7 results on '"Braddel, Amy"'
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2. Exploring the training needs of inherited cardiac conditions (ICC) nurses: Elucidating role boundaries and competencies for practice in the genomics era.
- Author
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Braddel, Amy and Watson, Melanie
- Abstract
Nurses represent the largest professional group within the National Health Service (NHS) and are therefore central to the successful integration of mainstreaming genomics into routine healthcare. Inherited cardiac conditions (ICC) nurse roles have been developed in recent years to streamline the care for patients and families affected by an ICC. Like many nurse specialists, ICC nurses' prior exposure to genomics and the wider implications surrounding inherited conditions is limited. The aim of the study was to explore the education needs and support required for ICC nurses to fulfill their role within the genomic medicine era. A convenience sampling approach was adopted to invite ICC nurses working within various NHS Trusts across the United Kingdom to take part. Semi‐structured interviews were conducted with ICC nurses (n = 8), which were recorded, transcribed, coded, and analyzed using an inductive thematic analysis approach. Analysis of interview data highlighted four core themes, which were transferrable core competencies; managing genomic information; mixed‐modality learning; defining multidisciplinary team boundaries. The study highlights areas for further training and demonstrates the importance of defining competencies and role boundaries within ICC services. The ICC nurses identified the limits of their practice and the complementary role of genetic counselors, indicating the need for both professions within the ICC service and proposing implications for practice. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
3. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease
- Author
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Sims, Rebecca, van der Lee, Sven J., Naj, Adam C., Bellenguez, Celine, 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, Noethen, Markus M., White, Charles C., Hamilton-Nelson, Kara L., Epelbaum, Jacques, Maier, Wolfgang, Choi, Seung-Hoan, Beecham, Gary W., Dulary, Cecile, Herms, Stefan, Smith, Albert V., Funk, Cory C., Derbois, Celine, 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, Sanchez-Juan, Pascual, Morgan, Taniesha, Wolters, Frank J., Zhao, Yi, Sanchez Garcia, Florentino, Denning, Nicola, Fornage, Myriam, Malamon, John, Deniz Naranjo, Maria Candida, Majounie, Elisa, Mosley, Thomas H., Dombroski, Beth, Wallon, David, Lupton, Michelle K., Dupuis, Josee, 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-Garcia, 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, Boccardi, Virginia, Henandez, Isabel, Barber, Robert C., Scherer, Martin, Tarraga, Lluis, Adams, Perrie M., Leber, Markus, Chen, Yuning, Albert, Marilyn S., Riedel-Heller, Steffi, Emilsson, Valur, Beekly, Duane, Braae, Anne, Schmidt, Reinhold, Blacker, Deborah, Masullo, Carlo, Schmidt, Helena, Doody, Rachelle S., Spalletta, Gianfranco, Longstreth, W. T., Jr., Fairchild, Thomas J., Bossu, Paola, Lopez, Oscar L., Frosch, Matthew P., Sacchinelli, Eleonora, Ghetti, Bernardino, Yang, Qiong, Huebinger, Ryan M., Jessen, Frank, Li, Shuo, Kamboh, M. Ilyas, Morris, John, Sotolongo-Grau, Oscar, Katz, Mindy J., Corcoran, Chris, Dunstan, Melanie, Braddel, Amy, Thomas, Charlene, Meggy, Alun, Marshall, Rachel, Gerrish, Amy, Chapman, Jade, Aguilar, Miquel, Taylor, Sarah, Hill, Matt, Diez Fairen, Mnica, Hodges, Angela, Vellas, Bruno, Soininen, Hilkka, Kloszewska, Iwona, Daniilidou, Makrina, Uphill, James, Patel, Yogen, Hughes, Joseph T., Lord, Jenny, Turton, James, Hartmann, Annette M., Cecchetti, Roberta, Fenoglio, Chiara, Serpente, Maria, Arcaro, Marina, Caltagirone, Carlo, Orfei, Maria Donata, Ciaramella, Antonio, Pichler, Sabrina, Mayhaus, Manuel, Gu, Wei, Lleo, Alberto, Forte, Juan, Blesa, Rafael, Barber, Imelda S., Brookes, Keeley, Cupidi, Chiara, Maletta, Raffaele Giovanni, Carrell, David, Sorbi, Sandro, Moebus, Susanne, Urbano, Maria, Pilotto, Alberto, Kornhuber, Johannes, Bosco, Paolo, Todd, Stephen, Craig, David, Johnston, Janet, Gill, Michael, Lawlor, Brian, Lynch, Aoibhinn, Fox, Nick C., Hardy, John, Albin, Roger L., Apostolova, Liana G., Arnold, Steven E., Asthana, Sanjay, Atwood, Craig S., Baldwin, Clinton T., Barnes, Lisa L., Barral, Sandra, Beach, Thomas G., Becker, James T., Bigio, Eileen H., Bird, Thomas D., Boeve, Bradley F., Bowen, James D., Boxer, Adam, Burke, James R., Burns, Jeffrey M., Buxbaum, Joseph D., Cairns, Nigel J., Cao, Chuanhai, Carlson, Chris S., Carlsson, Cynthia M., Carney, Regina M., Carrasquillo, Minerva M., Carroll, Steven L., Diaz, Carolina Ceballos, Chui, Helena C., Clark, David G., Cribbs, David H., Crocco, Elizabeth A., DeCarli, Charles, Dick, Malcolm, Duara, Ranjan, Evans, Denis A., Faber, Kelley M., Fallon, Kenneth B., Fardo, David W., Farlow, Martin R., Ferris, Steven, Foroud, Tatiana M., Galasko, Douglas R., Gearing, Marla, Geschwind, Daniel H., Gilbert, John R., Graff-Radford, Neill R., Green, Robert C., Growdon, John H., Hamilton, Ronald L., Harrell, Lindy E., Honig, Lawrence S., Huentelman, Matthew J., Hulette, Christine M., Hyman, Bradley T., Jarvik, Gail P., Abner, Erin, Jin, Lee-Way, Jun, Gyungah, Karydas, Anna, Kaye, Jeffrey A., Kim, Ronald, Kowall, Neil W., Kramer, Joel H., LaFerla, Frank M., Lah, James J., Leverenz, James B., Levey, Allan I., Li, Ge, Lieberman, Andrew P., Lunetta, Kathryn L., Lyketsos, Constantine G., Marson, Daniel C., 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., Morris, John C., Murrell, Jill R., Myers, Amanda J., O'Bryant, Sid, Pankratz, Vernon S., Parisi, Joseph E., Paulson, Henry L., Perry, William, Peskind, Elaine, Pierce, Aimee, Poon, Wayne W., Potter, Huntington, Quinn, Joseph F., Raj, Ashok, Raskind, Murray, Reisberg, Barry, Reitz, Christiane, Ringman, John M., Roberson, Erik D., Rogaeva, Ekaterina, Rosen, Howard J., Rosenberg, Roger N., Sager, Mark A., 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., 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, Woltjer, Randall L., Wright, Clinton B., Yu, Chang-En, Yu, Lei, Garzia, Fabienne, Golamaully, Feroze, Septier, Gislain, Engelborghs, Sebastien, Vandenberghe, Rik, De Deyn, Peter P., Munoz Fernadez, Carmen, Aladro Benito, Yoland, Thonberg, Hakan, Forsell, Charlotte, Lilius, Lena, Kinhult-Stahlbom, Anne, Kilander, Lena, Brundin, RoseMarie, Concari, Letizia, Helisalmi, Seppo, Koivisto, Anne Maria, Haapasalo, Annakaisa, Dermecourt, Vincent, Fievet, Nathalie, Hanon, Olivier, Dufouil, Carole, Brice, Alexis, Ritchie, Karen, Dubois, Bruno, Himali, Jayanadra J., Keene, C. Dirk, Tschanz, Joann, Fitzpatrick, Annette L., Kukull, Walter A., Norton, Maria, Aspelund, Thor, Larson, Eric B., Munger, Ron, Rotter, Jerome I., Lipton, Richard B., Bullido, Maria J., Hofman, Albert, Montine, Thomas J., Coto, Eliecer, Boerwinkle, Eric, Petersen, Ronald C., Alvarez, Victoria, Rivadeneira, Fernando, Reiman, Eric M., Gallo, Maura, O'Donnell, Christopher J., Reisch, Joan S., Bruni, Amalia Cecilia, Royall, Donald R., Dichgans, Martin, Sano, Mary, Galimberti, Daniela, St George-Hyslop, Peter, Scarpini, Elio, Tsuang, Debby W., Mancuso, Michelangelo, Bonuccelli, Ubaldo, Winslow, Ashley R., Daniele, Antonio, Wu, Chuang-Kuo, Peters, Oliver, Nacmias, Benedetta, Riemenschneider, Matthias, Heun, Reinhard, Brayne, Carol, Rubinsztein, David C., Bras, Jose, Guerreiro, Rita, Al-Chalabi, Ammar, Shaw, Christopher E., Collinge, John, Mann, David, Tsolaki, Magda, Clarimon, Jordi, Sussams, Rebecca, Lovestone, Simon, O'Donovan, Michael C., Owen, Michael J., Behrens, Timothy W., Mead, Simon, Goate, Alison M., Uitterlinden, Andre G., Holmes, Clive, Cruchaga, Carlos, Ingelsson, Martin, Bennett, David A., Powell, John, Golde, Todd E., Graff, Caroline, De Jager, Philip L., Morgan, Kevin, Ertekin-Taner, Nilufer, Combarros, Onofre, Psaty, Bruce M., Passmore, Peter, Younkin, Steven G., Berr, Claudine, Gudnason, Vilmundur, Rujescu, Dan, Dickson, Dennis W., Dartigues, Jean-Francois, DeStefano, Anita L., Ortega-Cubero, Sara, Hakonarson, Hakon, Campion, Dominique, Boada, Merce, Kauwe, John Keoni, Farrer, Lindsay A., Van Broeckhoven, Christine, Ikram, M. Arfan, Jones, Lesley, Haines, Jonathan L., Tzourio, Christophe, Launer, Lenore J., Escott-Price, Valentina, Mayeux-, Richard, Deleuze, Jean-Francois, Amin, Najaf, Holmans, Peter A., Pericak-Vance, Margaret A., Amouyel, Philippe, van Duijn, Cornelia M., Ramirez, Alfredo, Wang, Li-San, Lambert, Jean-Charles, Seshadri, Sudha, Williams, Julie, Schellenberg, Gerard D., Sims, Rebecca, van der Lee, Sven J., Naj, Adam C., Bellenguez, Celine, 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, Noethen, Markus M., White, Charles C., Hamilton-Nelson, Kara L., Epelbaum, Jacques, Maier, Wolfgang, Choi, Seung-Hoan, Beecham, Gary W., Dulary, Cecile, Herms, Stefan, Smith, Albert V., Funk, Cory C., Derbois, Celine, 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, Sanchez-Juan, Pascual, Morgan, Taniesha, Wolters, Frank J., Zhao, Yi, Sanchez Garcia, Florentino, Denning, Nicola, Fornage, Myriam, Malamon, John, Deniz Naranjo, Maria Candida, Majounie, Elisa, Mosley, Thomas H., Dombroski, Beth, Wallon, David, Lupton, Michelle K., Dupuis, Josee, 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-Garcia, 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, Boccardi, Virginia, Henandez, Isabel, Barber, Robert C., Scherer, Martin, Tarraga, Lluis, Adams, Perrie M., Leber, Markus, Chen, Yuning, Albert, Marilyn S., Riedel-Heller, Steffi, Emilsson, Valur, Beekly, Duane, Braae, Anne, Schmidt, Reinhold, Blacker, Deborah, Masullo, Carlo, Schmidt, Helena, Doody, Rachelle S., Spalletta, Gianfranco, Longstreth, W. T., Jr., Fairchild, Thomas J., Bossu, Paola, Lopez, Oscar L., Frosch, Matthew P., Sacchinelli, Eleonora, Ghetti, Bernardino, Yang, Qiong, Huebinger, Ryan M., Jessen, Frank, Li, Shuo, Kamboh, M. Ilyas, Morris, John, Sotolongo-Grau, Oscar, Katz, Mindy J., Corcoran, Chris, Dunstan, Melanie, Braddel, Amy, Thomas, Charlene, Meggy, Alun, Marshall, Rachel, Gerrish, Amy, Chapman, Jade, Aguilar, Miquel, Taylor, Sarah, Hill, Matt, Diez Fairen, Mnica, Hodges, Angela, Vellas, Bruno, Soininen, Hilkka, Kloszewska, Iwona, Daniilidou, Makrina, Uphill, James, Patel, Yogen, Hughes, Joseph T., Lord, Jenny, Turton, James, Hartmann, Annette M., Cecchetti, Roberta, Fenoglio, Chiara, Serpente, Maria, Arcaro, Marina, Caltagirone, Carlo, Orfei, Maria Donata, Ciaramella, Antonio, Pichler, Sabrina, Mayhaus, Manuel, Gu, Wei, Lleo, Alberto, Forte, Juan, Blesa, Rafael, Barber, Imelda S., Brookes, Keeley, Cupidi, Chiara, Maletta, Raffaele Giovanni, Carrell, David, Sorbi, Sandro, Moebus, Susanne, Urbano, Maria, Pilotto, Alberto, Kornhuber, Johannes, Bosco, Paolo, Todd, Stephen, Craig, David, Johnston, Janet, Gill, Michael, Lawlor, Brian, Lynch, Aoibhinn, Fox, Nick C., Hardy, John, Albin, Roger L., Apostolova, Liana G., Arnold, Steven E., Asthana, Sanjay, Atwood, Craig S., Baldwin, Clinton T., Barnes, Lisa L., Barral, Sandra, Beach, Thomas G., Becker, James T., Bigio, Eileen H., Bird, Thomas D., Boeve, Bradley F., Bowen, James D., Boxer, Adam, Burke, James R., Burns, Jeffrey M., Buxbaum, Joseph D., Cairns, Nigel J., Cao, Chuanhai, Carlson, Chris S., Carlsson, Cynthia M., Carney, Regina M., Carrasquillo, Minerva M., Carroll, Steven L., Diaz, Carolina Ceballos, Chui, Helena C., Clark, David G., Cribbs, David H., Crocco, Elizabeth A., DeCarli, Charles, Dick, Malcolm, Duara, Ranjan, Evans, Denis A., Faber, Kelley M., Fallon, Kenneth B., Fardo, David W., Farlow, Martin R., Ferris, Steven, Foroud, Tatiana M., Galasko, Douglas R., Gearing, Marla, Geschwind, Daniel H., Gilbert, John R., Graff-Radford, Neill R., Green, Robert C., Growdon, John H., Hamilton, Ronald L., Harrell, Lindy E., Honig, Lawrence S., Huentelman, Matthew J., Hulette, Christine M., Hyman, Bradley T., Jarvik, Gail P., Abner, Erin, Jin, Lee-Way, Jun, Gyungah, Karydas, Anna, Kaye, Jeffrey A., Kim, Ronald, Kowall, Neil W., Kramer, Joel H., LaFerla, Frank M., Lah, James J., Leverenz, James B., Levey, Allan I., Li, Ge, Lieberman, Andrew P., Lunetta, Kathryn L., Lyketsos, Constantine G., Marson, Daniel C., 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., Morris, John C., Murrell, Jill R., Myers, Amanda J., O'Bryant, Sid, Pankratz, Vernon S., Parisi, Joseph E., Paulson, Henry L., Perry, William, Peskind, Elaine, Pierce, Aimee, Poon, Wayne W., Potter, Huntington, Quinn, Joseph F., Raj, Ashok, Raskind, Murray, Reisberg, Barry, Reitz, Christiane, Ringman, John M., Roberson, Erik D., Rogaeva, Ekaterina, Rosen, Howard J., Rosenberg, Roger N., Sager, Mark A., 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., 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, Woltjer, Randall L., Wright, Clinton B., Yu, Chang-En, Yu, Lei, Garzia, Fabienne, Golamaully, Feroze, Septier, Gislain, Engelborghs, Sebastien, Vandenberghe, Rik, De Deyn, Peter P., Munoz Fernadez, Carmen, Aladro Benito, Yoland, Thonberg, Hakan, Forsell, Charlotte, Lilius, Lena, Kinhult-Stahlbom, Anne, Kilander, Lena, Brundin, RoseMarie, Concari, Letizia, Helisalmi, Seppo, Koivisto, Anne Maria, Haapasalo, Annakaisa, Dermecourt, Vincent, Fievet, Nathalie, Hanon, Olivier, Dufouil, Carole, Brice, Alexis, Ritchie, Karen, Dubois, Bruno, Himali, Jayanadra J., Keene, C. Dirk, Tschanz, Joann, Fitzpatrick, Annette L., Kukull, Walter A., Norton, Maria, Aspelund, Thor, Larson, Eric B., Munger, Ron, Rotter, Jerome I., Lipton, Richard B., Bullido, Maria J., Hofman, Albert, Montine, Thomas J., Coto, Eliecer, Boerwinkle, Eric, Petersen, Ronald C., Alvarez, Victoria, Rivadeneira, Fernando, Reiman, Eric M., Gallo, Maura, O'Donnell, Christopher J., Reisch, Joan S., Bruni, Amalia Cecilia, Royall, Donald R., Dichgans, Martin, Sano, Mary, Galimberti, Daniela, St George-Hyslop, Peter, Scarpini, Elio, Tsuang, Debby W., Mancuso, Michelangelo, Bonuccelli, Ubaldo, Winslow, Ashley R., Daniele, Antonio, Wu, Chuang-Kuo, Peters, Oliver, Nacmias, Benedetta, Riemenschneider, Matthias, Heun, Reinhard, Brayne, Carol, Rubinsztein, David C., Bras, Jose, Guerreiro, Rita, Al-Chalabi, Ammar, Shaw, Christopher E., Collinge, John, Mann, David, Tsolaki, Magda, Clarimon, Jordi, Sussams, Rebecca, Lovestone, Simon, O'Donovan, Michael C., Owen, Michael J., Behrens, Timothy W., Mead, Simon, Goate, Alison M., Uitterlinden, Andre G., Holmes, Clive, Cruchaga, Carlos, Ingelsson, Martin, Bennett, David A., Powell, John, Golde, Todd E., Graff, Caroline, De Jager, Philip L., Morgan, Kevin, Ertekin-Taner, Nilufer, Combarros, Onofre, Psaty, Bruce M., Passmore, Peter, Younkin, Steven G., Berr, Claudine, Gudnason, Vilmundur, Rujescu, Dan, Dickson, Dennis W., Dartigues, Jean-Francois, DeStefano, Anita L., Ortega-Cubero, Sara, Hakonarson, Hakon, Campion, Dominique, Boada, Merce, Kauwe, John Keoni, Farrer, Lindsay A., Van Broeckhoven, Christine, Ikram, M. Arfan, Jones, Lesley, Haines, Jonathan L., Tzourio, Christophe, Launer, Lenore J., Escott-Price, Valentina, Mayeux-, Richard, Deleuze, Jean-Francois, Amin, Najaf, Holmans, Peter A., Pericak-Vance, Margaret A., Amouyel, Philippe, van Duijn, Cornelia M., Ramirez, Alfredo, Wang, Li-San, Lambert, Jean-Charles, Seshadri, Sudha, Williams, Julie, and Schellenberg, Gerard D.
- 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 x 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 x 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 x 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 x 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 x 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
- Full Text
- View/download PDF
4. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease
- Author
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Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Sims, Rebecca, van der Lee, Sven J., Naj, Adam C., Bellenguez, Celine, 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, Nothen, Markus M., White, Charles C., Hamilton-Nelson, Kara L., Epelbaum, Jacques, Maier, Wolfgang, Choi, Seung-Hoan, Beecham, Gary W., Dulary, Cecile, Herms, Stefan, Smith, Albert V., Funk, Cory C., Derbois, Celine, 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, Sanchez-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, Josee, 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-Garcia, 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, Boccardi, Virginia, Henandez, Isabel, Barber, Robert C., Scherer, Martin, Tarraga, Lluis, Adams, Perrie M., Leber, Markus, Chen, Yuning, Albert, Marilyn S., Riedel-Heller, Steffi, Emilsson, Valur, Beekly, Duane, Braae, Anne, Schmidt, Reinhold, Blacker, Deborah, Masullo, Carlo, Schmidt, Helena, Doody, Rachelle S., Spalletta, Gianfranco, Jr, W. T. Longstreth, Fairchild, Thomas J., Bossu, Paola, Lopez, Oscar L., Frosch, Matthew P., Sacchinelli, Eleonora, Ghetti, Bernardino, Yang, Qiong, Huebinger, Ryan M., Jessen, Frank, Li, Shuo, Kamboh, M. Ilyas, Morris, John, Sotolongo-Grau, Oscar, Katz, Mindy J., Corcoran, Chris, Dunstan, Melanie, Braddel, Amy, Thomas, Charlene, Meggy, Alun, Marshall, Rachel, Gerrish, Amy, Chapman, Jade, Aguilar, Miquel, Taylor, Sarah, Hill, Matt, Fairen, Monica Diez, Hodges, Angela, Vellas, Bruno, Soininen, Hilkka, Kloszewska, Iwona, Daniilidou, Makrina, Uphill, James, Patel, Yogen, Hughes, Joseph T., Lord, Jenny, Turton, James, Hartmann, Annette M., Cecchetti, Roberta, Fenoglio, Chiara, Serpente, Maria, Arcaro, Marina, Caltagirone, Carlo, Orfei, Maria Donata, Ciaramella, Antonio, Pichler, Sabrina, Mayhaus, Manuel, Gu, Wei, Lleo, Alberto, Fortea, Juan, Blesa, Rafael, Barber, Imelda S., Brookes, Keeley, Cupidi, Chiara, Maletta, Raffaele Giovanni, Carrell, David, Sorbi, Sandro, Moebus, Susanne, Urbano, Maria, Pilotto, Alberto, Kornhuber, Johannes, Bosco, Paolo, Todd, Stephen, Craig, David, Johnston, Janet, Gill, Michael, Lawlor, Brian, Lynch, Aoibhinn, Fox, Nick C., Hardy, John, Consortium, A. R. U. K., Albin, Roger L., Apostolova, Liana G., Arnold, Steven E., Asthana, Sanjay, Atwood, Craig S., Baldwin, Clinton T., Barnes, Lisa L., Barral, Sandra, Beach, Thomas G., Becker, James T., Bigio, Eileen H., Bird, Thomas D., Boeve, Bradley F., Bowen, James D., Boxer, Adam, Burke, James R., Burns, Jeffrey M., Buxbaum, Joseph D., Cairns, Nigel J., Cao, Chuanhai, Carlson, Chris S., Carlsson, Cynthia M., Carney, Regina M., Carrasquillo, Minerva M., Carroll, Steven L., Diaz, Carolina Ceballos, Chui, Helena C., Clark, David G., Cribbs, David H., Crocco, Elizabeth A., DeCarli, Charles, Dick, Malcolm, Duara, Ranjan, Evans, Denis A., Faber, Kelley M., Fallon, Kenneth B., Fardo, David W., Farlow, Martin R., Ferris, Steven, Foroud, Tatiana M., Galasko, Douglas R., Gearing, Marla, Geschwind, Daniel H., Gilbert, John R., Graff-Radford, Neill R., Green, Robert C., Growdon, John H., Hamilton, Ronald L., Harrell, Lindy E., Honig, Lawrence S., Huentelman, Matthew J., Hulette, Christine M., Hyman, Bradley T., Jarvik, Gail P., Abner, Erin, Jin, Lee-Way, Jun, Gyungah, Karydas, Anna, Kaye, Jeffrey A., Kim, Ronald, Kowall, Neil W., Kramer, Joel H., LaFerla, Frank M., Lah, James J., Leverenz, James B., Levey, Allan I., Li, Ge, Lieberman, Andrew P., Lunetta, Kathryn L., Lyketsos, Constantine G., Marson, Daniel C., 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., Morris, John C., Murrell, Jill R., Myers, Amanda J., O'Bryant, Sid, Olichney, John M., Pankratz, Vernon S., Parisi, Joseph E., Paulson, Henry L., Perry, William, Peskind, Elaine, Pierce, Aimee, Poon, Wayne W., Potter, Huntington, Quinn, Joseph F., Raj, Ashok, Raskind, Murray, Reisberg, Barry, Reitz, Christiane, Ringman, John M., Roberson, Erik D., Rogaeva, Ekaterina, Rosen, Howard J., Rosenberg, Roger N., Sager, Mark A., 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., 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, Garzia, Fabienne, Golamaully, Feroze, Septier, Gislain, Engelborghs, Sebastien, Vandenberghe, Rik, De Deyn, Peter P., Fernadez, Carmen Munoz, Benito, Yoland Aladro, Thonberg, Hakan, Forsell, Charlotte, Lilius, Lena, Kinhult-Stahlbom, Anne, Kilander, Lena, Brundin, Rosemarie, Concari, Letizia, Helisalmi, Seppo, Koivisto, Anne Maria, Haapasalo, Annakaisa, Dermecourt, Vincent, Fievet, Nathalie, Hanon, Olivier, Dufouil, Carole, Brice, Alexis, Ritchie, Karen, Dubois, Bruno, Himali, Jayanadra J., Keene, C. Dirk, Tschanz, Joann, Fitzpatrick, Annette L., Kukull, Walter A., Norton, Maria, Aspelund, Thor, Larson, Eric B., Munger, Ron, Rotter, Jerome I., Lipton, Richard B., Bullido, Maria J., Hofman, Albert, Montine, Thomas J., Coto, Eliecer, Boerwinkle, Eric, Petersen, Ronald C., Alvarez, Victoria, Rivadeneira, Fernando, Reiman, Eric M., Gallo, Maura, O'Donnell, Christopher J., Reisch, Joan S., Bruni, Amalia Cecilia, Royall, Donald R., Dichgans, Martin, Sano, Mary, Galimberti, Daniela, St George-Hyslop, Peter, Scarpini, Elio, Tsuang, Debby W., Mancuso, Michelangelo, Bonuccelli, Ubaldo, Winslow, Ashley R., Daniele, Antonio, Wu, Chuang-Kuo, GERAD/PERADES, Charge Adgc Eadi, Peters, Oliver, Nacmias, Benedetta, Riemenschneider, Matthias, Heun, Reinhard, Brayne, Carol, Rubinsztein, David C., Bras, Jose, Guerreiro, Rita, Al-Chalabi, Ammar, Shaw, Christopher E., Collinge, John, Mann, David, Tsolaki, Magda, Clarimon, Jordi, Sussams, Rebecca, Lovestone, Simon, O'Donovan, Michael C., Owen, Michael J., Behrens, Timothy W., Mead, Simon, Goate, Alison M., Uitterlinden, Andre G., Holmes, Clive, Cruchaga, Carlos, Ingelsson, Martin, Bennett, David A., Powell, John, Golde, Todd E., Graff, Caroline, De Jager, Philip L., Morgan, Kevin, Ertekin-Taner, Nilufer, Combarros, Onofre, Psaty, Bruce M., Passmore, Peter, Younkin, Steven G., Berr, Claudine, Gudnason, Vilmundur, Rujescu, Dan, Dickson, Dennis W., Dartigues, Jean-Francois, DeStefano, Anita L., Ortega-Cubero, Sara, Hakonarson, Hakon, Campion, Dominique, Boada, Merce, Kauwe, John Keoni, Farrer, Lindsay A., Van Broeckhoven, Christine, Ikram, M. Arfan, Jones, Lesley, Haines, Jonathan L., Tzourio, Christophe, Launer, Lenore J., Escott-Price, Valentina, Mayeux, Richard, Deleuze, Jean-Francois, Amin, Najaf, Holmans, Peter A., Pericak-Vance, Margaret A., Amouyel, Philippe, van Duijn, Cornelia M., Ramirez, Alfredo, Wang, Li-San, Lambert, Jean-Charles, Seshadri, Sudha, Williams, Julie, Schellenberg, Gerard D., Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Sims, Rebecca, van der Lee, Sven J., Naj, Adam C., Bellenguez, Celine, 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, Nothen, Markus M., White, Charles C., Hamilton-Nelson, Kara L., Epelbaum, Jacques, Maier, Wolfgang, Choi, Seung-Hoan, Beecham, Gary W., Dulary, Cecile, Herms, Stefan, Smith, Albert V., Funk, Cory C., Derbois, Celine, 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, Sanchez-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, Josee, 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-Garcia, 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, Boccardi, Virginia, Henandez, Isabel, Barber, Robert C., Scherer, Martin, Tarraga, Lluis, Adams, Perrie M., Leber, Markus, Chen, Yuning, Albert, Marilyn S., Riedel-Heller, Steffi, Emilsson, Valur, Beekly, Duane, Braae, Anne, Schmidt, Reinhold, Blacker, Deborah, Masullo, Carlo, Schmidt, Helena, Doody, Rachelle S., Spalletta, Gianfranco, Jr, W. T. Longstreth, Fairchild, Thomas J., Bossu, Paola, Lopez, Oscar L., Frosch, Matthew P., Sacchinelli, Eleonora, Ghetti, Bernardino, Yang, Qiong, Huebinger, Ryan M., Jessen, Frank, Li, Shuo, Kamboh, M. Ilyas, Morris, John, Sotolongo-Grau, Oscar, Katz, Mindy J., Corcoran, Chris, Dunstan, Melanie, Braddel, Amy, Thomas, Charlene, Meggy, Alun, Marshall, Rachel, Gerrish, Amy, Chapman, Jade, Aguilar, Miquel, Taylor, Sarah, Hill, Matt, Fairen, Monica Diez, Hodges, Angela, Vellas, Bruno, Soininen, Hilkka, Kloszewska, Iwona, Daniilidou, Makrina, Uphill, James, Patel, Yogen, Hughes, Joseph T., Lord, Jenny, Turton, James, Hartmann, Annette M., Cecchetti, Roberta, Fenoglio, Chiara, Serpente, Maria, Arcaro, Marina, Caltagirone, Carlo, Orfei, Maria Donata, Ciaramella, Antonio, Pichler, Sabrina, Mayhaus, Manuel, Gu, Wei, Lleo, Alberto, Fortea, Juan, Blesa, Rafael, Barber, Imelda S., Brookes, Keeley, Cupidi, Chiara, Maletta, Raffaele Giovanni, Carrell, David, Sorbi, Sandro, Moebus, Susanne, Urbano, Maria, Pilotto, Alberto, Kornhuber, Johannes, Bosco, Paolo, Todd, Stephen, Craig, David, Johnston, Janet, Gill, Michael, Lawlor, Brian, Lynch, Aoibhinn, Fox, Nick C., Hardy, John, Consortium, A. R. U. K., Albin, Roger L., Apostolova, Liana G., Arnold, Steven E., Asthana, Sanjay, Atwood, Craig S., Baldwin, Clinton T., Barnes, Lisa L., Barral, Sandra, Beach, Thomas G., Becker, James T., Bigio, Eileen H., Bird, Thomas D., Boeve, Bradley F., Bowen, James D., Boxer, Adam, Burke, James R., Burns, Jeffrey M., Buxbaum, Joseph D., Cairns, Nigel J., Cao, Chuanhai, Carlson, Chris S., Carlsson, Cynthia M., Carney, Regina M., Carrasquillo, Minerva M., Carroll, Steven L., Diaz, Carolina Ceballos, Chui, Helena C., Clark, David G., Cribbs, David H., Crocco, Elizabeth A., DeCarli, Charles, Dick, Malcolm, Duara, Ranjan, Evans, Denis A., Faber, Kelley M., Fallon, Kenneth B., Fardo, David W., Farlow, Martin R., Ferris, Steven, Foroud, Tatiana M., Galasko, Douglas R., Gearing, Marla, Geschwind, Daniel H., Gilbert, John R., Graff-Radford, Neill R., Green, Robert C., Growdon, John H., Hamilton, Ronald L., Harrell, Lindy E., Honig, Lawrence S., Huentelman, Matthew J., Hulette, Christine M., Hyman, Bradley T., Jarvik, Gail P., Abner, Erin, Jin, Lee-Way, Jun, Gyungah, Karydas, Anna, Kaye, Jeffrey A., Kim, Ronald, Kowall, Neil W., Kramer, Joel H., LaFerla, Frank M., Lah, James J., Leverenz, James B., Levey, Allan I., Li, Ge, Lieberman, Andrew P., Lunetta, Kathryn L., Lyketsos, Constantine G., Marson, Daniel C., 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., Morris, John C., Murrell, Jill R., Myers, Amanda J., O'Bryant, Sid, Olichney, John M., Pankratz, Vernon S., Parisi, Joseph E., Paulson, Henry L., Perry, William, Peskind, Elaine, Pierce, Aimee, Poon, Wayne W., Potter, Huntington, Quinn, Joseph F., Raj, Ashok, Raskind, Murray, Reisberg, Barry, Reitz, Christiane, Ringman, John M., Roberson, Erik D., Rogaeva, Ekaterina, Rosen, Howard J., Rosenberg, Roger N., Sager, Mark A., 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., 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, Garzia, Fabienne, Golamaully, Feroze, Septier, Gislain, Engelborghs, Sebastien, Vandenberghe, Rik, De Deyn, Peter P., Fernadez, Carmen Munoz, Benito, Yoland Aladro, Thonberg, Hakan, Forsell, Charlotte, Lilius, Lena, Kinhult-Stahlbom, Anne, Kilander, Lena, Brundin, Rosemarie, Concari, Letizia, Helisalmi, Seppo, Koivisto, Anne Maria, Haapasalo, Annakaisa, Dermecourt, Vincent, Fievet, Nathalie, Hanon, Olivier, Dufouil, Carole, Brice, Alexis, Ritchie, Karen, Dubois, Bruno, Himali, Jayanadra J., Keene, C. Dirk, Tschanz, Joann, Fitzpatrick, Annette L., Kukull, Walter A., Norton, Maria, Aspelund, Thor, Larson, Eric B., Munger, Ron, Rotter, Jerome I., Lipton, Richard B., Bullido, Maria J., Hofman, Albert, Montine, Thomas J., Coto, Eliecer, Boerwinkle, Eric, Petersen, Ronald C., Alvarez, Victoria, Rivadeneira, Fernando, Reiman, Eric M., Gallo, Maura, O'Donnell, Christopher J., Reisch, Joan S., Bruni, Amalia Cecilia, Royall, Donald R., Dichgans, Martin, Sano, Mary, Galimberti, Daniela, St George-Hyslop, Peter, Scarpini, Elio, Tsuang, Debby W., Mancuso, Michelangelo, Bonuccelli, Ubaldo, Winslow, Ashley R., Daniele, Antonio, Wu, Chuang-Kuo, GERAD/PERADES, Charge Adgc Eadi, Peters, Oliver, Nacmias, Benedetta, Riemenschneider, Matthias, Heun, Reinhard, Brayne, Carol, Rubinsztein, David C., Bras, Jose, Guerreiro, Rita, Al-Chalabi, Ammar, Shaw, Christopher E., Collinge, John, Mann, David, Tsolaki, Magda, Clarimon, Jordi, Sussams, Rebecca, Lovestone, Simon, O'Donovan, Michael C., Owen, Michael J., Behrens, Timothy W., Mead, Simon, Goate, Alison M., Uitterlinden, Andre G., Holmes, Clive, Cruchaga, Carlos, Ingelsson, Martin, Bennett, David A., Powell, John, Golde, Todd E., Graff, Caroline, De Jager, Philip L., Morgan, Kevin, Ertekin-Taner, Nilufer, Combarros, Onofre, Psaty, Bruce M., Passmore, Peter, Younkin, Steven G., Berr, Claudine, Gudnason, Vilmundur, Rujescu, Dan, Dickson, Dennis W., Dartigues, Jean-Francois, DeStefano, Anita L., Ortega-Cubero, Sara, Hakonarson, Hakon, Campion, Dominique, Boada, Merce, Kauwe, John Keoni, Farrer, Lindsay A., Van Broeckhoven, Christine, Ikram, M. Arfan, Jones, Lesley, Haines, Jonathan L., Tzourio, Christophe, Launer, Lenore J., Escott-Price, Valentina, Mayeux, Richard, Deleuze, Jean-Francois, Amin, Najaf, Holmans, Peter A., Pericak-Vance, Margaret A., Amouyel, Philippe, van Duijn, Cornelia M., Ramirez, Alfredo, Wang, Li-San, Lambert, Jean-Charles, Seshadri, Sudha, Williams, Julie, and Schellenberg, Gerard D.
- Published
- 2017
5. 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, Boccardi, Virginia, Henández, Isabel, Barber, Robert C, Scherer, Martin, Tarraga, Lluis, Adams, Perrie M, Leber, Markus, Chen, Yuning, Albert, Marilyn S, Riedel-Heller, Steffi, Emilsson, Valur, Beekly, Duane, Braae, Anne, Schmidt, Reinhold, Blacker, Deborah, Masullo, Carlo, Schmidt, Helena, Doody, Rachelle S, Spalletta, Gianfranco, Longstreth, WT, Fairchild, Thomas J, Bossù, Paola, Lopez, Oscar L, Frosch, Matthew P, Sacchinelli, Eleonora, Ghetti, Bernardino, Yang, Qiong, Huebinger, Ryan M, Jessen, Frank, Li, Shuo, Kamboh, M Ilyas, Morris, John, Sotolongo-Grau, Oscar, Katz, Mindy J, Corcoran, Chris, Dunstan, Melanie, Braddel, Amy, Thomas, Charlene, Meggy, Alun, Marshall, Rachel, Gerrish, Amy, Chapman, Jade, Aguilar, Miquel, Taylor, Sarah, Hill, Matt, Fairén, Mònica Díez, Hodges, Angela, Vellas, Bruno, Soininen, Hilkka, Kloszewska, Iwona, Daniilidou, Makrina, Uphill, James, Patel, Yogen, Hughes, Joseph T, Lord, Jenny, Turton, James, Hartmann, Annette M, Cecchetti, Roberta, Fenoglio, Chiara, Serpente, Maria, Arcaro, Marina, Caltagirone, Carlo, Orfei, Maria Donata, Ciaramella, Antonio, Pichler, Sabrina, Mayhaus, Manuel, Gu, Wei, Lleó, Alberto, Fortea, Juan, Blesa, Rafael, Barber, Imelda S, Brookes, Keeley, Cupidi, Chiara, Maletta, Raffaele Giovanni, Carrell, David, Sorbi, Sandro, Moebus, Susanne, Urbano, Maria, Pilotto, Alberto, Kornhuber, Johannes, Bosco, Paolo, Todd, Stephen, Craig, David, Johnston, Janet, Gill, Michael, Lawlor, Brian, Lynch, Aoibhinn, Fox, Nick C, Hardy, John, ARUK Consortium, Albin, Roger L, Apostolova, Liana G, Arnold, Steven E, Asthana, Sanjay, Atwood, Craig S, Baldwin, Clinton T, Barnes, Lisa L, Barral, Sandra, Beach, Thomas G, Becker, James T, Bigio, Eileen H, Bird, Thomas D, Boeve, Bradley F, Bowen, James D, Boxer, Adam, Burke, James R, Burns, Jeffrey M, Buxbaum, Joseph D, Cairns, Nigel J, Cao, Chuanhai, Carlson, Chris S, Carlsson, Cynthia M, Carney, Regina M, Carrasquillo, Minerva M, Carroll, Steven L, Diaz, Carolina Ceballos, Chui, Helena C, Clark, David G, Cribbs, David H, Crocco, Elizabeth A, DeCarli, Charles, Dick, Malcolm, Duara, Ranjan, Evans, Denis A, Faber, Kelley M, Fallon, Kenneth B, Fardo, David W, Farlow, Martin R, Ferris, Steven, Foroud, Tatiana M, Galasko, Douglas R, Gearing, Marla, Geschwind, Daniel H, Gilbert, John R, Graff-Radford, Neill R, Green, Robert C, Growdon, John H, Hamilton, Ronald L, Harrell, Lindy E, Honig, Lawrence S, Huentelman, Matthew J, Hulette, Christine M, Hyman, Bradley T, Jarvik, Gail P, Abner, Erin, Jin, Lee-Way, Jun, Gyungah, Karydas, Anna, Kaye, Jeffrey A, Kim, Ronald, Kowall, Neil W, Kramer, Joel H, LaFerla, Frank M, Lah, James J, Leverenz, James B, Levey, Allan I, Li, Ge, Lieberman, Andrew P, Lunetta, Kathryn L, Lyketsos, Constantine G, Marson, Daniel C, 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, Morris, John C, Murrell, Jill R, Myers, Amanda J, O'Bryant, Sid, Olichney, John M, Pankratz, Vernon S, Parisi, Joseph E, Paulson, Henry L, Perry, William, Peskind, Elaine, Pierce, Aimee, Poon, Wayne W, Potter, Huntington, Quinn, Joseph F, Raj, Ashok, Raskind, Murray, Reisberg, Barry, Reitz, Christiane, Ringman, John M, Roberson, Erik D, Rogaeva, Ekaterina, Rosen, Howard J, Rosenberg, Roger N, Sager, Mark A, 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, 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, Garzia, Fabienne, Golamaully, Feroze, Septier, Gislain, Engelborghs, Sebastien, Vandenberghe, Rik, De Deyn, Peter P, Fernadez, Carmen Muñoz, Benito, Yoland Aladro, Thonberg, Hakan, Forsell, Charlotte, Lilius, Lena, Kinhult-Stählbom, Anne, Kilander, Lena, Brundin, RoseMarie, Concari, Letizia, Helisalmi, Seppo, Koivisto, Anne Maria, Haapasalo, Annakaisa, Dermecourt, Vincent, Fievet, Nathalie, Hanon, Olivier, Dufouil, Carole, Brice, Alexis, Ritchie, Karen, Dubois, Bruno, Himali, Jayanadra J, Keene, C Dirk, Tschanz, JoAnn, Fitzpatrick, Annette L, Kukull, Walter A, Norton, Maria, Aspelund, Thor, Larson, Eric B, Munger, Ron, Rotter, Jerome I, Lipton, Richard B, Bullido, María J, Hofman, Albert, Montine, Thomas J, Coto, Eliecer, Boerwinkle, Eric, Petersen, Ronald C, Alvarez, Victoria, Rivadeneira, Fernando, Reiman, Eric M, Gallo, Maura, O'Donnell, Christopher J, Reisch, Joan S, Bruni, Amalia Cecilia, Royall, Donald R, Dichgans, Martin, Sano, Mary, Galimberti, Daniela, St George-Hyslop, Peter, Scarpini, Elio, Tsuang, Debby W, Mancuso, Michelangelo, Bonuccelli, Ubaldo, Winslow, Ashley R, Daniele, Antonio, Wu, Chuang-Kuo, GERAD/PERADES, CHARGE, Peters, Oliver, Nacmias, Benedetta, Riemenschneider, Matthias, Heun, Reinhard, Brayne, Carol, Rubinsztein, David C, Bras, Jose, Guerreiro, Rita, Al-Chalabi, Ammar, Shaw, Christopher E, Collinge, John, Mann, David, Tsolaki, Magda, Clarimón, Jordi, Sussams, Rebecca, Lovestone, Simon, O'Donovan, Michael C, Owen, Michael J, Behrens, Timothy W, Mead, Simon, Goate, Alison M, Uitterlinden, Andre G, Holmes, Clive, Cruchaga, Carlos, Ingelsson, Martin, Bennett, David A, Powell, John, Golde, Todd E, Graff, Caroline, De Jager, Philip L, Morgan, Kevin, Ertekin-Taner, Nilufer, Combarros, Onofre, Psaty, Bruce M, Passmore, Peter, Younkin, Steven G, Berr, Claudine, Gudnason, Vilmundur, Rujescu, Dan, Dickson, Dennis W, Dartigues, Jean-François, DeStefano, Anita L, Ortega-Cubero, Sara, Hakonarson, Hakon, Campion, Dominique, Boada, Merce, Kauwe, John Keoni, Farrer, Lindsay A, Van Broeckhoven, Christine, Ikram, M Arfan, Jones, Lesley, Haines, Jonathan L, Tzourio, Christophe, Launer, Lenore J, Escott-Price, Valentina, Mayeux, Richard, Deleuze, Jean-François, Amin, Najaf, Holmans, Peter A, Pericak-Vance, Margaret A, Amouyel, Philippe, Van Duijn, Cornelia M, Ramirez, Alfredo, Wang, Li-San, Lambert, Jean-Charles, Seshadri, Sudha, Williams, Julie, and Schellenberg, Gerard D
- Subjects
Membrane Glycoproteins ,Genotype ,Sequence Homology, Amino Acid ,Phospholipase C gamma ,Gene Expression Profiling ,Polymorphism, Single Nucleotide ,Immunity, Innate ,Linkage Disequilibrium ,3. Good health ,Gene Frequency ,Alzheimer Disease ,Case-Control Studies ,Odds Ratio ,Humans ,Exome ,Genetic Predisposition to Disease ,Amino Acid Sequence ,Microglia ,Protein Interaction Maps ,Receptors, Immunologic ,Adaptor Proteins, Signal Transducing - 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.
6. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease
- Author
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Taylor, Sarah, Craig, David, Qu, Liming, Haines, Jonathan L., Morgan, Taniesha, Sager, Mark A., Jun, Gyungah, Beiser, Alexa S., St George-Hyslop, Peter, Levey, Allan I., Vellas, Bruno, Collinge, John, Himali, Jayanadra J., Katz, Mindy J., Frank-García, Ana, Thonberg, Hakan, Grenier-Boley, Benjamin, Emilsson, Valur, Chouraki, Vincent, Jarvik, Gail P., Rotter, Jerome I., Nacmias, Benedetta, Chapman, Jade, Coto, Eliecer, Eiriksdottir, Gudny, Burgess, Jeremy D., Tsolaki, Magda, Saykin, Andrew J., Clarimón, Jordi, Hartmann, Annette M., Beekly, Duane, Peters, Oliver, Fairén, Mònica Díez, Brayne, Carol, Bras, Jose, Zhao, Yi, Riemenschneider, Matthias, Corcoran, Chris, Norton, Maria, Ikram, M Arfan, Gudnason, Vilmundur, Wallon, David, Serpente, Maria, Septier, Gislain, Atwood, Craig S., Yu, Chang-En, Sorbi, Sandro, Carlsson, Cynthia M., McCormick, Wayne C., Urbano, Maria, Galasko, Douglas R., Potter, Huntington, Raj, Ashok, Dufouil, Carole, Reisberg, Barry, Braae, Anne, Fratiglioni, Laura, Forsell, Charlotte, Shaw, Christopher E., Pastor, Pau, Jin, Lee-Way, Carrasquillo, Minerva M., Epelbaum, Jacques, Psaty, Bruce M., McDavid, Andrew N., Lilius, Lena, Ramirez, Alfredo, Berr, Claudine, Green, Robert C., Riedel-Heller, Steffi, Kornhuber, Johannes, Heilmann-Heimbach, Stefanie, Kauwe, John Keoni, Dunstan, Melanie, Miller, Bruce L., McKee, Ann C., Van Broeckhoven, Christine, Harold, Denise, Turton, James, Brookes, Keeley, Owen, Michael J., Brown, Kristelle, Dick, Malcolm, Pilotto, Alberto, Hill, Matt, Carney, Regina M., Thomas, Rhodri, Barber, Imelda S., Gearing, Marla, Brody, Jennifer A, Scarpini, Elio, Graff, Caroline, Pierce, Aimee, Miller, Joshua W., Ruiz, Agustin, Hofman, Albert, Seeley, William W., Hyman, Bradley T., Schellenberg, Gerard D., Campion, Dominique, Patel, Yogen, Welsh-Bohmer, Kathleen A., Martiniuk, Frank, Moreno-Grau, Sonia, Funk, Cory C., Hamilton-Nelson, Kara L., Cribbs, David H., Chakrabarty, Paramita, Keller, Lina, Golde, Todd E., Cao, Chuanhai, Petersen, Ronald C., Evans, Denis A., Leverenz, James B., Frosch, Matthew P., Laferla, Frank M., Pericak-Vance, Margaret A., Woltjer, Randall L., Smith, Albert V., Rogaeva, Ekaterina, Fenoglio, Chiara, Lyketsos, Constantine G., Sussams, Rebecca, Kamboh, M Ilyas, Becker, James T., Mayeux, Richard, Raybould, Rachel, Alvarez, Victoria, Yu, Lei, O'Bryant, Sid, Kim, Ronald, Vinters, Harry V., Aspelund, Thor, Lieberman, Andrew P., Vardarajan, Badri N., Tzourio, Christophe, Tsuang, Debby W., Albert, Marilyn S., Hodges, Angela, Honig, Lawrence S., Sonnen, Joshua A., Hughes, Joseph T., Sacchinelli, Eleonora, Pankratz, Vernon S., Koivisto, Anne Maria, Sleegers, Kristel, Dickson, Dennis W, Vronskaya, Maria, Mead, Simon, Rosenberg, Roger N., Boccardi, Virginia, Graff-Radford, Neill R., Sotolongo-Grau, Oscar, Maier, Wolfgang, Gerrish, Amy, Peskind, Elaine, O'Donnell, Christopher J., Carroll, Steven L., Masullo, Carlo, Garcia, Florentino Sanchez, Sano, Mary, Schmidt, Reinhold, Vonsattel, Jean Paul, Raskind, Murray, McCurry, Susan M., Reitz, Christiane, Dermecourt, Vincent, Hannequin, Didier, Lynch, Aoibhinn, Adams, Perrie M., Gill, Michael, Ahmad, Shahzad, Bacq, Delphine, Stern, Robert A., Burke, James R., Hakonarson, Hakon, Naj, Adam C, Fallon, Kenneth B., De Deyn, Peter P., Masliah, Eliezer, Brundin, Rosemarie, Dubois, Bruno, Schneider, Lon S., Morris, John C., Holmes, Clive, Lunetta, Kathryn L., Duara, Ranjan, Boeve, Bradley F., Larson, Eric B., Fornage, Myriam, Lopez, Oscar L., Lupton, Michelle K., Winslow, Ashley R., Giegling, Ina, Spina, Salvatore, Nöthen, Markus M., Paulson, Henry L., Uphill, James, Blacker, Deborah, Arnold, Steven E., Jakobsdottir, Johanna, Li, Hongdong, Choi, Seung-Hoan, Arcaro, Marina, Dupuis, Josée, Schmidt, Helena, Majounie, Elisa, Powell, John, Pichler, Sabrina, Thornton-Wells, Tricia A., Foroud, Tatiana M., Carlson, Chris S., Jessen, Frank, Boerwinkle, Eric, Younkin, Steven G., Amin, Najaf, Van Deerlin, Vivianna M., Ferris, Steven, Leber, Markus, Thomas, Charlene, Johnston, Janet, Whitehead, Patrice, Dombroski, Beth, Kaye, Jeffrey A., Royall, Donald R., Engelborghs, Sebastien, Spalletta, Gianfranco, Hoffmann, Per, Marshall, Rachel, Orfei, Maria Donata, Bellenguez, Céline, Beach, Thomas G., Haapasalo, Annakaisa, Perry, William, Cecchetti, Roberta, Blesa, Rafael, Bullido, María J., Daniele, Antonio, Fievet, Nathalie, Troncoso, Juan C., Chui, Helena C., Benito, Yoland Aladro, Grove, Megan L., Lord, Jenny, Daniilidou, Makrina, Cairns, Nigel J., Cupples, L Adrienne, Tanzi, Rudolph E., Lipton, Richard B., Galimberti, Daniela, Parisi, Joseph E., Garcia, Melissa E., Ciaramella, Antonio, Mesulam, Marsel, Bigio, Eileen H., Tschanz, Joann, Fernadez, Carmen Muñoz, Giedraitis, Vilmantas, Van Eldik, Linda J., Weintraub, Sandra, Karydas, Anna, Burns, Jeffrey M., Van Duijn, Cornelia M., Farrer, Lindsay A., Derbois, Céline, Combarros, Onofre, Growdon, John H., Satizabal, Claudia L., Escott-Price, Valentina, Ritchie, Karen, Kinhult-Stählbom, Anne, Braddel, Amy, Barnes, Lisa L., Diaz, Carolina Ceballos, Morgan, Kevin, Kramer, Joel H., Ingelsson, Martin, Williams, Julie, Boxer, Adam, Caffarra, Paolo, Aguilar, Miquel, Barral, Sandra, Doody, Rachelle S., Hiltunen, Mikko, Ortega-Cubero, Sara, Concari, Letizia, Passmore, Peter, Huebinger, Ryan M., Sánchez-Juan, Pascual, Fardo, David W., Olichney, John M., Dichgans, Martin, Lambert, Jean-Charles, Gu, Wei, Hardy, John, Gallo, Maura, Lannfelt, Lars, Allen, Mariet, Yang, Qiong, Behrens, Timothy W., Uitterlinden, Andre G., Adams, Hieab H, Henández, Isabel, Levy, Daniel, Cantwell, Laura B., Hulette, Christine M., Lin, Honghuang, Crocco, Elizabeth A., Deleuze, Jean-François, Keene, C Dirk, De Jager, Philip L, Boada, Merce, Soininen, Hilkka, Olaso, Robert, Mayhaus, Manuel, Maletta, Raffaele Giovanni, Graham, Robert R, Trojanowski, John Q., Mancuso, Michelangelo, Mash, Deborah C., Golamaully, Feroze, Naranjo, Maria Candida Deniz, Hamilton, Ronald L., Wang, Xue, Kowall, Neil W., Fox, Nick C., Valladares, Otto, Buxbaum, Joseph D., Bis, Joshua C., Quinn, Joseph F., Martin, Eden R., Brice, Alexis, Cupidi, Chiara, Farlow, Martin R., Wright, Clinton B., Badarinarayan, Nandini, Kukull, Walter A., Price, Nathan D., Hanon, Olivier, Mosley, Thomas H., Chen, Yuning, Proitsi, Petra, Swerdlow, Russell H., Al-Chalabi, Ammar, Williamson, Jennifer, Murrell, Jill R., Panza, Francesco, Boland, Anne, Wolters, Frank J, Rosen, Howard J., Dulary, Cécile, Goate, Alison M., Li, Shuo, Hampel, Harald, Pasquier, Florence, Clark, David G., Schneider, Julie A., Jr, W T Longstreth, Todd, Stephen, Roberson, Erik D., Bird, Thomas D., Lleó, Alberto, Bowen, James D., Reisch, Joan S., Fairchild, Thomas J., Malamon, John, Bosco, Paolo, Garzia, Fabienne, Marson, Daniel C., Reiman, Eric M., Bossù, Paola, Kuzma, Amanda B., Kloszewska, Iwona, Apostolova, Liana G., Carrell, David, Mecocci, Patrizia, Ertekin-Taner, Nilufer, Wilhelmsen, Kirk C., Miller, Carol A., Ghetti, Bernardino, Montine, Thomas J., Kilander, Lena, Jones, Lesley, Lovestone, Simon, Gilbert, John R., Forstner, Andreas J., Wang, Li-San, Smith, Amanda G., Decarli, Charles, Tarraga, Lluis, Seshadri, Sudha, Rivadeneira, Fernando, Crane, Paul K., Helisalmi, Seppo, Squassina, Alessio, Heun, Reinhard, Bonuccelli, Ubaldo, Amouyel, Philippe, Ringman, John M., Destefano, Anita L., Myers, Amanda J., Meggy, Alun, Van Der Lee, Sven J, White, Charles C., Lah, James J., McGuinness, Bernadette, Rubinsztein, David C, Bruni, Amalia Cecilia, Seripa, Davide, Denning, Nicola, Baldwin, Clinton T., Caltagirone, Carlo, Huentelman, Matthew J., Albin, Roger L., Rujescu, Dan, Solfrizzi, Vincenzo, Bennett, David A., Harrell, Lindy E., Herms, Stefan, Faber, Kelley M., Geschwind, Daniel H., Asthana, Sanjay, Beecham, Gary W., Barber, Robert C., Fortea, Juan, Poon, Wayne W., Jian, Xueqiu, Moebus, Susanne, O'Donovan, Michael C., Abner, Erin, Fitzpatrick, Annette L., Mukherjee, Shubhabrata, Wu, Chuang-Kuo, Lawlor, Brian, Guerreiro, Rita, Vandenberghe, Rik, Sims, Rebecca, Kunkle, Brian W., Dartigues, Jean-François, Munger, Ron, Medway, Christopher, Wingo, Thomas S., Li, Ge, Scherer, Martin, and Cruchaga, Carlos
- Subjects
3. Good health - Abstract
We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P
7. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease.
- Author
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Sims R, van der Lee SJ, Naj AC, Bellenguez C, Badarinarayan N, Jakobsdottir J, Kunkle BW, Boland A, Raybould R, Bis JC, Martin ER, Grenier-Boley B, Heilmann-Heimbach S, Chouraki V, Kuzma AB, Sleegers K, Vronskaya M, Ruiz A, Graham RR, Olaso R, Hoffmann P, Grove ML, Vardarajan BN, Hiltunen M, Nöthen MM, White CC, Hamilton-Nelson KL, Epelbaum J, Maier W, Choi SH, Beecham GW, Dulary C, Herms S, Smith AV, Funk CC, Derbois C, Forstner AJ, Ahmad S, Li H, Bacq D, Harold D, Satizabal CL, Valladares O, Squassina A, Thomas R, Brody JA, Qu L, Sánchez-Juan P, Morgan T, Wolters FJ, Zhao Y, Garcia FS, Denning N, Fornage M, Malamon J, Naranjo MCD, Majounie E, Mosley TH, Dombroski B, Wallon D, Lupton MK, Dupuis J, Whitehead P, Fratiglioni L, Medway C, Jian X, Mukherjee S, Keller L, Brown K, Lin H, Cantwell LB, Panza F, McGuinness B, Moreno-Grau S, Burgess JD, Solfrizzi V, Proitsi P, Adams HH, Allen M, Seripa D, Pastor P, Cupples LA, Price ND, Hannequin D, Frank-García A, Levy D, Chakrabarty P, Caffarra P, Giegling I, Beiser AS, Giedraitis V, Hampel H, Garcia ME, Wang X, Lannfelt L, Mecocci P, Eiriksdottir G, Crane PK, Pasquier F, Boccardi V, Henández I, Barber RC, Scherer M, Tarraga L, Adams PM, Leber M, Chen Y, Albert MS, Riedel-Heller S, Emilsson V, Beekly D, Braae A, Schmidt R, Blacker D, Masullo C, Schmidt H, Doody RS, Spalletta G, Longstreth WT Jr, Fairchild TJ, Bossù P, Lopez OL, Frosch MP, Sacchinelli E, Ghetti B, Yang Q, Huebinger RM, Jessen F, Li S, Kamboh MI, Morris J, Sotolongo-Grau O, Katz MJ, Corcoran C, Dunstan M, Braddel A, Thomas C, Meggy A, Marshall R, Gerrish A, Chapman J, Aguilar M, Taylor S, Hill M, Fairén MD, Hodges A, Vellas B, Soininen H, Kloszewska I, Daniilidou M, Uphill J, Patel Y, Hughes JT, Lord J, Turton J, Hartmann AM, Cecchetti R, Fenoglio C, Serpente M, Arcaro M, Caltagirone C, Orfei MD, Ciaramella A, Pichler S, Mayhaus M, Gu W, Lleó A, Fortea J, Blesa R, Barber IS, Brookes K, Cupidi C, Maletta RG, Carrell D, Sorbi S, Moebus S, Urbano M, Pilotto A, Kornhuber J, Bosco P, Todd S, Craig D, Johnston J, Gill M, Lawlor B, Lynch A, Fox NC, Hardy J, Albin RL, Apostolova LG, Arnold SE, Asthana S, Atwood CS, Baldwin CT, Barnes LL, Barral S, Beach TG, Becker JT, Bigio EH, Bird TD, Boeve BF, Bowen JD, Boxer A, Burke JR, Burns JM, Buxbaum JD, Cairns NJ, Cao C, Carlson CS, Carlsson CM, Carney RM, Carrasquillo MM, Carroll SL, Diaz CC, Chui HC, Clark DG, Cribbs DH, Crocco EA, DeCarli C, Dick M, Duara R, Evans DA, Faber KM, Fallon KB, Fardo DW, Farlow MR, Ferris S, Foroud TM, Galasko DR, Gearing M, Geschwind DH, Gilbert JR, Graff-Radford NR, Green RC, Growdon JH, Hamilton RL, Harrell LE, Honig LS, Huentelman MJ, Hulette CM, Hyman BT, Jarvik GP, Abner E, Jin LW, Jun G, Karydas A, Kaye JA, Kim R, Kowall NW, Kramer JH, LaFerla FM, Lah JJ, Leverenz JB, Levey AI, Li G, Lieberman AP, Lunetta KL, Lyketsos CG, Marson DC, Martiniuk F, Mash DC, Masliah E, McCormick WC, McCurry SM, McDavid AN, McKee AC, Mesulam M, Miller BL, Miller CA, Miller JW, Morris JC, Murrell JR, Myers AJ, O'Bryant S, Olichney JM, Pankratz VS, Parisi JE, Paulson HL, Perry W, Peskind E, Pierce A, Poon WW, Potter H, Quinn JF, Raj A, Raskind M, Reisberg B, Reitz C, Ringman JM, Roberson ED, Rogaeva E, Rosen HJ, Rosenberg RN, Sager MA, Saykin AJ, Schneider JA, Schneider LS, Seeley WW, Smith AG, Sonnen JA, Spina S, Stern RA, Swerdlow RH, Tanzi RE, Thornton-Wells TA, Trojanowski JQ, Troncoso JC, Van Deerlin VM, Van Eldik LJ, Vinters HV, Vonsattel JP, Weintraub S, Welsh-Bohmer KA, Wilhelmsen KC, Williamson J, Wingo TS, Woltjer RL, Wright CB, Yu CE, Yu L, Garzia F, Golamaully F, Septier G, Engelborghs S, Vandenberghe R, De Deyn PP, Fernadez CM, Benito YA, Thonberg H, Forsell C, Lilius L, Kinhult-Stählbom A, Kilander L, Brundin R, Concari L, Helisalmi S, Koivisto AM, Haapasalo A, Dermecourt V, Fievet N, Hanon O, Dufouil C, Brice A, Ritchie K, Dubois B, Himali JJ, Keene CD, Tschanz J, Fitzpatrick AL, Kukull WA, Norton M, Aspelund T, Larson EB, Munger R, Rotter JI, Lipton RB, Bullido MJ, Hofman A, Montine TJ, Coto E, Boerwinkle E, Petersen RC, Alvarez V, Rivadeneira F, Reiman EM, Gallo M, O'Donnell CJ, Reisch JS, Bruni AC, Royall DR, Dichgans M, Sano M, Galimberti D, St George-Hyslop P, Scarpini E, Tsuang DW, Mancuso M, Bonuccelli U, Winslow AR, Daniele A, Wu CK, Peters O, Nacmias B, Riemenschneider M, Heun R, Brayne C, Rubinsztein DC, Bras J, Guerreiro R, Al-Chalabi A, Shaw CE, Collinge J, Mann D, Tsolaki M, Clarimón J, Sussams R, Lovestone S, O'Donovan MC, Owen MJ, Behrens TW, Mead S, Goate AM, Uitterlinden AG, Holmes C, Cruchaga C, Ingelsson M, Bennett DA, Powell J, Golde TE, Graff C, De Jager PL, Morgan K, Ertekin-Taner N, Combarros O, Psaty BM, Passmore P, Younkin SG, Berr C, Gudnason V, Rujescu D, Dickson DW, Dartigues JF, DeStefano AL, Ortega-Cubero S, Hakonarson H, Campion D, Boada M, Kauwe JK, Farrer LA, Van Broeckhoven C, Ikram MA, Jones L, Haines JL, Tzourio C, Launer LJ, Escott-Price V, Mayeux R, Deleuze JF, Amin N, Holmans PA, Pericak-Vance MA, Amouyel P, van Duijn CM, Ramirez A, Wang LS, Lambert JC, Seshadri S, Williams J, and Schellenberg GD
- Subjects
- Amino Acid Sequence, Case-Control Studies, Exome genetics, Gene Expression Profiling, Gene Frequency, Genetic Predisposition to Disease genetics, Genotype, Humans, Linkage Disequilibrium, Odds Ratio, Protein Interaction Maps genetics, Sequence Homology, Amino Acid, Adaptor Proteins, Signal Transducing genetics, Alzheimer Disease genetics, Immunity, Innate genetics, Membrane Glycoproteins genetics, Microglia metabolism, Phospholipase C gamma genetics, Polymorphism, Single Nucleotide, Receptors, Immunologic genetics
- 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
- Full Text
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