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

Rebecca Sims, Sven J. Van Der Lee, Adam C. Naj, Céline Bellenguez, Nandini Badarinarayan, Johanna Jakobsdottir, Brian W. Kunkle, Anne Boland, Rachel Raybould, Joshua C. Bis, Eden R. Martin, Benjamin Grenier-Boley, Stefanie Heilmann-Heimbach, Vincent Chouraki, Amanda B. Kuzma, Kristel Sleegers, Maria Vronskaya, Agustin Ruiz, Robert R. Graham, Robert OlasoPer Hoffmann, Megan L. Grove, Badri N. Vardarajan, Mikko Hiltunen, Markus M. Nöthen, Charles C. White, Kara L. Hamilton-Nelson, Jacques Epelbaum, Wolfgang Maier, Seung Hoan Choi, Gary W. Beecham, Cécile Dulary, Stefan Herms, Albert V. Smith, Cory C. Funk, Céline Derbois, Andreas J. Forstner, Shahzad Ahmad, Hongdong Li, Delphine Bacq, Denise Harold, Claudia L. Satizabal, Otto Valladares, Alessio Squassina, Rhodri Thomas, Jennifer A. Brody, Liming Qu, Pascual Sánchez-Juan, Taniesha Morgan, Frank J. Wolters, Yi Zhao, Florentino Sanchez Garcia, Nicola Denning, Myriam Fornage, John Malamon, Maria Candida Deniz Naranjo, Elisa Majounie, Thomas H. Mosley, Beth Dombroski, David Wallon, Michelle K. Lupton, Josée Dupuis, Patrice Whitehead, Laura Fratiglioni, Christopher Medway, Xueqiu Jian, Shubhabrata Mukherjee, Lina Keller, Kristelle Brown, Honghuang Lin, Laura B. Cantwell, Francesco Panza, Bernadette McGuinness, Sonia Moreno-Grau, Jeremy D. Burgess, Vincenzo Solfrizzi, Petra Proitsi, Hieab H. Adams, Mariet Allen, Davide Seripa, Pau Pastor, L. Adrienne Cupples, Nathan D. Price, Didier Hannequin, Ana Frank-García, Daniel Levy, Paramita Chakrabarty, Paolo Caffarra, Ina Giegling, Alexa S. Beiser, Vilmantas Giedraitis, Harald Hampel, Melissa E. Garcia, Xue Wang, Lars Lannfelt, Patrizia Mecocci, Gudny Eiriksdottir, Paul K. Crane, Florence Pasquier, Virginia Boccardi, Isabel Henández, Robert C. Barber, Martin Scherer, Lluis Tarraga, Perrie M. Adams, Markus Leber, Yuning Chen, Marilyn S. Albert, Steffi Riedel-Heller, Valur Emilsson, Duane Beekly, Anne Braae, Reinhold Schmidt, Deborah Blacker, Carlo Masullo, Helena Schmidt, Rachelle S. Doody, Gianfranco Spalletta, W. T.Longstreth Jr, Thomas J. Fairchild, Paola Bossù, Oscar L. Lopez, Matthew P. Frosch, Eleonora Sacchinelli, Bernardino Ghetti, Qiong Yang, Ryan M. Huebinger, Frank Jessen, Shuo Li, M. Ilyas Kamboh, John Morris, Oscar Sotolongo-Grau, Mindy Joy Katz, Chris Corcoran, Melanie Dunstan, Amy Braddel, Charlene Thomas, Alun Meggy, Rachel Marshall, Amy Gerrish, Jade Chapman, Miquel Aguilar, Sarah Taylor, Matt Hill, Mònica Díez Fairén, Angela Hodges, Bruno Vellas, Hilkka Soininen, Iwona Kloszewska, Makrina Daniilidou, James Uphill, Yogen Patel, Joseph T. Hughes, Jenny Lord, James Turton, Annette M. Hartmann, Roberta Cecchetti, Chiara Fenoglio, Maria Serpente, Marina Arcaro, Carlo Caltagirone, Maria Donata Orfei, Antonio Ciaramella, Sabrina Pichler, Manuel Mayhaus, Wei Gu, Alberto Lleó, Juan Fortea, Rafael Blesa, Imelda S. Barber, Keeley Brookes, Chiara Cupidi, Raffaele Giovanni Maletta, David Carrell, Sandro Sorbi, Susanne Moebus, Maria Urbano, Alberto Pilotto, Johannes Kornhuber, Paolo Bosco, Stephen Todd, David Craig, Janet Johnston, Michael Gill, Brian Lawlor, Aoibhinn Lynch, Nick C. Fox, John Hardy, Roger L. Albin, Liana G. Apostolova, Steven E. Arnold, Sanjay Asthana, Craig S. Atwood, Clinton T. Baldwin, Lisa L. Barnes, Sandra Barral, Thomas G. Beach, James T. Becker, Eileen H. Bigio, Thomas D. Bird, Bradley F. Boeve, James D. Bowen, Adam Boxer, James R. Burke, Jeffrey M. Burns, Joseph D. Buxbaum, Nigel J. Cairns, Chuanhai Cao, Chris S. Carlson, Cynthia M. Carlsson, Regina M. Carney, Minerva M. Carrasquillo, Steven L. Carroll, Carolina Ceballos Diaz, Helena C. Chui, David G. Clark, David H. Cribbs, Elizabeth A. Crocco, Charles Decarli, Malcolm Dick, Ranjan Duara, Denis A. Evans, Kelley M. Faber, Kenneth B. Fallon, David W. Fardo, Martin R. Farlow, Steven Ferris, Tatiana M. Foroud, Douglas R. Galasko, Marla Gearing, Daniel H. Geschwind, John R. Gilbert, Neill R. Graff-Radford, Robert C. Green, John H. Growdon, Ronald L. Hamilton, Lindy E. Harrell, Lawrence S. Honig, Matthew J. Huentelman, Christine M. Hulette, Bradley T. Hyman, Gail P. Jarvik, Erin Abner, Lee Way Jin, Gyungah Jun, Anna Karydas, Jeffrey A. Kaye, Ronald Kim, Neil W. Kowall, Joel H. Kramer, Frank M. Laferla, James J. Lah, James B. Leverenz, Allan I. Levey, Ge Li, Andrew P. Lieberman, Kathryn L. Lunetta, Constantine G. Lyketsos, Daniel C. Marson, Frank Martiniuk, Deborah C. Mash, Eliezer Masliah, Wayne C. McCormick, Susan M. McCurry, Andrew N. McDavid, Ann C. McKee, Marsel Mesulam, Bruce L. Miller, Carol A. Miller, Joshua W. Miller, John C. Morris, Jill R. Murrell, Amanda J. Myers, Sid O'Bryant, John M. Olichney, Vernon S. Pankratz, Joseph E. Parisi, Henry L. Paulson, William Perry, Elaine Peskind, Aimee Pierce, Wayne W. Poon, Huntington Potter, Joseph F. Quinn, Ashok Raj, Murray Raskind, Barry Reisberg, Christiane Reitz, John M. Ringman, Erik D. Roberson, Ekaterina Rogaeva, Howard J. Rosen, Roger N. Rosenberg, Mark A. Sager, Andrew J. Saykin, Julie A. Schneider, Lon S. Schneider, William W. Seeley, Amanda G. Smith, Joshua A. Sonnen, Salvatore Spina, Robert A. Stern, Russell H. Swerdlow, Rudolph E. Tanzi, Tricia A. Thornton-Wells, John Q. Trojanowski, Juan C. Troncoso, Vivianna M. Van Deerlin, Linda J. Van Eldik, Harry V. Vinters, Jean Paul Vonsattel, Sandra Weintraub, Kathleen A. Welsh-Bohmer, Kirk C. Wilhelmsen, Jennifer Williamson, Thomas S. Wingo, Randall L. Woltjer, Clinton B. Wright, Chang En Yu, Lei Yu, Fabienne Garzia, Feroze Golamaully, Gislain Septier, Sebastien Engelborghs, Rik Vandenberghe, Peter P. De Deyn, Carmen Muñoz Fernadez, Yoland Aladro Benito, Hakan Thonberg, Charlotte Forsell, Lena Lilius, Anne Kinhult-Stählbom, Lena Kilander, Rosemarie Brundin, Letizia Concari, Seppo Helisalmi, Anne Maria Koivisto, Annakaisa Haapasalo, Vincent Dermecourt, Nathalie Fievet, Olivier Hanon, Carole Dufouil, Alexis Brice, Karen Ritchie, Bruno Dubois, Jayanadra J. Himali, C. Dirk Keene, Joann Tschanz, Annette L. Fitzpatrick, Walter A. Kukull, Maria Norton, Thor Aspelund, Eric B. Larson, Ron Munger, Richard B. Lipton, Richard B. Lipton, María J. Bullido, Albert Hofman, Thomas J. Montine, Eliecer Coto, Eric Boerwinkle, Ronald C. Petersen, Victoria Alvarez, Fernando Rivadeneira, Eric M. Reiman, Maura Gallo, Christopher J. O'Donnell, Joan S. Reisch, Amalia Cecilia Bruni, Donald R. Royall, Martin Dichgans, Mary Sano, Daniela Galimberti, Peter St George-Hyslop, Elio Scarpini, Debby W. Tsuang, Michelangelo Mancuso, Ubaldo Bonuccelli, Ashley R. Winslow, Antonio Daniele, Chuang Kuo Wu, Oliver Peters, Benedetta Nacmias, Matthias Riemenschneider, Reinhard Heun, Carol Brayne, David C. Rubinsztein, Jose Bras, Rita Guerreiro, Ammar Al-Chalabi, Christopher E. Shaw, John Collinge, David Mann, Magda Tsolaki, Jordi Clarimón, Rebecca Sussams, Simon Lovestone, Michael C. O'Donovan, Michael J. Owen, Timothy W. Behrens, Simon Mead, Alison M. Goate, Andre G. Uitterlinden, Clive Holmes, Carlos Cruchaga, Martin Ingelsson, David A. Bennett, John Powell, Todd E. Golde, Caroline Graff, Philip L. De Jager, Kevin Morgan, Nilufer Ertekin-Taner, Onofre Combarros, Bruce M. Psaty, Peter Passmore, Steven G. Younkin, Claudine Berr, Vilmundur Gudnason, Dan Rujescu, Dennis W. Dickson, Jean François Dartigues, Anita L. Destefano, Sara Ortega-Cubero, Hakon Hakonarson, Dominique Campion, Merce Boada, John Keoni Kauwe, Lindsay A. Farrer, Christine Van Broeckhoven, M. Arfan Ikram, Lesley Jones, Jonathan L. Haines, Christophe Tzourio, Lenore J. Launer, Valentina Escott-Price, Richard Mayeux, Jean François Deleuze, Najaf Amin, Peter A. Holmans, Margaret A. Pericak-Vance, Philippe Amouyel, Cornelia M. Van Duijn, Alfredo Ramirez, Li San Wang, Jean Charles Lambert, Sudha Seshadri, Julie Williams, Gerard D. Schellenberg

Research output: Contribution to journalArticle

176 Citations (Scopus)

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 (rs74905: p.Pro522Arg, P = 5.38 × 10 '10, odds ratio (OR) = 0.68, minor allele frequency (MAF) cases = 0.0059, MAF controls = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10 '10, OR = 1.43, MAF cases = 0.011, MAF controls = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10 '14, OR = 1.67, MAF cases = 0.0143, MAF controls = 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.

Original languageEnglish (US)
Pages (from-to)1373-1384
Number of pages12
JournalNature Genetics
Volume49
Issue number9
DOIs
StatePublished - Sep 1 2017

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Innate Immunity
Gene Frequency
Alzheimer Disease
Odds Ratio
Microglia
Genotype
Genome
Genes
Exome
Protein Interaction Maps
Case-Control Studies
Proteins

ASJC Scopus subject areas

  • Genetics

Cite this

Sims, R., Van Der Lee, S. J., Naj, A. C., Bellenguez, C., Badarinarayan, N., Jakobsdottir, J., ... Schellenberg, G. D. (2017). Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Nature Genetics, 49(9), 1373-1384. https://doi.org/10.1038/ng.3916

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. / 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; Jr, W. T.Longstreth; 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 Joy; 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; 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; Lipton, Richard B.; 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; 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; Schellenberg, Gerard D.

In: Nature Genetics, Vol. 49, No. 9, 01.09.2017, p. 1373-1384.

Research output: Contribution to journalArticle

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, Jr, WTL, 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, Lipton, RB, 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 & Schellenberg, GD 2017, 'Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease', Nature Genetics, vol. 49, no. 9, pp. 1373-1384. https://doi.org/10.1038/ng.3916
Sims R, Van Der Lee SJ, Naj AC, Bellenguez C, Badarinarayan N, Jakobsdottir J et al. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Nature Genetics. 2017 Sep 1;49(9):1373-1384. https://doi.org/10.1038/ng.3916
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 ; Jr, W. T.Longstreth ; 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 Joy ; 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 ; 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 ; Lipton, Richard B. ; 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 ; 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 ; Schellenberg, Gerard D. / Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. In: Nature Genetics. 2017 ; Vol. 49, No. 9. pp. 1373-1384.
@article{3bab440827c0408b8e9f36a9da123b0a,
title = "Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease",
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 (rs74905: p.Pro522Arg, P = 5.38 × 10 '10, odds ratio (OR) = 0.68, minor allele frequency (MAF) cases = 0.0059, MAF controls = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10 '10, OR = 1.43, MAF cases = 0.011, MAF controls = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10 '14, OR = 1.67, MAF cases = 0.0143, MAF controls = 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.",
author = "Rebecca Sims and {Van Der Lee}, {Sven J.} and Naj, {Adam C.} and C{\'e}line Bellenguez and Nandini Badarinarayan and Johanna Jakobsdottir and Kunkle, {Brian W.} and Anne Boland and Rachel Raybould and Bis, {Joshua C.} and Martin, {Eden R.} and Benjamin Grenier-Boley and Stefanie Heilmann-Heimbach and Vincent Chouraki and Kuzma, {Amanda B.} and Kristel Sleegers and Maria Vronskaya and Agustin Ruiz and Graham, {Robert R.} and Robert Olaso and Per Hoffmann and Grove, {Megan L.} and Vardarajan, {Badri N.} and Mikko Hiltunen and N{\"o}then, {Markus M.} and White, {Charles C.} and Hamilton-Nelson, {Kara L.} and Jacques Epelbaum and Wolfgang Maier and Choi, {Seung Hoan} and Beecham, {Gary W.} and C{\'e}cile Dulary and Stefan Herms and Smith, {Albert V.} and Funk, {Cory C.} and C{\'e}line Derbois and Forstner, {Andreas J.} and Shahzad Ahmad and Hongdong Li and Delphine Bacq and Denise Harold and Satizabal, {Claudia L.} and Otto Valladares and Alessio Squassina and Rhodri Thomas and Brody, {Jennifer A.} and Liming Qu and Pascual S{\'a}nchez-Juan and Taniesha Morgan and Wolters, {Frank J.} and Yi Zhao and Garcia, {Florentino Sanchez} and Nicola Denning and Myriam Fornage and John Malamon and Naranjo, {Maria Candida Deniz} and Elisa Majounie and Mosley, {Thomas H.} and Beth Dombroski and David Wallon and Lupton, {Michelle K.} and Jos{\'e}e Dupuis and Patrice Whitehead and Laura Fratiglioni and Christopher Medway and Xueqiu Jian and Shubhabrata Mukherjee and Lina Keller and Kristelle Brown and Honghuang Lin and Cantwell, {Laura B.} and Francesco Panza and Bernadette McGuinness and Sonia Moreno-Grau and Burgess, {Jeremy D.} and Vincenzo Solfrizzi and Petra Proitsi and Adams, {Hieab H.} and Mariet Allen and Davide Seripa and Pau Pastor and Cupples, {L. Adrienne} and Price, {Nathan D.} and Didier Hannequin and Ana Frank-Garc{\'i}a and Daniel Levy and Paramita Chakrabarty and Paolo Caffarra and Ina Giegling and Beiser, {Alexa S.} and Vilmantas Giedraitis and Harald Hampel and Garcia, {Melissa E.} and Xue Wang and Lars Lannfelt and Patrizia Mecocci and Gudny Eiriksdottir and Crane, {Paul K.} and Florence Pasquier and Virginia Boccardi and Isabel Hen{\'a}ndez and Barber, {Robert C.} and Martin Scherer and Lluis Tarraga and Adams, {Perrie M.} and Markus Leber and Yuning Chen and Albert, {Marilyn S.} and Steffi Riedel-Heller and Valur Emilsson and Duane Beekly and Anne Braae and Reinhold Schmidt and Deborah Blacker and Carlo Masullo and Helena Schmidt and Doody, {Rachelle S.} and Gianfranco Spalletta and Jr, {W. T.Longstreth} and Fairchild, {Thomas J.} and Paola Boss{\`u} and Lopez, {Oscar L.} and Frosch, {Matthew P.} and Eleonora Sacchinelli and Bernardino Ghetti and Qiong Yang and Huebinger, {Ryan M.} and Frank Jessen and Shuo Li and Kamboh, {M. Ilyas} and John Morris and Oscar Sotolongo-Grau and Katz, {Mindy Joy} and Chris Corcoran and Melanie Dunstan and Amy Braddel and Charlene Thomas and Alun Meggy and Rachel Marshall and Amy Gerrish and Jade Chapman and Miquel Aguilar and Sarah Taylor and Matt Hill and Fair{\'e}n, {M{\`o}nica D{\'i}ez} and Angela Hodges and Bruno Vellas and Hilkka Soininen and Iwona Kloszewska and Makrina Daniilidou and James Uphill and Yogen Patel and Hughes, {Joseph T.} and Jenny Lord and James Turton and Hartmann, {Annette M.} and Roberta Cecchetti and Chiara Fenoglio and Maria Serpente and Marina Arcaro and Carlo Caltagirone and Orfei, {Maria Donata} and Antonio Ciaramella and Sabrina Pichler and Manuel Mayhaus and Wei Gu and Alberto Lle{\'o} and Juan Fortea and Rafael Blesa and Barber, {Imelda S.} and Keeley Brookes and Chiara Cupidi and Maletta, {Raffaele Giovanni} and David Carrell and Sandro Sorbi and Susanne Moebus and Maria Urbano and Alberto Pilotto and Johannes Kornhuber and Paolo Bosco and Stephen Todd and David Craig and Janet Johnston and Michael Gill and Brian Lawlor and Aoibhinn Lynch and Fox, {Nick C.} and John Hardy and Albin, {Roger L.} and Apostolova, {Liana G.} and Arnold, {Steven E.} and Sanjay Asthana and Atwood, {Craig S.} and Baldwin, {Clinton T.} and Barnes, {Lisa L.} and Sandra Barral and Beach, {Thomas G.} and Becker, {James T.} and Bigio, {Eileen H.} and Bird, {Thomas D.} and Boeve, {Bradley F.} and Bowen, {James D.} and Adam Boxer and Burke, {James R.} and Burns, {Jeffrey M.} and Buxbaum, {Joseph D.} and Cairns, {Nigel J.} and Chuanhai Cao and Carlson, {Chris S.} and Carlsson, {Cynthia M.} and Carney, {Regina M.} and Carrasquillo, {Minerva M.} and Carroll, {Steven L.} and Diaz, {Carolina Ceballos} and Chui, {Helena C.} and Clark, {David G.} and Cribbs, {David H.} and Crocco, {Elizabeth A.} and Charles Decarli and Malcolm Dick and Ranjan Duara and Evans, {Denis A.} and Faber, {Kelley M.} and Fallon, {Kenneth B.} and Fardo, {David W.} and Farlow, {Martin R.} and Steven Ferris and Foroud, {Tatiana M.} and Galasko, {Douglas R.} and Marla Gearing and Geschwind, {Daniel H.} and Gilbert, {John R.} and Graff-Radford, {Neill R.} and Green, {Robert C.} and Growdon, {John H.} and Hamilton, {Ronald L.} and Harrell, {Lindy E.} and Honig, {Lawrence S.} and Huentelman, {Matthew J.} and Hulette, {Christine M.} and Hyman, {Bradley T.} and Jarvik, {Gail P.} and Erin Abner and Jin, {Lee Way} and Gyungah Jun and Anna Karydas and Kaye, {Jeffrey A.} and Ronald Kim and Kowall, {Neil W.} and Kramer, {Joel H.} and Laferla, {Frank M.} and Lah, {James J.} and Leverenz, {James B.} and Levey, {Allan I.} and Ge Li and Lieberman, {Andrew P.} and Lunetta, {Kathryn L.} and Lyketsos, {Constantine G.} and Marson, {Daniel C.} and Frank Martiniuk and Mash, {Deborah C.} and Eliezer Masliah and McCormick, {Wayne C.} and McCurry, {Susan M.} and McDavid, {Andrew N.} and McKee, {Ann C.} and Marsel Mesulam and Miller, {Bruce L.} and Miller, {Carol A.} and Miller, {Joshua W.} and Morris, {John C.} and Murrell, {Jill R.} and Myers, {Amanda J.} and Sid O'Bryant and Olichney, {John M.} and Pankratz, {Vernon S.} and Parisi, {Joseph E.} and Paulson, {Henry L.} and William Perry and Elaine Peskind and Aimee Pierce and Poon, {Wayne W.} and Huntington Potter and Quinn, {Joseph F.} and Ashok Raj and Murray Raskind and Barry Reisberg and Christiane Reitz and Ringman, {John M.} and Roberson, {Erik D.} and Ekaterina Rogaeva and Rosen, {Howard J.} and Rosenberg, {Roger N.} and Sager, {Mark A.} and Saykin, {Andrew J.} and Schneider, {Julie A.} and Schneider, {Lon S.} and Seeley, {William W.} and Smith, {Amanda G.} and Sonnen, {Joshua A.} and Salvatore Spina and Stern, {Robert A.} and Swerdlow, {Russell H.} and Tanzi, {Rudolph E.} and Thornton-Wells, {Tricia A.} and Trojanowski, {John Q.} and Troncoso, {Juan C.} and {Van Deerlin}, {Vivianna M.} and {Van Eldik}, {Linda J.} and Vinters, {Harry V.} and Vonsattel, {Jean Paul} and Sandra Weintraub and Welsh-Bohmer, {Kathleen A.} and Wilhelmsen, {Kirk C.} and Jennifer Williamson and Wingo, {Thomas S.} and Woltjer, {Randall L.} and Wright, {Clinton B.} and Yu, {Chang En} and Lei Yu and Fabienne Garzia and Feroze Golamaully and Gislain Septier and Sebastien Engelborghs and Rik Vandenberghe and {De Deyn}, {Peter P.} and Fernadez, {Carmen Mu{\~n}oz} and Benito, {Yoland Aladro} and Hakan Thonberg and Charlotte Forsell and Lena Lilius and Anne Kinhult-St{\"a}hlbom and Lena Kilander and Rosemarie Brundin and Letizia Concari and Seppo Helisalmi and Koivisto, {Anne Maria} and Annakaisa Haapasalo and Vincent Dermecourt and Nathalie Fievet and Olivier Hanon and Carole Dufouil and Alexis Brice and Karen Ritchie and Bruno Dubois and Himali, {Jayanadra J.} and Keene, {C. Dirk} and Joann Tschanz and Fitzpatrick, {Annette L.} and Kukull, {Walter A.} and Maria Norton and Thor Aspelund and Larson, {Eric B.} and Ron Munger and Lipton, {Richard B.} and Lipton, {Richard B.} and Bullido, {Mar{\'i}a J.} and Albert Hofman and Montine, {Thomas J.} and Eliecer Coto and Eric Boerwinkle and Petersen, {Ronald C.} and Victoria Alvarez and Fernando Rivadeneira and Reiman, {Eric M.} and Maura Gallo and O'Donnell, {Christopher J.} and Reisch, {Joan S.} and Bruni, {Amalia Cecilia} and Royall, {Donald R.} and Martin Dichgans and Mary Sano and Daniela Galimberti and {St George-Hyslop}, Peter and Elio Scarpini and Tsuang, {Debby W.} and Michelangelo Mancuso and Ubaldo Bonuccelli and Winslow, {Ashley R.} and Antonio Daniele and Wu, {Chuang Kuo} and Oliver Peters and Benedetta Nacmias and Matthias Riemenschneider and Reinhard Heun and Carol Brayne and Rubinsztein, {David C.} and Jose Bras and Rita Guerreiro and Ammar Al-Chalabi and Shaw, {Christopher E.} and John Collinge and David Mann and Magda Tsolaki and Jordi Clarim{\'o}n and Rebecca Sussams and Simon Lovestone and O'Donovan, {Michael C.} and Owen, {Michael J.} and Behrens, {Timothy W.} and Simon Mead and Goate, {Alison M.} and Uitterlinden, {Andre G.} and Clive Holmes and Carlos Cruchaga and Martin Ingelsson and Bennett, {David A.} and John Powell and Golde, {Todd E.} and Caroline Graff and {De Jager}, {Philip L.} and Kevin Morgan and Nilufer Ertekin-Taner and Onofre Combarros and Psaty, {Bruce M.} and Peter Passmore and Younkin, {Steven G.} and Claudine Berr and Vilmundur Gudnason and Dan Rujescu and Dickson, {Dennis W.} and Dartigues, {Jean Fran{\cc}ois} and Destefano, {Anita L.} and Sara Ortega-Cubero and Hakon Hakonarson and Dominique Campion and Merce Boada and Kauwe, {John Keoni} and Farrer, {Lindsay A.} and {Van Broeckhoven}, Christine and Ikram, {M. Arfan} and Lesley Jones and Haines, {Jonathan L.} and Christophe Tzourio and Launer, {Lenore J.} and Valentina Escott-Price and Richard Mayeux and Deleuze, {Jean Fran{\cc}ois} and Najaf Amin and Holmans, {Peter A.} and Pericak-Vance, {Margaret A.} and Philippe Amouyel and {Van Duijn}, {Cornelia M.} and Alfredo Ramirez and Wang, {Li San} and Lambert, {Jean Charles} and Sudha Seshadri and Julie Williams and Schellenberg, {Gerard D.}",
year = "2017",
month = "9",
day = "1",
doi = "10.1038/ng.3916",
language = "English (US)",
volume = "49",
pages = "1373--1384",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "9",

}

TY - JOUR

T1 - Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

AU - Sims, Rebecca

AU - Van Der Lee, Sven J.

AU - Naj, Adam C.

AU - Bellenguez, Céline

AU - Badarinarayan, Nandini

AU - Jakobsdottir, Johanna

AU - Kunkle, Brian W.

AU - Boland, Anne

AU - Raybould, Rachel

AU - Bis, Joshua C.

AU - Martin, Eden R.

AU - Grenier-Boley, Benjamin

AU - Heilmann-Heimbach, Stefanie

AU - Chouraki, Vincent

AU - Kuzma, Amanda B.

AU - Sleegers, Kristel

AU - Vronskaya, Maria

AU - Ruiz, Agustin

AU - Graham, Robert R.

AU - Olaso, Robert

AU - Hoffmann, Per

AU - Grove, Megan L.

AU - Vardarajan, Badri N.

AU - Hiltunen, Mikko

AU - Nöthen, Markus M.

AU - White, Charles C.

AU - Hamilton-Nelson, Kara L.

AU - Epelbaum, Jacques

AU - Maier, Wolfgang

AU - Choi, Seung Hoan

AU - Beecham, Gary W.

AU - Dulary, Cécile

AU - Herms, Stefan

AU - Smith, Albert V.

AU - Funk, Cory C.

AU - Derbois, Céline

AU - Forstner, Andreas J.

AU - Ahmad, Shahzad

AU - Li, Hongdong

AU - Bacq, Delphine

AU - Harold, Denise

AU - Satizabal, Claudia L.

AU - Valladares, Otto

AU - Squassina, Alessio

AU - Thomas, Rhodri

AU - Brody, Jennifer A.

AU - Qu, Liming

AU - Sánchez-Juan, Pascual

AU - Morgan, Taniesha

AU - Wolters, Frank J.

AU - Zhao, Yi

AU - Garcia, Florentino Sanchez

AU - Denning, Nicola

AU - Fornage, Myriam

AU - Malamon, John

AU - Naranjo, Maria Candida Deniz

AU - Majounie, Elisa

AU - Mosley, Thomas H.

AU - Dombroski, Beth

AU - Wallon, David

AU - Lupton, Michelle K.

AU - Dupuis, Josée

AU - Whitehead, Patrice

AU - Fratiglioni, Laura

AU - Medway, Christopher

AU - Jian, Xueqiu

AU - Mukherjee, Shubhabrata

AU - Keller, Lina

AU - Brown, Kristelle

AU - Lin, Honghuang

AU - Cantwell, Laura B.

AU - Panza, Francesco

AU - McGuinness, Bernadette

AU - Moreno-Grau, Sonia

AU - Burgess, Jeremy D.

AU - Solfrizzi, Vincenzo

AU - Proitsi, Petra

AU - Adams, Hieab H.

AU - Allen, Mariet

AU - Seripa, Davide

AU - Pastor, Pau

AU - Cupples, L. Adrienne

AU - Price, Nathan D.

AU - Hannequin, Didier

AU - Frank-García, Ana

AU - Levy, Daniel

AU - Chakrabarty, Paramita

AU - Caffarra, Paolo

AU - Giegling, Ina

AU - Beiser, Alexa S.

AU - Giedraitis, Vilmantas

AU - Hampel, Harald

AU - Garcia, Melissa E.

AU - Wang, Xue

AU - Lannfelt, Lars

AU - Mecocci, Patrizia

AU - Eiriksdottir, Gudny

AU - Crane, Paul K.

AU - Pasquier, Florence

AU - Boccardi, Virginia

AU - Henández, Isabel

AU - Barber, Robert C.

AU - Scherer, Martin

AU - Tarraga, Lluis

AU - Adams, Perrie M.

AU - Leber, Markus

AU - Chen, Yuning

AU - Albert, Marilyn S.

AU - Riedel-Heller, Steffi

AU - Emilsson, Valur

AU - Beekly, Duane

AU - Braae, Anne

AU - Schmidt, Reinhold

AU - Blacker, Deborah

AU - Masullo, Carlo

AU - Schmidt, Helena

AU - Doody, Rachelle S.

AU - Spalletta, Gianfranco

AU - Jr, W. T.Longstreth

AU - Fairchild, Thomas J.

AU - Bossù, Paola

AU - Lopez, Oscar L.

AU - Frosch, Matthew P.

AU - Sacchinelli, Eleonora

AU - Ghetti, Bernardino

AU - Yang, Qiong

AU - Huebinger, Ryan M.

AU - Jessen, Frank

AU - Li, Shuo

AU - Kamboh, M. Ilyas

AU - Morris, John

AU - Sotolongo-Grau, Oscar

AU - Katz, Mindy Joy

AU - Corcoran, Chris

AU - Dunstan, Melanie

AU - Braddel, Amy

AU - Thomas, Charlene

AU - Meggy, Alun

AU - Marshall, Rachel

AU - Gerrish, Amy

AU - Chapman, Jade

AU - Aguilar, Miquel

AU - Taylor, Sarah

AU - Hill, Matt

AU - Fairén, Mònica Díez

AU - Hodges, Angela

AU - Vellas, Bruno

AU - Soininen, Hilkka

AU - Kloszewska, Iwona

AU - Daniilidou, Makrina

AU - Uphill, James

AU - Patel, Yogen

AU - Hughes, Joseph T.

AU - Lord, Jenny

AU - Turton, James

AU - Hartmann, Annette M.

AU - Cecchetti, Roberta

AU - Fenoglio, Chiara

AU - Serpente, Maria

AU - Arcaro, Marina

AU - Caltagirone, Carlo

AU - Orfei, Maria Donata

AU - Ciaramella, Antonio

AU - Pichler, Sabrina

AU - Mayhaus, Manuel

AU - Gu, Wei

AU - Lleó, Alberto

AU - Fortea, Juan

AU - Blesa, Rafael

AU - Barber, Imelda S.

AU - Brookes, Keeley

AU - Cupidi, Chiara

AU - Maletta, Raffaele Giovanni

AU - Carrell, David

AU - Sorbi, Sandro

AU - Moebus, Susanne

AU - Urbano, Maria

AU - Pilotto, Alberto

AU - Kornhuber, Johannes

AU - Bosco, Paolo

AU - Todd, Stephen

AU - Craig, David

AU - Johnston, Janet

AU - Gill, Michael

AU - Lawlor, Brian

AU - Lynch, Aoibhinn

AU - Fox, Nick C.

AU - Hardy, John

AU - Albin, Roger L.

AU - Apostolova, Liana G.

AU - Arnold, Steven E.

AU - Asthana, Sanjay

AU - Atwood, Craig S.

AU - Baldwin, Clinton T.

AU - Barnes, Lisa L.

AU - Barral, Sandra

AU - Beach, Thomas G.

AU - Becker, James T.

AU - Bigio, Eileen H.

AU - Bird, Thomas D.

AU - Boeve, Bradley F.

AU - Bowen, James D.

AU - Boxer, Adam

AU - Burke, James R.

AU - Burns, Jeffrey M.

AU - Buxbaum, Joseph D.

AU - Cairns, Nigel J.

AU - Cao, Chuanhai

AU - Carlson, Chris S.

AU - Carlsson, Cynthia M.

AU - Carney, Regina M.

AU - Carrasquillo, Minerva M.

AU - Carroll, Steven L.

AU - Diaz, Carolina Ceballos

AU - Chui, Helena C.

AU - Clark, David G.

AU - Cribbs, David H.

AU - Crocco, Elizabeth A.

AU - Decarli, Charles

AU - Dick, Malcolm

AU - Duara, Ranjan

AU - Evans, Denis A.

AU - Faber, Kelley M.

AU - Fallon, Kenneth B.

AU - Fardo, David W.

AU - Farlow, Martin R.

AU - Ferris, Steven

AU - Foroud, Tatiana M.

AU - Galasko, Douglas R.

AU - Gearing, Marla

AU - Geschwind, Daniel H.

AU - Gilbert, John R.

AU - Graff-Radford, Neill R.

AU - Green, Robert C.

AU - Growdon, John H.

AU - Hamilton, Ronald L.

AU - Harrell, Lindy E.

AU - Honig, Lawrence S.

AU - Huentelman, Matthew J.

AU - Hulette, Christine M.

AU - Hyman, Bradley T.

AU - Jarvik, Gail P.

AU - Abner, Erin

AU - Jin, Lee Way

AU - Jun, Gyungah

AU - Karydas, Anna

AU - Kaye, Jeffrey A.

AU - Kim, Ronald

AU - Kowall, Neil W.

AU - Kramer, Joel H.

AU - Laferla, Frank M.

AU - Lah, James J.

AU - Leverenz, James B.

AU - Levey, Allan I.

AU - Li, Ge

AU - Lieberman, Andrew P.

AU - Lunetta, Kathryn L.

AU - Lyketsos, Constantine G.

AU - Marson, Daniel C.

AU - Martiniuk, Frank

AU - Mash, Deborah C.

AU - Masliah, Eliezer

AU - McCormick, Wayne C.

AU - McCurry, Susan M.

AU - McDavid, Andrew N.

AU - McKee, Ann C.

AU - Mesulam, Marsel

AU - Miller, Bruce L.

AU - Miller, Carol A.

AU - Miller, Joshua W.

AU - Morris, John C.

AU - Murrell, Jill R.

AU - Myers, Amanda J.

AU - O'Bryant, Sid

AU - Olichney, John M.

AU - Pankratz, Vernon S.

AU - Parisi, Joseph E.

AU - Paulson, Henry L.

AU - Perry, William

AU - Peskind, Elaine

AU - Pierce, Aimee

AU - Poon, Wayne W.

AU - Potter, Huntington

AU - Quinn, Joseph F.

AU - Raj, Ashok

AU - Raskind, Murray

AU - Reisberg, Barry

AU - Reitz, Christiane

AU - Ringman, John M.

AU - Roberson, Erik D.

AU - Rogaeva, Ekaterina

AU - Rosen, Howard J.

AU - Rosenberg, Roger N.

AU - Sager, Mark A.

AU - Saykin, Andrew J.

AU - Schneider, Julie A.

AU - Schneider, Lon S.

AU - Seeley, William W.

AU - Smith, Amanda G.

AU - Sonnen, Joshua A.

AU - Spina, Salvatore

AU - Stern, Robert A.

AU - Swerdlow, Russell H.

AU - Tanzi, Rudolph E.

AU - Thornton-Wells, Tricia A.

AU - Trojanowski, John Q.

AU - Troncoso, Juan C.

AU - Van Deerlin, Vivianna M.

AU - Van Eldik, Linda J.

AU - Vinters, Harry V.

AU - Vonsattel, Jean Paul

AU - Weintraub, Sandra

AU - Welsh-Bohmer, Kathleen A.

AU - Wilhelmsen, Kirk C.

AU - Williamson, Jennifer

AU - Wingo, Thomas S.

AU - Woltjer, Randall L.

AU - Wright, Clinton B.

AU - Yu, Chang En

AU - Yu, Lei

AU - Garzia, Fabienne

AU - Golamaully, Feroze

AU - Septier, Gislain

AU - Engelborghs, Sebastien

AU - Vandenberghe, Rik

AU - De Deyn, Peter P.

AU - Fernadez, Carmen Muñoz

AU - Benito, Yoland Aladro

AU - Thonberg, Hakan

AU - Forsell, Charlotte

AU - Lilius, Lena

AU - Kinhult-Stählbom, Anne

AU - Kilander, Lena

AU - Brundin, Rosemarie

AU - Concari, Letizia

AU - Helisalmi, Seppo

AU - Koivisto, Anne Maria

AU - Haapasalo, Annakaisa

AU - Dermecourt, Vincent

AU - Fievet, Nathalie

AU - Hanon, Olivier

AU - Dufouil, Carole

AU - Brice, Alexis

AU - Ritchie, Karen

AU - Dubois, Bruno

AU - Himali, Jayanadra J.

AU - Keene, C. Dirk

AU - Tschanz, Joann

AU - Fitzpatrick, Annette L.

AU - Kukull, Walter A.

AU - Norton, Maria

AU - Aspelund, Thor

AU - Larson, Eric B.

AU - Munger, Ron

AU - Lipton, Richard B.

AU - Lipton, Richard B.

AU - Bullido, María J.

AU - Hofman, Albert

AU - Montine, Thomas J.

AU - Coto, Eliecer

AU - Boerwinkle, Eric

AU - Petersen, Ronald C.

AU - Alvarez, Victoria

AU - Rivadeneira, Fernando

AU - Reiman, Eric M.

AU - Gallo, Maura

AU - O'Donnell, Christopher J.

AU - Reisch, Joan S.

AU - Bruni, Amalia Cecilia

AU - Royall, Donald R.

AU - Dichgans, Martin

AU - Sano, Mary

AU - Galimberti, Daniela

AU - St George-Hyslop, Peter

AU - Scarpini, Elio

AU - Tsuang, Debby W.

AU - Mancuso, Michelangelo

AU - Bonuccelli, Ubaldo

AU - Winslow, Ashley R.

AU - Daniele, Antonio

AU - Wu, Chuang Kuo

AU - Peters, Oliver

AU - Nacmias, Benedetta

AU - Riemenschneider, Matthias

AU - Heun, Reinhard

AU - Brayne, Carol

AU - Rubinsztein, David C.

AU - Bras, Jose

AU - Guerreiro, Rita

AU - Al-Chalabi, Ammar

AU - Shaw, Christopher E.

AU - Collinge, John

AU - Mann, David

AU - Tsolaki, Magda

AU - Clarimón, Jordi

AU - Sussams, Rebecca

AU - Lovestone, Simon

AU - O'Donovan, Michael C.

AU - Owen, Michael J.

AU - Behrens, Timothy W.

AU - Mead, Simon

AU - Goate, Alison M.

AU - Uitterlinden, Andre G.

AU - Holmes, Clive

AU - Cruchaga, Carlos

AU - Ingelsson, Martin

AU - Bennett, David A.

AU - Powell, John

AU - Golde, Todd E.

AU - Graff, Caroline

AU - De Jager, Philip L.

AU - Morgan, Kevin

AU - Ertekin-Taner, Nilufer

AU - Combarros, Onofre

AU - Psaty, Bruce M.

AU - Passmore, Peter

AU - Younkin, Steven G.

AU - Berr, Claudine

AU - Gudnason, Vilmundur

AU - Rujescu, Dan

AU - Dickson, Dennis W.

AU - Dartigues, Jean François

AU - Destefano, Anita L.

AU - Ortega-Cubero, Sara

AU - Hakonarson, Hakon

AU - Campion, Dominique

AU - Boada, Merce

AU - Kauwe, John Keoni

AU - Farrer, Lindsay A.

AU - Van Broeckhoven, Christine

AU - Ikram, M. Arfan

AU - Jones, Lesley

AU - Haines, Jonathan L.

AU - Tzourio, Christophe

AU - Launer, Lenore J.

AU - Escott-Price, Valentina

AU - Mayeux, Richard

AU - Deleuze, Jean François

AU - Amin, Najaf

AU - Holmans, Peter A.

AU - Pericak-Vance, Margaret A.

AU - Amouyel, Philippe

AU - Van Duijn, Cornelia M.

AU - Ramirez, Alfredo

AU - Wang, Li San

AU - Lambert, Jean Charles

AU - Seshadri, Sudha

AU - Williams, Julie

AU - Schellenberg, Gerard D.

PY - 2017/9/1

Y1 - 2017/9/1

N2 - 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 (rs74905: p.Pro522Arg, P = 5.38 × 10 '10, odds ratio (OR) = 0.68, minor allele frequency (MAF) cases = 0.0059, MAF controls = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10 '10, OR = 1.43, MAF cases = 0.011, MAF controls = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10 '14, OR = 1.67, MAF cases = 0.0143, MAF controls = 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.

AB - 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 (rs74905: p.Pro522Arg, P = 5.38 × 10 '10, odds ratio (OR) = 0.68, minor allele frequency (MAF) cases = 0.0059, MAF controls = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10 '10, OR = 1.43, MAF cases = 0.011, MAF controls = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10 '14, OR = 1.67, MAF cases = 0.0143, MAF controls = 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.

UR - http://www.scopus.com/inward/record.url?scp=85028725970&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85028725970&partnerID=8YFLogxK

U2 - 10.1038/ng.3916

DO - 10.1038/ng.3916

M3 - Article

C2 - 28714976

AN - SCOPUS:85028725970

VL - 49

SP - 1373

EP - 1384

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 9

ER -