [Alzheimer Disease] ,Research Support, N.I.H., Extramural ,Alzheimer Disease ,blood [Triglycerides] ,Mendelian randomization ,Journal Article ,Genetics ,Genetic predisposition ,Humans ,Genetic Predisposition to Disease ,ddc:610 ,education ,Molecular Biology ,Triglycerides ,Aged ,Biology and Life Sciences ,Lipid metabolism ,Cell Biology ,Odds ratio ,Geriatrics ,RC0321 ,Research Support, U.S. Gov't, Non-P.H.S ,Neuroscience ,Genome-Wide Association Study - Abstract
In this study, Proitsi and colleagues use a Mendelian randomization approach to dissect the causal nature of the association between circulating lipid levels and late onset Alzheimer's Disease (LOAD) and find that genetic predisposition to increased plasma cholesterol and triglyceride lipid levels is not associated with elevated LOAD risk. Please see later in the article for the Editors' Summary, Background Although altered lipid metabolism has been extensively implicated in the pathogenesis of Alzheimer disease (AD) through cell biological, epidemiological, and genetic studies, the molecular mechanisms linking cholesterol and AD pathology are still not well understood and contradictory results have been reported. We have used a Mendelian randomization approach to dissect the causal nature of the association between circulating lipid levels and late onset AD (LOAD) and test the hypothesis that genetically raised lipid levels increase the risk of LOAD. Methods and Findings We included 3,914 patients with LOAD, 1,675 older individuals without LOAD, and 4,989 individuals from the general population from six genome wide studies drawn from a white population (total n = 10,578). We constructed weighted genotype risk scores (GRSs) for four blood lipid phenotypes (high-density lipoprotein cholesterol [HDL-c], low-density lipoprotein cholesterol [LDL-c], triglycerides, and total cholesterol) using well-established SNPs in 157 loci for blood lipids reported by Willer and colleagues (2013). Both full GRSs using all SNPs associated with each trait at p, Editors' Summary Background Currently, about 44 million people worldwide have dementia, a group of brain disorders characterized by an irreversible decline in memory, communication, and other “cognitive” functions. Dementia mainly affects older people and, because people are living longer, experts estimate that more than 135 million people will have dementia by 2050. The commonest form of dementia is Alzheimer disease. In this type of dementia, protein clumps called plaques and neurofibrillary tangles form in the brain and cause its degeneration. The earliest sign of Alzheimer disease is usually increasing forgetfulness. As the disease progresses, affected individuals gradually lose their ability to deal with normal daily activities such as dressing. They may become anxious or aggressive or begin to wander. They may also eventually lose control of their bladder and of other physical functions. At present, there is no cure for Alzheimer disease although some of its symptoms can be managed with drugs. Most people with the disease are initially cared for at home by relatives and other unpaid carers, but many patients end their days in a care home or specialist nursing home. Why Was This Study Done? Several lines of evidence suggest that lipid metabolism (how the body handles cholesterol and other fats) is altered in patients whose Alzheimer disease develops after the age of 60 years (late onset Alzheimer disease, LOAD). In particular, epidemiological studies (observational investigations that examine the patterns and causes of disease in populations) have found an association between high amounts of cholesterol in the blood in midlife and the risk of LOAD. However, observational studies cannot prove that abnormal lipid metabolism (dyslipidemia) causes LOAD. People with dyslipidemia may share other characteristics that cause both dyslipidemia and LOAD (confounding) or LOAD might actually cause dyslipidemia (reverse causation). Here, the researchers use “Mendelian randomization” to examine whether lifetime changes in lipid metabolism caused by genes have a causal impact on LOAD risk. In Mendelian randomization, causality is inferred from associations between genetic variants that mimic the effect of a modifiable risk factor and the outcome of interest. Because gene variants are inherited randomly, they are not prone to confounding and are free from reverse causation. So, if dyslipidemia causes LOAD, genetic variants that affect lipid metabolism should be associated with an altered risk of LOAD. What Did the Researchers Do and Find? The researchers investigated whether genetic predisposition to raised lipid levels increased the risk of LOAD in 10,578 participants (3,914 patients with LOAD, 1,675 elderly people without LOAD, and 4,989 population controls) using data collected in six genome wide studies looking for gene variants associated with Alzheimer disease. The researchers constructed a genotype risk score (GRS) for each participant using genetic risk markers for four types of blood lipids on the basis of the presence of single nucleotide polymorphisms (SNPs, a type of gene variant) in their DNA. When the researchers used statistical methods to investigate the association between the GRS and LOAD among all the study participants, they found no association between the GRS and LOAD. What Do These Findings Mean? These findings suggest that the genetic predisposition to raised blood levels of four types of lipid is not causally associated with LOAD risk. The accuracy of this finding may be affected by several limitations of this study, including the small proportion of lipid variance explained by the GRS and the validity of several assumptions that underlie all Mendelian randomization studies. Moreover, because all the participants in this study were white, these findings may not apply to people of other ethnic backgrounds. Given their findings, the researchers suggest that the observed epidemiological associations between abnormal lipid levels in the blood and variation in lipid levels for reasons other than genetics, or to LOAD risk could be secondary to variation in lipid levels for reasons other than genetics, or to LOAD, a possibility that can be investigated by studying blood lipid levels and other markers of lipid metabolism over time in large groups of patients with LOAD. Importantly, however, these findings provide new information about the role of lipids in LOAD development that may eventually lead to new therapeutic and public-health interventions for Alzheimer disease. Additional Information Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001713. The UK National Health Service Choices website provides information (including personal stories) about Alzheimer's disease The UK not-for-profit organization Alzheimer's Society provides information for patients and carers about dementia, including personal experiences of living with Alzheimer's disease The US not-for-profit organization Alzheimer's Association also provides information for patients and carers about dementia and personal stories about dementia Alzheimer's Disease International is the international federation of Alzheimer disease associations around the world; it provides links to individual associations, information about dementia, and links to World Alzheimer Reports MedlinePlus provides links to additional resources about Alzheimer's disease (in English and Spanish) Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
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- 2014
43. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease (vol 41, pg 1088, 2009)
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Harold, Denise, Abraham, Richard, Hollingworth, Paul, Sims, Rebecca, Gerrish, Amy, Hamshere, Marian L., Pahwa, Jaspreet Singh, Moskvina, Valentina, Dowzell, Kimberley, Williams, A., Jones, Nicola, Thomas, Charlene, Stretton, Alexandra, Morgan, Angharad R., Lovestone, Simon, Powell, John, Proitsi, Petroula, Lupton, Michelle K., Brayne, Carol, Rubinsztein, David C., Gill, Michael, Lawlor, Brian, Lynch, Aoibhinn, Morgan, Kevin, Brown, Kristelle S., Passmore, Peter A., Craig, David, McGuinness, Bernadette, Todd, Stephen, Holmes, Clive, Mann, David, Smith, A. David, Love, Seth, Kehoe, Patrick G., Hardy, John, Mead, Simon, Fox, Nick, Rossor, Martin, Collinge, John, Maier, Wolfgang, Jessen, Frank, Schürmann, Britta, van den Bussche, Hendrik, Heuser, Isabella, Kornhuber, Johannes, Wiltfang, Jens, Dichgans, Martin, Frölich, Lutz, Hampel, Harald, Hüll, Michael, Rujescu, Dan, Goate, Alison M., Kauwe, John S. K., Cruchaga, Carlos, Nowotny, Petra, Morris, John C., Mayo, Kevin, Sleegers, Kristel, Bettens, Karolien, Engelborghs, Sebastiaan, De Deyn, Peter P., Van Broeckhoven, Christine, Livingston, Gill, Bass, Nicholas J., Gurling, Hugh, McQuillin, Andrew, Gwilliam, Rhian, Deloukas, Panagiotis, Al-Chalabi, Ammar, Shaw, Christopher E., Tsolaki, Magda, Singleton, Andrew B., Guerreiro, Rita, Muehleisen, Thomas W., Noethen, Markus M., Moebus, Susanne, Jöckel, Karl-Heinz, Klopp, Norman, Wichmann, H-Erich, Carrasquillo, Minerva M., Pankratz, V. Shane, Younkin, Steven G., Holmans, Peter A., O'Donovan, Michael, Owen, Michael J., Williams, Julie, Clinical sciences, Neuroprotection & Neuromodulation, and Neurology
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Medicine(all) ,Alzheimer's disease - Published
- 2013
44. Genetics of Alzheimer’s Disease
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Ridge, Perry G., Ebbert, Mark T. W., and Kauwe, John S. K.
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Article Subject - Abstract
Alzheimer’s disease is the most common form of dementia and is the only top 10 cause of death in the United States that lacks disease-altering treatments. It is a complex disorder with environmental and genetic components. There are two major types of Alzheimer’s disease, early onset and the more common late onset. The genetics of early-onset Alzheimer’s disease are largely understood with variants in three different genes leading to disease. In contrast, while several common alleles associated with late-onset Alzheimer’s disease, including APOE, have been identified using association studies, the genetics of late-onset Alzheimer’s disease are not fully understood. Here we review the known genetics of early- and late-onset Alzheimer’s disease.
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- 2013
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45. Common DNA Variants Accurately Rank an Individual of Extreme Height.
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Sexton, Corinne E., Ebbert, Mark T. W., Miller, Ryan H., Ferrel, Meganne, Tschanz, Jo Ann T., Corcoran, Christopher D., Ridge, Perry G., and Kauwe, John S. K.
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HUMAN genetic variation ,DNA ,MONOGENIC & polygenic inheritance (Genetics) ,STATURE ,SINGLE nucleotide polymorphisms ,PHENOTYPES - Abstract
Polygenic scores (or genetic risk scores) quantify the aggregate of small effects from many common genetic loci that have been associated with a trait through genome-wide association. Polygenic scores were first used successfully in schizophrenia and have since been applied to multiple phenotypes including multiple sclerosis, rheumatoid arthritis, and height. Because human height is an easily-measured and complex polygenic trait, polygenic height scores provide exciting insights into the predictability of aggregate common variant effect on the phenotype. Shawn Bradley is an extremely tall former professional basketball player from Brigham Young University and the National Basketball Association (NBA), measuring 2.29 meters (7′6″, 99.99999th percentile for height) tall, with no known medical conditions. Here, we present a case where a rare combination of common SNPs in one individual results in an extremely high polygenic height score that is correlated with an extreme phenotype. While polygenic scores are not clinically significant in the average case, our findings suggest that for extreme phenotypes, polygenic scores may be more successful for the prediction of individuals. [ABSTRACT FROM AUTHOR]
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- 2018
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46. Sex Differences in Risk for Alzheimer's Disease Related to Neurotrophin Gene Polymorphisms: The Cache County Memory Study.
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Matyi, Joshua, Tschanz, JoAnn T., Rattinger, Gail B., Sanders, Chelsea, Vernon, Elizabeth K., Corcoran, Chris, Kauwe, John S. K., and Buhusi, Mona
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NEUROTROPHINS ,NERVE growth factor ,GROWTH factors ,ALZHEIMER'S disease ,GENETIC polymorphisms ,COMPARATIVE studies ,RESEARCH methodology ,MEDICAL cooperation ,RESEARCH ,RISK assessment ,SEX distribution ,EVALUATION research - Abstract
Neurotrophins, including nerve-growth factor and brain-derived neurotrophic factor, have been implicated in Alzheimer's disease (AD). Associations between AD and neurotrophin signaling genes have been inconsistent, with few studies examining sex differences in risk. We examined four single-nucleotide polymorphisms (SNPs) involved in neurotrophin signaling (rs6265, rs56164415, rs2289656, rs2072446) and risk for AD by sex in a population-based sample of older adults. Three thousand four hundred and ninety-nine individuals without dementia at baseline [mean (standard deviation) age = 74.64 (6.84), 58% female] underwent dementia screening and assessment over four triennial waves. Cox regression was used to examine time to AD or right censoring for each SNP. Female carriers of the minor T allele for rs2072446 and rs56164415 had a 60% (hazard ratio [HR] = 1.60, 95% confidence interval [CI] = 1.02-2.51) and 93% (HR = 1.93, 95% CI = 1.30-2.84) higher hazard for AD, respectively, than male noncarriers of the T allele. Furthermore, male carriers of the T allele of rs2072446 had a 61% lower hazard (HR = 0.39, 95% CI = 0.14-1.06) than male noncarriers at trend-level significance (p = .07). The association between certain neurotrophin gene polymorphisms and AD differs by sex and may explain inconsistent findings in the literature. [ABSTRACT FROM AUTHOR]
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- 2017
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47. The Opioid Abuse Risk Screener predicts aberrant same-day urine drug tests and 1-year controlled substance database checks: A brief report.
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Averill, Lynnette A., Averill, Christopher L., Staley, Lyndsay A., Ozawa-Kirk, J. L., Kauwe, John S. k., and Henrie-Barrus, Patricia
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- 2017
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48. Discovery and Confirmation of Diagnostic Serum Lipid Biomarkers for Alzheimer's Disease Using Direct Infusion Mass Spectrometry.
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Anand, Swati, Barnes, Justin M., Young, Sydney A., Garcia, Diana M., Tolley, H. Dennis, Kauwe, John S. K., and Graves, Steven W.
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BLOOD lipids ,NEURODEGENERATION ,ALZHEIMER'S disease ,BIOLOGICAL tags ,MASS spectrometry ,ALZHEIMER'S disease diagnosis ,APOLIPOPROTEINS ,LIPIDS ,PROBABILITY theory ,CASE-control method ,RECEIVER operating characteristic curves ,STATISTICAL models - Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder lacking early biochemical diagnosis and treatment. Lipids have been implicated in neurodegenerative disorders including AD. A shotgun lipidomic approach was undertaken to determine if lipid biomarkers exist that can discriminate AD cases from controls. The discovery study involved sera from 29 different stage AD cases and 32 controls. Lipid extraction was performed using organic solvent and the samples were directly infused into a time-of-flight mass spectrometer. Differences between AD cases and controls were detected with 87 statistically significant lipid candidate markers found. These potential lipid markers were reevaluated in a second confirmatory study involving 27 cases and 30 controls. Of the 87 candidates from the first study, 35 continued to be statistically significant in the second confirmatory set. Tandem MS studies were performed and almost all confirmed markers were characterized and classified. Using a Bayesian lasso probit regression model on the confirmed markers, a multi-marker set with AUC = 0.886 was developed comparing all stages of AD with controls. Additionally, using confirmed biomarkers, multi-marker sets with AUCs >0.90 were developed for each specific AD Clinical Dementia Rating versus controls, including the earliest stage of AD. More conservative and likely more realistic statistical analyses still found multi-marker sets that appeared useful in diagnosing AD. Finally, using ordinal modeling a set of markers was developed that staged AD accurately 70% of the time, p = 0.0079. These results suggest that these serum lipidomic biomarkers may help diagnose and perhaps even stage AD. [ABSTRACT FROM AUTHOR]
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- 2017
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49. Evaluating the necessity of PCR duplicate removal from next-generation sequencing data and a comparison of approaches.
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Ebbert, Mark T. W., Wadsworth, Mark E., Staley, Lyndsay A., Hoyt, Kaitlyn L., Pickett, Brandon, Miller, Justin, Duce, John, Kauwe, John S. K., and Ridge, Perry G.
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POLYMERASE chain reaction ,NUCLEOTIDE sequencing ,GENOTYPES ,BIOINFORMATICS ,DATA analysis ,ALGORITHMS - Abstract
Background: Analyzing next-generation sequencing data is difficult because datasets are large, second generation sequencing platforms have high error rates, and because each position in the target genome (exome, transcriptome, etc.) is sequenced multiple times. Given these challenges, numerous bioinformatic algorithms have been developed to analyze these data. These algorithms aim to find an appropriate balance between data loss, errors, analysis time, and memory footprint. Typical analysis pipelines require multiple steps. If one or more of these steps is unnecessary, it would significantly decrease compute time and data manipulation to remove the step. One step in many pipelines is PCR duplicate removal, where PCR duplicates arise from multiple PCR products from the same template molecule binding on the flowcell. These are often removed because there is concern they can lead to false positive variant calls. Picard (MarkDuplicates) and SAMTools (rmdup) are the two main softwares used for PCR duplicate removal. Results: Approximately 92 % of the 17+ million variants called were called whether we removed duplicates with Picard or SAMTools, or left the PCR duplicates in the dataset. There were no significant differences between the unique variant sets when comparing the transition/transversion ratios (p = 1.0), percentage of novel variants (p = 0.99), average population frequencies (p = 0.99), and the percentage of protein-changing variants (p = 1.0). Results were similar for variants in the American College of Medical Genetics genes. Genotype concordance between NGS and SNP chips was above 99 % for all genotype groups (e.g., homozygous reference). Conclusions: Our results suggest that PCR duplicate removal has minimal effect on the accuracy of subsequent variant calls. [ABSTRACT FROM AUTHOR]
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- 2016
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50. Variants in CCL16 are associated with blood plasma and cerebrospinal fluid CCL16 protein levels.
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Ebbert, Mark T. W., Staley, Lyndsay A., Parker, Joshua, Parker, Sheradyn, Bailey, Matthew, Ridge, Perry G., Goate, Alison M., and Kauwe, John S. K.
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CHEMOKINES ,BLOOD plasma ,CEREBROSPINAL fluid proteins ,IMMUNOREGULATION ,NEOVASCULARIZATION ,GENETIC regulation - Abstract
Background: CCL16 is a chemokine predominantly expressed in the liver, but is also found in the blood and brain, and is known to play important roles in immune response and angiogenesis. Little is known about the gene's regulation. Methods: Here, we test for potential causal SNPs that affect CCL16 protein levels in both blood plasma and cerebrospinal fluid in a genome-wide association study across two datasets. We then use METAL to performed meta-analyses with a significance threshold of p<5×10
-8 . We removed SNPs where the direction of the effect was different between the two datasets. Results: We identify 10 SNPs associated with increased CCL16 protein levels in both biological fluids. Conclusions: Our results will help understand CCL16's regulation, allowing researchers to better understand the gene's effects on human health. [ABSTRACT FROM AUTHOR]- Published
- 2016
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