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 language | English (US) |
|---|---|
| Pages (from-to) | 1373-1384 |
| Number of pages | 12 |
| Journal | Nature Genetics |
| Volume | 49 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 1 2017 |
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- Genetics
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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 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; 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.; Olichney, John M; 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; 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 journal › Article
}
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 J.
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 - Olichney, John M
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 - Rotter, Jerome I.
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.
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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 -