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1. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease.

Author

Sims, Rebecca, van der Lee, Sven J, Naj, Adam C, Bellenguez, Céline, Badarinarayan, Nandini, Jakobsdottir, Johanna, Kunkle, Brian W, Boland, Anne, Raybould, Rachel, Bis, Joshua C, Martin, Eden R, Grenier-Boley, Benjamin, Heilmann-Heimbach, Stefanie, Chouraki, Vincent, Kuzma, Amanda B, Sleegers, Kristel, Vronskaya, Maria, Ruiz, Agustin, Graham, Robert R, Olaso, Robert, Hoffmann, Per, Grove, Megan L, Vardarajan, Badri N, Hiltunen, Mikko, Nöthen, Markus M, White, Charles C, Hamilton-Nelson, Kara L, Epelbaum, Jacques, Maier, Wolfgang, Choi, Seung-Hoan, Beecham, Gary W, Dulary, Cécile, Herms, Stefan, Smith, Albert V, Funk, Cory C, Derbois, Céline, Forstner, Andreas J, Ahmad, Shahzad, Li, Hongdong, Bacq, Delphine, Harold, Denise, Satizabal, Claudia L, Valladares, Otto, Squassina, Alessio, Thomas, Rhodri, Brody, Jennifer A, Qu, Liming, Sánchez-Juan, Pascual, Morgan, Taniesha, Wolters, Frank J, Zhao, Yi, Garcia, Florentino Sanchez, Denning, Nicola, Fornage, Myriam, Malamon, John, Naranjo, Maria Candida Deniz, Majounie, Elisa, Mosley, Thomas H, Dombroski, Beth, Wallon, David, Lupton, Michelle K, Dupuis, Josée, Whitehead, Patrice, Fratiglioni, Laura, Medway, Christopher, Jian, Xueqiu, Mukherjee, Shubhabrata, Keller, Lina, Brown, Kristelle, Lin, Honghuang, Cantwell, Laura B, Panza, Francesco, McGuinness, Bernadette, Moreno-Grau, Sonia, Burgess, Jeremy D, Solfrizzi, Vincenzo, Proitsi, Petra, Adams, Hieab H, Allen, Mariet, Seripa, Davide, Pastor, Pau, Cupples, L Adrienne, Price, Nathan D, Hannequin, Didier, Frank-García, Ana, Levy, Daniel, Chakrabarty, Paramita, Caffarra, Paolo, Giegling, Ina, Beiser, Alexa S, Giedraitis, Vilmantas, Hampel, Harald, Garcia, Melissa E, Wang, Xue, Lannfelt, Lars, Mecocci, Patrizia, Eiriksdottir, Gudny, Crane, Paul K, Pasquier, Florence, and Boccardi, Virginia

Subjects
ARUK Consortium, GERAD/PERADES, CHARGE, ADGC, EADI, Microglia, Humans, Alzheimer Disease, Genetic Predisposition to Disease, Adaptor Proteins, Signal Transducing, Membrane Glycoproteins, Receptors, Immunologic, Odds Ratio, Case-Control Studies, Gene Expression Profiling, Amino Acid Sequence, Sequence Homology, Amino Acid, Gene Frequency, Genotype, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Phospholipase C gamma, Immunity, Innate, Protein Interaction Maps, Exome, Neurodegenerative, Brain Disorders, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Dementia, Alzheimer's Disease, Aging, Acquired Cognitive Impairment, 2.1 Biological and endogenous factors, Developmental Biology, Biological Sciences, Medical and Health Sciences
Abstract

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

Published
2017

2. Genetic Risk Underlying Psychiatric and Cognitive Symptoms in Huntington’s Disease

Author

Ellis, Natalie, Tee, Amelia, McAllister, Branduff, Massey, Thomas, McLauchlan, Duncan, Stone, Timothy, Correia, Kevin, Loupe, Jacob, Kim, Kyung-Hee, Barker, Douglas, Hong, Eun Pyo, Chao, Michael J., Long, Jeffrey D., Lucente, Diane, Vonsattel, Jean Paul G., Pinto, Ricardo Mouro, Elneel, Kawther Abu, Ramos, Eliana Marisa, Mysore, Jayalakshmi Srinidhi, Gillis, Tammy, Wheeler, Vanessa C., Medway, Christopher, Hall, Lynsey, Kwak, Seung, Sampaio, Cristina, Ciosi, Marc, Maxwell, Alastair, Chatzi, Afroditi, Monckton, Darren G., Orth, Michael, Landwehrmeyer, G. Bernhard, Paulsen, Jane S., Shoulson, Ira, Myers, Richard H., van Duijn, Erik, Rickards, Hugh, MacDonald, Marcy E., Lee, Jong-min, Gusella, James F., Jones, Lesley, and Holmans, Peter

Published
2020
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3. Exploring the association of common and rare variants in CNTN2, FGA and SPARCL1 with late-onset Alzheimer’s disease

Author

Medway, Christopher William

Subjects
616.831042
Abstract

Alzheimer's disease (AD) is an incurable neurodegenerative disorder, and the most common form of dementia, characterised neuropathologically by Aβ plaques and tau tangles. Although the late-onset form of AD (LOAD) is highly heritable (-80%), genetic studies to date have only accounted for approximately half of this. Identification of the remaining risk may require new approaches. In this thesis three candidate genes/loci (CNTN2, FGA and SPARCL 1), encoding putative LOAD cerebro-spinal fluid biomarkers (Contactin-2, Fibrinogen alpha-chain and Sparc-like-1), have been subjected to complementary genetic approaches to unearth novel LOAD risk alleles. An 'LD-aware' meta-analysis of three LOAD genome-wide datasets was conducted to investigate disease association with common (MAF>5%) variation in each candidate gene. Secondly, SOliD next-generation resequencing of 150 samples (75 LOAD, 75 controls), PCR enriched for candidate loci, was conducted to identify novel rare variation. Selected variants were subsequently validated and replicated in larger series (n=1453) using TaqMan genotyping. Meta-analysis revealed linked SNPs (rs7523477, rs4951168) downstream of CNTN2 associated with LOAD (p=3x10-5, OR=1.23(1.01-1.49) n=4898). However, this has not been replicated by subsequent GWAS. Resequencing identified 28 novel rare variations over all candidate loci. A SPARCL 1 variant (located at 88451921 (hg19)) showed association with LOAD in a UK population (p=0.023, OR=1.95(1.1 0-3.46)). Replication of this association will be required in independent series. In the post-GWAS era, new approaches to identify the remaining heritability of LOAD must be embraced. Not only will the identification of new mutations conferring risk for Alzheimer's disease benefit diagnosis, it will also foster a greater understanding of disease pathways - to which treatments can be targeted.

Published
2012

4. A candidate regulatory variant at the TREM gene cluster associates with decreased Alzheimer's disease risk and increased TREML1 and TREM2 brain gene expression

Author

Carrasquillo, Minerva M., Allen, Mariet, Burgess, Jeremy D., Wang, Xue, Strickland, Samantha L., Aryal, Shivani, Siuda, Joanna, Kachadoorian, Michaela L., Medway, Christopher, Younkin, Curtis S., Nair, Asha, Wang, Chen, Chanana, Pritha, Serie, Daniel, Nguyen, Thuy, Lincoln, Sarah, Malphrus, Kimberly G., Morgan, Kevin, Golde, Todd E., Price, Nathan D., White, Charles C., De Jager, Philip L., Bennett, David A., Asmann, Yan W., Crook, Julia E., Petersen, Ronald C., Graff-Radford, Neill R., Dickson, Dennis W., Younkin, Steven G., and Ertekin-Taner, Nilüfer

Published
2017
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5. Author Correction: Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing

Author

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.

Published
2019
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9. Mendelian adult-onset leukodystrophy genes in Alzheimer's disease: critical influence of CSF1R and NOTCH3

Author

Passmore, Peter, Craig, David, Johnston, Janet, McGuinness, Bernadette, Todd, Stephen, Heun, Reinhard, Kölsch, Heike, Kehoe, Patrick G., Vardy, Emma R.L.C., Hooper, Nigel M., Mann, David M., Pickering-Brown, Stuart, Brown, Kristelle, Lowe, James, Morgan, Kevin, Smith, A. David, Wilcock, Gordon, Warden, Donald, Holmes, Clive, Sassi, Celeste, Nalls, Michael A., Ridge, Perry G., Gibbs, Jesse R., Lupton, Michelle K., Troakes, Claire, Lunnon, Katie, Al-Sarraj, Safa, Brown, Kristelle S., Medway, Christopher, Lord, Jenny, Turton, James, Bras, Jose, Blumenau, Sonja, Thielke, Mareike, Josties, Christa, Freyer, Dorette, Dietrich, Annette, Hammer, Monia, Baier, Michael, Dirnagl, Ulrich, Powell, John F., Kauwe, John S., Cruchaga, Carlos, Goate, Alison M., Singleton, Andrew B., Guerreiro, Rita, Hodges, Angela, and Hardy, John

Published
2018
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10. Mutation analysis of sporadic early-onset Alzheimer's disease using the NeuroX array

Author

Passmore, Peter, Craig, David, Johnston, Janet, McGuinness, Bernadette, Todd, Stephen, Heun, Reinhard, Kölsch, Heike, Kehoe, Patrick G., Vardy, Emma R.L.C., Hooper, Nigel M., Pickering-Brown, Stuart, Snowden, Julie, Richardson, Anna, Jones, Matthew, Neary, David, Harris, Jennifer, Lowe, James, Smith, A. David, Wilcock, Gordon, Warden, Donald, Holmes, Clive, Barber, Imelda S., Braae, Anne, Clement, Naomi, Patel, Tulsi, Guetta-Baranes, Tamar, Brookes, Keeley, Medway, Christopher, Chappell, Sally, Guerreiro, Rita, Bras, Jose, Hernandez, Dena, Singleton, Andrew, Hardy, John, Mann, David M., and Morgan, Kevin

Published
2017
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11. ABCA7 p.G215S as potential protective factor for Alzheimer's disease

Author

Passmore, Peter, Craig, David, Johnston, Janet, McGuinness, Bernadette, Todd, Stephen, Heun, Reinhard, Kölsch, Heike, Kehoe, Patrick G., Vardy, Emma R.L.C., Hooper, Nigel M., Mann, David M., Pickering-Brown, Stuart, Brown, Kristelle, Lowe, James, Morgan, Kevin, Smith, A. David, Wilcock, Gordon, Warden, Donald, Holmes, Clive, Sassi, Celeste, Nalls, Michael A., Ridge, Perry G., Gibbs, Jesse R., Ding, Jinhui, Lupton, Michelle K., Troakes, Claire, Lunnon, Katie, Al-Sarraj, Safa, Brown, Kristelle S., Medway, Christopher, Clement, Naomi, Lord, Jenny, Turton, James, Bras, Jose, Almeida, Maria R., Holstege, Henne, Louwersheimer, Eva, van der Flier, Wiesje M., Scheltens, Philip, Van Swieten, John C., Santana, Isabel, Oliveira, Catarina, Powell, John F., Kauwe, John S., Cruchaga, Carlos, Goate, Alison M., Singleton, Andrew B., Guerreiro, Rita, and Hardy, John

Published
2016
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13. Screening exons 16 and 17 of the amyloid precursor protein gene in sporadic early-onset Alzheimer's disease

Author

Passmore, Peter, Craig, David, Johnston, Janet, McGuinness, Bernadette, Todd, Stephen, Heun, Reinhard, Kölsch, Heike, Kehoe, Patrick G., Vardy, Emma R.L.C., Hooper, Nigel M., Pickering-Brown, Stuart, Snowden, Julie, Richardson, Anna, Jones, Matt, Neary, David, Harris, Jenny, Medway, Christopher, Lowe, James, Smith, A. David, Wilcock, Gordon, Warden, Donald, Holmes, Clive, Barber, Imelda S., García-Cárdenas, Jennyfer M., Sakdapanichkul, Chidchanok, Deacon, Christopher, Zapata Erazo, Gabriela, Guerreiro, Rita, Bras, Jose, Hernandez, Dena, Singleton, Andrew, Guetta-Baranes, Tamar, Braae, Anne, Clement, Naomi, Patel, Tulsi, Brookes, Keeley, Chappell, Sally, Mann, David M., and Morgan, Kevin

Published
2016
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15. Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer’s disease

Author

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.

Published
2014
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16. Investigating the role of rare coding variability in Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP) in late-onset Alzheimer's disease

Author

Sassi, Celeste, Guerreiro, Rita, Gibbs, Raphael, Ding, Jinhui, Lupton, Michelle K., Troakes, Claire, Al-Sarraj, Safa, Niblock, Michael, Gallo, Jean-Marc, Adnan, Jihad, Killick, Richard, Brown, Kristelle S., Medway, Christopher, Lord, Jenny, Turton, James, Bras, Jose, Morgan, Kevin, Powell, John F., Singleton, Andrew, and Hardy, John

Published
2014
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17. Missense variant in TREML2 protects against Alzheimer's disease

Author

Benitez, Bruno A., Jin, Sheng Chih, Guerreiro, Rita, Graham, Rob, Lord, Jenny, Harold, Denise, Sims, Rebecca, Lambert, Jean-Charles, Gibbs, J. Raphael, Bras, Jose, Sassi, Celeste, Harari, Oscar, Bertelsen, Sarah, Lupton, Michelle K., Powell, John, Bellenguez, Celine, Brown, Kristelle, Medway, Christopher, Haddick, Patrick CG., van der Brug, Marcel P., Bhangale, Tushar, Ortmann, Ward, Behrens, Tim, Mayeux, Richard, Pericak-Vance, Margaret A., Farrer, Lindsay A., Schellenberg, Gerard D., Haines, Jonathan L., Turton, Jim, Braae, Anne, Barber, Imelda, Fagan, Anne M., Holtzman, David M., Morris, John C., Williams, Julie, Kauwe, John S.K., Amouyel, Philippe, Morgan, Kevin, Singleton, Andy, Hardy, John, Goate, Alison M., and Cruchaga, Carlos

Published
2014
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18. A transcriptome-wide association study implicates specific pre- and post-synaptic abnormalities in schizophrenia

Author

Hall, Lynsey S, primary, Medway, Christopher W, additional, Pain, Oliver, additional, Pardiñas, Antonio F, additional, Rees, Elliott G, additional, Escott-Price, Valentina, additional, Pocklington, Andrew, additional, Bray, Nicholas J, additional, Holmans, Peter A, additional, Walters, James T R, additional, Owen, Michael J, additional, and O’Donovan, Michael C, additional

Published
2019
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19. FAN1 modifies Huntington's disease progression by stabilising the expanded HTT CAG repeat

Author

Goold, Robert, Flower, Michael, Moss, Davina Hensman, Medway, Christopher, Wood-Kaczmar, Alison, Andre, Ralph, Farshim, Pamela, Bates, Gill P, Holmans, Peter, Jones, Lesley, and Tabrizi, Sarah J

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, mental disorders, nervous system diseases
Abstract

Huntington’s disease (HD) is an inherited neurodegenerative disease caused by an expanded CAG repeat in the HTT gene. CAG repeat length explains around half of the variation in age-at-onset, but genetic variation elsewhere in the genome accounts for a significant proportion of the remainder. Genome-wide association studies have identified a bidirectional signal on chromosome 15, likely underlain by FAN1 (FANCD2 and FANCI Associated Nuclease 1), a nuclease involved in DNA interstrand cross link repair. Here we show that increased FAN1 expression is significantly associated with delayed age-at-onset and slower progression of HD suggesting FAN1 is protective in the context of an expanded HTT CAG repeat. FAN1 overexpression in human cells reduces CAG repeat expansion in exogenously expressed mutant HTT exon 1, and in patient-derived stem cells and differentiated medium spiny neurons, FAN1 knockdown increases CAG repeat expansion. The stabilising effect is FAN1 concentration and CAG repeat length dependent. We show that FAN1 binds to the expanded HTT CAG repeat DNA and its nuclease activity is not required for protection against CAG repeat expansion. These data shed new mechanistic insights into how the genetic modifiers of HD act to alter disease progression, and show that FAN1 affects somatic expansion of the CAG repeat through a nuclease-independent mechanism. This provides new avenues for therapeutic interventions in HD and potentially other triplet repeat disorders.

Published
2019

20. Discovery by the Epistasis Project of an epistatic interaction between the GSTM3 gene and the HHEX/IDE/KIF11 locus in the risk of Alzheimer's disease

Author

Bullock, James M., Medway, Christopher, Cortina-Borja, Mario, Turton, James C., Prince, Jonathan A., Ibrahim-Verbaas, Carla A., Schuur, Maaike, Breteler, Monique M., van Duijn, Cornelia M., Kehoe, Patrick G., Barber, Rachel, Coto, Eliecer, Alvarez, Victoria, Deloukas, Panos, Hammond, Naomi, Combarros, Onofre, Mateo, Ignacio, Warden, Donald R., Lehmann, Michael G., Belbin, Olivia, Brown, Kristelle, Wilcock, Gordon K., Heun, Reinhard, Kölsch, Heike, Smith, A. David, Lehmann, Donald J., and Morgan, Kevin

Published
2013
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22. Mendelian adult-onset leukodystrophy genes in Alzheimer's disease:critical influence of CSF1R and NOTCH3

Author

Sassi, Celeste, Nalls, Michael A., Ridge, Perry G., Gibbs, Jesse R., Lupton, Michelle K., Troakes, Claire, Lunnon, Katie, Al-Sarraj, Safa, Brown, Kristelle, Medway, Christopher, Lord, Jenny, Turton, James, Bras, Jose, Blumenau, Sonja, Thielke, Mareike, Josties, Christa, Freyer, Dorette, and Hardy, John

Subjects
NOTCH3, Alzheimer's disease, CSF1R, Mendelian leukodystrophies
Abstract

Mendelian adult-onset leukodystrophies are a spectrum of rare inherited progressive neurodegenerative disorders affecting the white matter of the central nervous system. Among these, cerebral autosomal dominant and recessive arteriopathy with subcortical infarcts and leukoencephalopathy, cerebroretinal vasculopathy, metachromatic leukodystrophy, hereditary diffuse leukoencephalopathy with spheroids, and vanishing white matter disease present with rapidly progressive dementia as dominant feature and are caused by mutations in NOTCH3, HTRA1, TREX1, ARSA, CSF1R, EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5, respectively. Given the rare incidence of these disorders and the lack of unequivocally diagnostic features, leukodystrophies are frequently misdiagnosed with common sporadic dementing diseases such as Alzheimer's disease (AD), raising the question of whether these overlapping phenotypes may be explained by shared genetic risk factors. To investigate this intriguing hypothesis, we have combined gene expression analysis (1) in 6 different AD mouse strains (APPPS1, HOTASTPM, HETASTPM, TPM, TAS10, and TAU) at 5 different developmental stages (embryo [E15], 2, 4, 8, and 18 months), (2) in APPPS1 primary cortical neurons under stress conditions (oxygen-glucose deprivation) and single-variant–based and single-gene–based (c-alpha test and sequence kernel association test (SKAT)) genetic screening in a cohort composed of 332 Caucasian late-onset AD patients and 676 Caucasian elderly controls. Csf1r was significantly overexpressed (log2FC > 1, adj. p-value < 0.05) in the cortex and hippocampus of aged HOTASTPM mice with extensive Aβ dense-core plaque pathology. We identified 3 likely pathogenic mutations in CSF1R TK domain (p.L868R, p.Q691H, and p.H703Y) in our discovery and validation cohort, composed of 465 AD and mild cognitive impairment (MCI) Caucasian patients from the United Kingdom. Moreover, NOTCH3 was a significant hit in the c-alpha test (adj p-value = 0.01). Adult-onset Mendelian leukodystrophy genes are not common factors implicated in AD. Nevertheless, our study suggests a potential pathogenic link between NOTCH3, CSF1R, and sporadic late-onset AD, which warrants further investigation.

Published
2018

23. Mendelian adult-onset leukodystrophy genes in Alzheimer's disease: critical influence of CSF1R and NOTCH3

Author

Sassi, Celeste, Nalls, Michael A., Ridge, Perry G., Gibbs, Jesse R., Lupton, Michelle K., Troakes, Claire, Lunnon, Katie, Al-Sarraj, Safa, Brown, Kristelle S., Medway, Christopher, Lord, Jenny, Turton, James, Bras, Jose, Passmore, Peter, Craig, David, Johnston, Janet, McGuinness, Bernadette, Todd, Stephen, Heun, Reinhard, Kölsch, Heike, Kehoe, Patrick G., Vardy, Emma R. L. C., Hooper, Nigel M., Smith, A. David, Wilcock, Gordon, Warden, Donald, Holmes, Clive, Blumenau, Sonja, Thielke, Mareike, Josties, Christa, Freyer, Dorette, Dietrich, Annette, Hammer, Monia, Baier, Michael, Dirnagl, Ulrich, Morgan, Kevin, Powell, John F., Kauwe, John S., Cruchaga, Carlos, Goate, Alison M., Singleton, Andrew B., Guerreiro, Rita, Hodges, Angela, and Hardy, John

Subjects
NOTCH3, ddc:610, Alzheimer's disease, Mendelian leukodystrophies, CSF1R, 610 Medizin und Gesundheit
Abstract

Mendelian adult-onset leukodystrophies are a spectrum of rare inherited progressive neurodegenerative disorders affecting the white matter of the central nervous system. Among these, cerebral autosomal dominant and recessive arteriopathy with subcortical infarcts and leukoencephalopathy, cerebroretinal vasculopathy, metachromatic leukodystrophy, hereditary diffuse leukoencephalopathy with spheroids, and vanishing white matter disease present with rapidly progressive dementia as dominant feature and are caused by mutations in NOTCH3, HTRA1, TREX1, ARSA, CSF1R, EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5, respectively. Given the rare incidence of these disorders and the lack of unequivocally diagnostic features, leukodystrophies are frequently misdiagnosed with common sporadic dementing diseases such as Alzheimer's disease (AD), raising the question of whether these overlapping phenotypes may be explained by shared genetic risk factors. To investigate this intriguing hypothesis, we have combined gene expression analysis (1) in 6 different AD mouse strains (APPPS1, HOTASTPM, HETASTPM, TPM, TAS10, and TAU) at 5 different developmental stages (embryo [E15], 2, 4, 8, and 18 months), (2) in APPPS1 primary cortical neurons under stress conditions (oxygen-glucose deprivation) and single-variant–based and single-gene–based (c-alpha test and sequence kernel association test (SKAT)) genetic screening in a cohort composed of 332 Caucasian late-onset AD patients and 676 Caucasian elderly controls. Csf1r was significantly overexpressed (log2FC > 1, adj. p-value < 0.05) in the cortex and hippocampus of aged HOTASTPM mice with extensive Aβ dense-core plaque pathology. We identified 3 likely pathogenic mutations in CSF1R TK domain (p.L868R, p.Q691H, and p.H703Y) in our discovery and validation cohort, composed of 465 AD and mild cognitive impairment (MCI) Caucasian patients from the United Kingdom. Moreover, NOTCH3 was a significant hit in the c-alpha test (adj p-value = 0.01). Adult-onset Mendelian leukodystrophy genes are not common factors implicated in AD. Nevertheless, our study suggests a potential pathogenic link between NOTCH3, CSF1R, and sporadic late-onset AD, which warrants further investigation.

Published
2018

24. CAG Repeat Not Polyglutamine Length Determines Timing of Huntington’s Disease Onset

Author

Lee, Jong-Min, primary, Correia, Kevin, additional, Loupe, Jacob, additional, Kim, Kyung-Hee, additional, Barker, Douglas, additional, Hong, Eun Pyo, additional, Chao, Michael J., additional, Long, Jeffrey D., additional, Lucente, Diane, additional, Vonsattel, Jean Paul G., additional, Pinto, Ricardo Mouro, additional, Abu Elneel, Kawther, additional, Ramos, Eliana Marisa, additional, Mysore, Jayalakshmi Srinidhi, additional, Gillis, Tammy, additional, Wheeler, Vanessa C., additional, MacDonald, Marcy E., additional, Gusella, James F., additional, McAllister, Branduff, additional, Massey, Thomas, additional, Medway, Christopher, additional, Stone, Timothy C., additional, Hall, Lynsey, additional, Jones, Lesley, additional, Holmans, Peter, additional, Kwak, Seung, additional, Ehrhardt, Anka G., additional, Sampaio, Cristina, additional, Ciosi, Marc, additional, Maxwell, Alastair, additional, Chatzi, Afroditi, additional, Monckton, Darren G., additional, Orth, Michael, additional, Landwehrmeyer, G. Bernhard, additional, Paulsen, Jane S., additional, Dorsey, E. Ray, additional, Shoulson, Ira, additional, and Myers, Richard H., additional

Published
2019
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25. Pharmacogenomic Variants and Drug Interactions Identified Through the Genetic Analysis of Clozapine Metabolism

Author

Pardiñas, Antonio F., primary, Nalmpanti, Mariana, additional, Pocklington, Andrew J., additional, Legge, Sophie E., additional, Medway, Christopher, additional, King, Adrian, additional, Jansen, John, additional, Helthuis, Marinka, additional, Zammit, Stanley, additional, MacCabe, James, additional, Owen, Michael J., additional, O’Donovan, Michael C., additional, and Walters, James T.R., additional

Published
2019
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26. Genetic risk underlying psychiatric and cognitive symptoms in Huntington’s Disease

Author

Ellis, Natalie, primary, Tee, Amelia, additional, McAllister, Branduff, additional, Massey, Thomas, additional, McLauchlan, Duncan, additional, Stone, Timothy, additional, Correia, Kevin, additional, Loupe, Jacob, additional, Kim, Kyung-Hee, additional, Barker, Douglas, additional, Hong, Eun Pyo, additional, Chao, Michael J., additional, Long, Jeffrey D., additional, Lucente, Diane, additional, Vonsattel, Jean Paul G., additional, Pinto, Ricardo Mouro, additional, Elneel, Kawther Abu, additional, Ramos, Eliana Marisa, additional, Mysore, Jayalakshmi Srinidhi, additional, Gillis, Tammy, additional, Wheeler, Vanessa C., additional, Medway, Christopher, additional, Hall, Lynsey, additional, Kwak, Seung, additional, Sampaio, Cristina, additional, Ciosi, Marc, additional, Maxwell, Alastair, additional, Chatzi, Afroditi, additional, Monckton, Darren G., additional, Orth, Michael, additional, Landwehrmeyer, G. Bernhard, additional, Paulsen, Jane S., additional, Shoulson, Ira, additional, Myers, Richard H., additional, van Duijn, Erik, additional, Rickards, Hugh, additional, MacDonald, Marcy E., additional, Lee, Jong-min, additional, Gusella, James F., additional, Jones, Lesley, additional, and Holmans, Peter, additional

Published
2019
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28. 47TRANSCRIPTOME-WIDE ASSOCIATION ANALYSIS OF SCHIZOPHRENIA IMPLICATES PROCESSES INVOLVED IN SYNAPTIC DEVELOPMENT AND PLASTICITY, AND IMPAIRED LONG-TERM POTENTIATION

Author

Hall, Lynsey, primary, Medway, Christopher, additional, Pardiñas, Antonio, additional, Rees, Elliott, additional, Escott-Price, Valentina, additional, Pocklington, Andrew, additional, Walters, James, additional, Holmans, Peter, additional, Owen, Michael, additional, and O'Donovan, Michael, additional

Published
2019
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29. PHARMACOGENOMIC ARCHITECTURE OF CLOZAPINE PLASMA CONCENTRATIONS

Author

Pardiñas, Antonio, primary, Nalmpanti, Mariana, additional, Pocklington, Andrew, additional, Sophie, Sophie, additional, Medway, Christopher, additional, King, Adrian, additional, Jansen, John, additional, Helthuis, Marinka, additional, Owen, Michael, additional, O'Donovan, Michael, additional, and Walters, James, additional

Published
2019
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31. TLR5 decoy receptor as a novel anti-amyloid therapeutic for Alzheimer’s disease

Author

Chakrabarty, Paramita, primary, Li, Andrew, additional, Ladd, Thomas B., additional, Strickland, Michael R., additional, Koller, Emily J., additional, Burgess, Jeremy D., additional, Funk, Cory C., additional, Cruz, Pedro E., additional, Allen, Mariet, additional, Yaroshenko, Mariya, additional, Wang, Xue, additional, Younkin, Curtis, additional, Reddy, Joseph, additional, Lohrer, Benjamin, additional, Mehrke, Leonie, additional, Moore, Brenda D., additional, Liu, Xuefei, additional, Ceballos-Diaz, Carolina, additional, Rosario, Awilda M., additional, Medway, Christopher, additional, Janus, Christopher, additional, Li, Hong-Dong, additional, Dickson, Dennis W., additional, Giasson, Benoit I., additional, Price, Nathan D., additional, Younkin, Steven G., additional, Ertekin-Taner, Nilüfer, additional, and Golde, Todd E., additional

Published
2018
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33. Mendelian adult-onset leukodystrophy genes in Alzheimer's disease: critical influence of CSF1R and NOTCH3

Author

Sassi, Celeste, primary, Nalls, Michael A., additional, Ridge, Perry G., additional, Gibbs, Jesse R., additional, Lupton, Michelle K., additional, Troakes, Claire, additional, Lunnon, Katie, additional, Al-Sarraj, Safa, additional, Brown, Kristelle S., additional, Medway, Christopher, additional, Lord, Jenny, additional, Turton, James, additional, Bras, Jose, additional, Blumenau, Sonja, additional, Thielke, Mareike, additional, Josties, Christa, additional, Freyer, Dorette, additional, Dietrich, Annette, additional, Hammer, Monia, additional, Baier, Michael, additional, Dirnagl, Ulrich, additional, Morgan, Kevin, additional, Powell, John F., additional, Kauwe, John S., additional, Cruchaga, Carlos, additional, Goate, Alison M., additional, Singleton, Andrew B., additional, Guerreiro, Rita, additional, Hodges, Angela, additional, Hardy, John, additional, Passmore, Peter, additional, Craig, David, additional, Johnston, Janet, additional, McGuinness, Bernadette, additional, Todd, Stephen, additional, Heun, Reinhard, additional, Kölsch, Heike, additional, Kehoe, Patrick G., additional, Vardy, Emma R.L.C., additional, Hooper, Nigel M., additional, Mann, David M., additional, Pickering-Brown, Stuart, additional, Brown, Kristelle, additional, Lowe, James, additional, Smith, A. David, additional, Wilcock, Gordon, additional, Warden, Donald, additional, and Holmes, Clive, additional

Published
2018
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34. Influence of Coding Variability in APP-Aβ Metabolism Genes in Sporadic Alzheimer’s Disease

Author

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

Subjects
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

Published
2016

35. Screening exons 16 and 17 of the amyloid precursor protein gene in sporadic early-onset Alzheimer’s disease

Author

Barber, Imelda S., Sakdapanichkul, Chidchanok, Deacon, Christopher, Zapata Erazo, Gabriela, Guerreiro, Rita, Bras, Jose, Hernandez, Dena, Singleton, Andrew, Guetta-Baranes, Tamar, Braae, Anne, Clement, Naomi, Patel, Tulsi, Brookes, Keeley, Medway, Christopher, Chappell, Sally, and Mann, David M.

Subjects
Alzheimer's disease, early-onset, sporadic, screening, APP, rs367709245
Abstract

Early-onset Alzheimer’s disease (EOAD) can be familial (FAD) or sporadic (sEOAD); both have a disease onset ≤ 65 years of age. 451 sEOAD samples were screened for known causative mutations in exon 16 and 17 of the Amyloid Precursor Protein gene (APP). Four samples were shown to be heterozygous for one of three known causative mutations: p.A713T, p.V717I and p.V717G, this highlights the importance of screening EOAD patients for causative mutations. Additionally, we document an intronic 6 base pair (bp) deletion located 83 bp downstream of exon 17 (rs367709245, IVS17 83-88delAAGTAT), which has a nonsignificantly increased minor allele frequency in our sEOAD cohort (0.006) compared to LOAD (0.002) and controls (0.002). To assess the effect of the 6 bp deletion on splicing, COS-7 and BE(2)-C cells were transfected with a minigene vector encompassing exon 17. There was no change in splicing of exon 17 from constructs containing either wild type or deletion inserts. Sequencing of cDNA generated from cerebellum and temporal cortex of a patient harbouring the deletion found no evidence of transcripts with exon 17 removed.

Published
2016

36. ABCA7 p.G215S as potential protective factor for Alzheimer's disease

Author

Sassi, Celeste, Nalls, Michael A, Medway, Christopher, Clement, Naomi, Lord, Jenny, Turton, James, Bras, Jose, Almeida, Maria R, Consortium, ARUK, Holstege, Henne, Louwersheimer, Eva, van der Flier, Wiesje M, Ridge, Perry G, Scheltens, Philip, Van Swieten, John C, Santana, Isabel, Oliveira, Catarina, Morgan, Kevin, Powell, John F, Kauwe, John S, Cruchaga, Carlos, Goate, Alison M, Singleton, Andrew B, Gibbs, Jesse R, Guerreiro, Rita, Hardy, John, Passmore, Peter, Craig, David, Johnston, Janet, McGuinness, Bernadette, Todd, Stephen, Heun, Reinhard, Kölsch, Heike, Kehoe, Patrick G, Ding, Jinhui, Vardy, Emma R L C, Hooper, Nigel M, Mann, David M, Pickering-Brown, Stuart, Brown, Kristelle, Lowe, James, Smith, A David, Wilcock, Gordon, Warden, Donald, Lupton, Michelle K, Holmes, Clive, Troakes, Claire, Lunnon, Katie, Al-Sarraj, Safa, Brown, Kristelle S, Neurology, Human genetics, Amsterdam Neuroscience - Neurodegeneration, and Epidemiology and Data Science

Subjects
Adult, Male, Risk, ABCA7 protein, human, Protective variant, genetics [Alzheimer Disease], Genetic Reports Abstracts, ABCA7, Cohort Studies, Alzheimer Disease, Humans, Genetic Predisposition to Disease, ddc:610, genetics [Genetic Predisposition to Disease], Aged, Aged, 80 and over, Whole genome sequencing (WGS), Middle Aged, Genome-wide association studies (GWASs), Alzheimer's disease (AD), physiology [ATP-Binding Cassette Transporters], Female, ATP-Binding Cassette Transporters, genetics [ATP-Binding Cassette Transporters], Whole exome sequencing (WES), Genome-Wide Association Study
Abstract

Genome-wide association studies (GWASs) have been effective approaches to dissect common genetic variability underlying complex diseases in a systematic and unbiased way. Recently, GWASs have led to the discovery of over 20 susceptibility loci for Alzheimer's disease (AD). Despite the evidence showing the contribution of these loci to AD pathogenesis, their genetic architecture has not been extensively investigated, leaving the possibility that low frequency and rare coding variants may also occur and contribute to the risk of disease. We have used exome and genome sequencing data to analyze the single independent and joint effect of rare and low-frequency protein coding variants in 9 AD GWAS loci with the strongest effect sizes after APOE (BIN1, CLU, CR1, PICALM, MS4A6A, ABCA7, EPHA1, CD33, and CD2AP) in a cohort of 332 sporadic AD cases and 676 elderly controls of British and North-American ancestry. We identified coding variability in ABCA7 as contributing to AD risk. This locus harbors a low-frequency coding variant (p.G215S, rs72973581, minor allele frequency = 4.3%) conferring a modest but statistically significant protection against AD (p-value = 0.024, odds ratio = 0.57, 95% confidence interval = 0.41-0.80). Notably, our results are not driven by an enrichment of loss of function variants in ABCA7, recently reported as main pathogenic factor underlying AD risk at this locus. In summary, our study confirms the role of ABCA7 in AD and provides new insights that should address functional studies.

Published
2016

37. Mutation analysis of sporadic early-onset Alzheimer's disease using the NeuroX array

Author

Barber, Imelda S., primary, Braae, Anne, additional, Clement, Naomi, additional, Patel, Tulsi, additional, Guetta-Baranes, Tamar, additional, Brookes, Keeley, additional, Medway, Christopher, additional, Chappell, Sally, additional, Guerreiro, Rita, additional, Bras, Jose, additional, Hernandez, Dena, additional, Singleton, Andrew, additional, Hardy, John, additional, Mann, David M., additional, Morgan, Kevin, additional, Passmore, Peter, additional, Craig, David, additional, Johnston, Janet, additional, McGuinness, Bernadette, additional, Todd, Stephen, additional, Heun, Reinhard, additional, Kölsch, Heike, additional, Kehoe, Patrick G., additional, Vardy, Emma R.L.C., additional, Hooper, Nigel M., additional, Pickering-Brown, Stuart, additional, Snowden, Julie, additional, Richardson, Anna, additional, Jones, Matthew, additional, Neary, David, additional, Harris, Jennifer, additional, Lowe, James, additional, Smith, A. David, additional, Wilcock, Gordon, additional, Warden, Donald, additional, and Holmes, Clive, additional

Published
2017
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38. A candidate regulatory variant at the TREM gene cluster associates with decreased Alzheimer's disease risk and increased TREML1 and TREM2 brain gene expression

Author

Carrasquillo, Minerva M., primary, Allen, Mariet, additional, Burgess, Jeremy D., additional, Wang, Xue, additional, Strickland, Samantha L., additional, Aryal, Shivani, additional, Siuda, Joanna, additional, Kachadoorian, Michaela L., additional, Medway, Christopher, additional, Younkin, Curtis S., additional, Nair, Asha, additional, Wang, Chen, additional, Chanana, Pritha, additional, Serie, Daniel, additional, Nguyen, Thuy, additional, Lincoln, Sarah, additional, Malphrus, Kimberly G., additional, Morgan, Kevin, additional, Golde, Todd E., additional, Price, Nathan D., additional, White, Charles C., additional, De Jager, Philip L., additional, Bennett, David A., additional, Asmann, Yan W., additional, Crook, Julia E., additional, Petersen, Ronald C., additional, Graff‐Radford, Neill R., additional, Dickson, Dennis W., additional, Younkin, Steven G., additional, and Ertekin‐Taner, Nilüfer, additional

Published
2016
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39. Influence of Coding Variability in APP-Aβ Metabolism Genes in Sporadic Alzheimer's Disease

Author

Sassi, Celeste, Ridge, Perry G, Medway, Christopher, Lord, Jenny, Turton, James, Consortium, ARUK, Morgan, Kevin, Powell, John F, Kauwe, John S, Cruchaga, Carlos, Bras, Jose, Goate, Alison M, Nalls, Michael A, Singleton, Andrew B, Guerreiro, Rita, Hardy, John, Gibbs, Raphael, Ding, Jinhui, Lupton, Michelle K, Troakes, Claire, Lunnon, Katie, Al-Sarraj, Safa, and Brown, Kristelle S

Subjects
Science, metabolism [Amyloid beta-Peptides], genetics [Alzheimer Disease], Research and Analysis Methods, Biochemistry, Amyloid beta-Protein Precursor, Elderly, Alzheimer Disease, metabolism [Amyloid beta-Protein Precursor], Mental Health and Psychiatry, Medicine and Health Sciences, Genetics, genetics [Amyloid beta-Peptides], Humans, Exome, ddc:610, Genome Sequencing, Molecular Biology Techniques, Sequencing Techniques, Molecular Biology, Alleles, Computational Neuroscience, Damage Mechanics, Coding Mechanisms, Amyloid beta-Peptides, Physics, Computational Biology, Classical Mechanics, Biology and Life Sciences, Catabolism, Neurodegenerative Diseases, Metabolism, Neurology, genetics [Amyloid beta-Protein Precursor], Age Groups, Geriatrics, Genetic Loci, Physical Sciences, People and Places, Medicine, Dementia, Population Groupings, metabolism [Alzheimer Disease], Research Article, Neuroscience
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 AD pathogenesis, we selected 29 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 AD cases 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

Published
2015

40. O2-10-04: A Regulatory Variant at the TREM Gene Cluster Associates with Decreased Alzheimer’s Disease Risk and Increased TREML1 and TREM2 Brain Gene Expression

Author

Carrasquillo, Minerva M., primary, Allen, Mariet, additional, Burgess, Jeremy D., additional, Strickland, Samantha L., additional, Aryal, Shivani, additional, Siuda, Joanna, additional, Kachadoorian, Michaela, additional, Medway, Christopher, additional, Younkin, Curtis S., additional, Nair, Asha, additional, Chanana, Pritha, additional, Wang, Xue, additional, Serie, Daniel, additional, Nguyen, Thuy, additional, Lincoln, Sarah, additional, Malphrus, Kimberly G., additional, Morgan, Kevin, additional, Golde, Todd E., additional, Price, Nathan D., additional, White, Charles, additional, de Jager, Philip, additional, Bennett, David A., additional, Asmann, Yan W., additional, Crook, Julia E., additional, Dickson, Dennis W., additional, Younkin, Steven G., additional, and Ertekin-Taner, Nilufer, additional

Published
2016
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42. P3-092: Mapping Regulatory Variants in the Alzheimer's Disease Candidate Gene ABCA7

Author

Clement, Naomi S., primary, Medway, Christopher, additional, Ertekin-Taner, Nilufer, additional, Carrasquillo, Minerva M., additional, Younkin, Steven G., additional, Guetta-Baranes, Tamar, additional, Burgess, Jeremy D., additional, Allen, Mariet, additional, Tam, Tammie, additional, Dickson, Dennis W., additional, Petersen, Ronald C., additional, Graff-Radford, Neill R., additional, Chappell, Sally, additional, and Morgan, Kevin, additional

Published
2016
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43. Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing

Author

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, 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, Andre Uitterlinden, A. G., 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, 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, C. O’Donovan, Michael, 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.

Abstract

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

Published
2019
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44. Next generation sequencing of CLU, PICALM and CR1: pitfalls and potential solutions

Author

Lord, Jenny, Turton, James, Medway, Christopher, Shi, Hui, Brown, Kristelle, Lowe, James, Mann, David, Pickering-Brown, Stuart, Kalsheker, Noor, Passmore, Peter, Morgan, Kevin, and Alzheimers Research UK Consortium

Abstract

CLU, PICALM and CR1 were identified as genetic risk factors for late onset Alzheimer’s disease (AD) in two large genome wide association studies (GWAS) published in 2009, but the variants that convey this alteration in disease risk, and how the genes relate to AD pathology is yet to be discovered. A next generation sequencing (NGS) project was conducted targeting CLU, CR1 and PICALM, in 96 AD samples (8 pools of 12), in an attempt to discover rare variants within these AD associated genes. Inclusion of repetitive regions in the design of the SureSelect capture lead to significant issues in alignment of the data, leading to poor specificity and a lower than expected depth of coverage. A strong positive correlation (0.964, p

Published
2012

45. Late-onset Alzheimer disease risk variants mark brain regulatory loci

Author

Allen, Mariet, primary, Kachadoorian, Michaela, additional, Carrasquillo, Minerva M., additional, Karhade, Aditya, additional, Manly, Lester, additional, Burgess, Jeremy D., additional, Wang, Chen, additional, Serie, Daniel, additional, Wang, Xue, additional, Siuda, Joanna, additional, Zou, Fanggeng, additional, Chai, High Seng, additional, Younkin, Curtis, additional, Crook, Julia, additional, Medway, Christopher, additional, Nguyen, Thuy, additional, Ma, Li, additional, Malphrus, Kimberly, additional, Lincoln, Sarah, additional, Petersen, Ronald C., additional, Graff-Radford, Neill R., additional, Asmann, Yan W., additional, Dickson, Dennis W., additional, Younkin, Steven G., additional, and Ertekin-Taner, Nilüfer, additional

Published
2015
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50. P1-055: MULTIPLE ABCA7 MISSENSE VARIANTS MINED FROM THE EXOME VARIANT SERVER SHOW INDEPENDENT ASSOCIATION WITH INCREASED OR DECREASED RISK OF LATE-ONSET ALZHEIMER'S DISEASE (LOAD)

Author

Medway, Christopher William, primary, Abdul-Hay, Samer, additional, Mims, Tynickwa, additional, Zou, Fanggeng, additional, Ma, Li, additional, Bisceglio, Gina, additional, Pankratz, Shane, additional, Sando, Sigrid, additional, Aasly, Jan, additional, Barcikowska, Maria, additional, Siuda, Joanna, additional, Wszolek, Zbigniew, additional, Ross, Owen, additional, Carrasquillo, Minerva M., additional, Dickson, Dennis W., additional, Graff-Radford, Neill R., additional, Petersen, Ronald Carl, additional, Ertekin-Taner, Nilufer, additional, Morgan, Kevin, additional, and Younkin, Steven, additional

Published
2014
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