%0 Journal Article %J JAMA %D 2010 %T Genome-wide analysis of genetic loci associated with Alzheimer disease. %A Seshadri, Sudha %A Fitzpatrick, Annette L %A Ikram, M Arfan %A DeStefano, Anita L %A Gudnason, Vilmundur %A Boada, Merce %A Bis, Joshua C %A Smith, Albert V %A Carassquillo, Minerva M %A Lambert, Jean Charles %A Harold, Denise %A Schrijvers, Elisabeth M C %A Ramirez-Lorca, Reposo %A Debette, Stephanie %A Longstreth, W T %A Janssens, A Cecile J W %A Pankratz, V Shane %A Dartigues, Jean François %A Hollingworth, Paul %A Aspelund, Thor %A Hernandez, Isabel %A Beiser, Alexa %A Kuller, Lewis H %A Koudstaal, Peter J %A Dickson, Dennis W %A Tzourio, Christophe %A Abraham, Richard %A Antunez, Carmen %A Du, Yangchun %A Rotter, Jerome I %A Aulchenko, Yurii S %A Harris, Tamara B %A Petersen, Ronald C %A Berr, Claudine %A Owen, Michael J %A Lopez-Arrieta, Jesus %A Varadarajan, Badri N %A Becker, James T %A Rivadeneira, Fernando %A Nalls, Michael A %A Graff-Radford, Neill R %A Campion, Dominique %A Auerbach, Sanford %A Rice, Kenneth %A Hofman, Albert %A Jonsson, Palmi V %A Schmidt, Helena %A Lathrop, Mark %A Mosley, Thomas H %A Au, Rhoda %A Psaty, Bruce M %A Uitterlinden, André G %A Farrer, Lindsay A %A Lumley, Thomas %A Ruiz, Agustin %A Williams, Julie %A Amouyel, Philippe %A Younkin, Steve G %A Wolf, Philip A %A Launer, Lenore J %A Lopez, Oscar L %A van Duijn, Cornelia M %A Breteler, Monique M B %K Age of Onset %K Aged %K Alzheimer Disease %K Case-Control Studies %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Odds Ratio %K Polymorphism, Single Nucleotide %X

CONTEXT: Genome-wide association studies (GWAS) have recently identified CLU, PICALM, and CR1 as novel genes for late-onset Alzheimer disease (AD).

OBJECTIVES: To identify and strengthen additional loci associated with AD and confirm these in an independent sample and to examine the contribution of recently identified genes to AD risk prediction in a 3-stage analysis of new and previously published GWAS on more than 35,000 persons (8371 AD cases).

DESIGN, SETTING, AND PARTICIPANTS: In stage 1, we identified strong genetic associations (P < 10(-3)) in a sample of 3006 AD cases and 14,642 controls by combining new data from the population-based Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (1367 AD cases [973 incident]) with previously reported results from the Translational Genomics Research Institute and the Mayo AD GWAS. We identified 2708 single-nucleotide polymorphisms (SNPs) with P < 10(-3). In stage 2, we pooled results for these SNPs with the European AD Initiative (2032 cases and 5328 controls) to identify 38 SNPs (10 loci) with P < 10(-5). In stage 3, we combined data for these 10 loci with data from the Genetic and Environmental Risk in AD consortium (3333 cases and 6995 controls) to identify 4 SNPs with P < 1.7x10(-8). These 4 SNPs were replicated in an independent Spanish sample (1140 AD cases and 1209 controls). Genome-wide association analyses were completed in 2007-2008 and the meta-analyses and replication in 2009.

MAIN OUTCOME MEASURE: Presence of Alzheimer disease.

RESULTS: Two loci were identified to have genome-wide significance for the first time: rs744373 near BIN1 (odds ratio [OR],1.13; 95% confidence interval [CI],1.06-1.21 per copy of the minor allele; P = 1.59x10(-11)) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (OR, 1.18; 95% CI, 1.07-1.29; P = 6.45x10(-9)). Associations of these 2 loci plus the previously identified loci CLU and PICALM with AD were confirmed in the Spanish sample (P < .05). However, although CLU and PICALM were confirmed to be associated with AD in this independent sample, they did not improve the ability of a model that included age, sex, and APOE to predict incident AD (improvement in area under the receiver operating characteristic curve from 0.847 to 0.849 in the Rotterdam Study and 0.702 to 0.705 in the Cardiovascular Health Study).

CONCLUSIONS: Two genetic loci for AD were found for the first time to reach genome-wide statistical significance. These findings were replicated in an independent population. Two recently reported associations were also confirmed. These loci did not improve AD risk prediction. While not clinically useful, they may implicate biological pathways useful for future research.

%B JAMA %V 303 %P 1832-40 %8 2010 May 12 %G eng %N 18 %1 http://www.ncbi.nlm.nih.gov/pubmed/20460622?dopt=Abstract %R 10.1001/jama.2010.574 %0 Journal Article %J PLoS One %D 2014 %T Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease. %A Escott-Price, Valentina %A Bellenguez, Céline %A Wang, Li-San %A Choi, Seung-Hoan %A Harold, Denise %A Jones, Lesley %A Holmans, Peter %A Gerrish, Amy %A Vedernikov, Alexey %A Richards, Alexander %A DeStefano, Anita L %A Lambert, Jean-Charles %A Ibrahim-Verbaas, Carla A %A Naj, Adam C %A Sims, Rebecca %A Jun, Gyungah %A Bis, Joshua C %A Beecham, Gary W %A Grenier-Boley, Benjamin %A Russo, Giancarlo %A Thornton-Wells, Tricia A %A Denning, Nicola %A Smith, Albert V %A Chouraki, Vincent %A Thomas, Charlene %A Ikram, M Arfan %A Zelenika, Diana %A Vardarajan, Badri N %A Kamatani, Yoichiro %A Lin, Chiao-Feng %A Schmidt, Helena %A Kunkle, Brian %A Dunstan, Melanie L %A Vronskaya, Maria %A Johnson, Andrew D %A Ruiz, Agustin %A Bihoreau, Marie-Thérèse %A Reitz, Christiane %A Pasquier, Florence %A Hollingworth, Paul %A Hanon, Olivier %A Fitzpatrick, Annette L %A Buxbaum, Joseph D %A Campion, Dominique %A Crane, Paul K %A Baldwin, Clinton %A Becker, Tim %A Gudnason, Vilmundur %A Cruchaga, Carlos %A Craig, David %A Amin, Najaf %A Berr, Claudine %A Lopez, Oscar L %A De Jager, Philip L %A Deramecourt, Vincent %A Johnston, Janet A %A Evans, Denis %A Lovestone, Simon %A Letenneur, Luc %A Hernandez, Isabel %A Rubinsztein, David C %A Eiriksdottir, Gudny %A Sleegers, Kristel %A Goate, Alison M %A Fiévet, Nathalie %A Huentelman, Matthew J %A Gill, Michael %A Brown, Kristelle %A Kamboh, M Ilyas %A Keller, Lina %A Barberger-Gateau, Pascale %A McGuinness, Bernadette %A Larson, Eric B %A Myers, Amanda J %A Dufouil, Carole %A Todd, Stephen %A Wallon, David %A Love, Seth %A Rogaeva, Ekaterina %A Gallacher, John %A George-Hyslop, Peter St %A Clarimon, Jordi %A Lleo, Alberto %A Bayer, Anthony %A Tsuang, Debby W %A Yu, Lei %A Tsolaki, Magda %A Bossù, Paola %A Spalletta, Gianfranco %A Proitsi, Petra %A Collinge, John %A Sorbi, Sandro %A Garcia, Florentino Sanchez %A Fox, Nick C %A Hardy, John %A Naranjo, Maria Candida Deniz %A Bosco, Paolo %A Clarke, Robert %A Brayne, Carol %A Galimberti, Daniela %A Scarpini, Elio %A Bonuccelli, Ubaldo %A Mancuso, Michelangelo %A Siciliano, Gabriele %A Moebus, Susanne %A Mecocci, Patrizia %A Zompo, Maria Del %A Maier, Wolfgang %A Hampel, Harald %A Pilotto, Alberto %A Frank-García, Ana %A Panza, Francesco %A Solfrizzi, Vincenzo %A Caffarra, Paolo %A Nacmias, Benedetta %A Perry, William %A Mayhaus, Manuel %A Lannfelt, Lars %A Hakonarson, Hakon %A Pichler, Sabrina %A Carrasquillo, Minerva M %A Ingelsson, Martin %A Beekly, Duane %A Alvarez, Victoria %A Zou, Fanggeng %A Valladares, Otto %A Younkin, Steven G %A Coto, Eliecer %A Hamilton-Nelson, Kara L %A Gu, Wei %A Razquin, Cristina %A Pastor, Pau %A Mateo, Ignacio %A Owen, Michael J %A Faber, Kelley M %A Jonsson, Palmi V %A Combarros, Onofre %A O'Donovan, Michael C %A Cantwell, Laura B %A Soininen, Hilkka %A Blacker, Deborah %A Mead, Simon %A Mosley, Thomas H %A Bennett, David A %A Harris, Tamara B %A Fratiglioni, Laura %A Holmes, Clive %A de Bruijn, Renee F A G %A Passmore, Peter %A Montine, Thomas J %A Bettens, Karolien %A Rotter, Jerome I %A Brice, Alexis %A Morgan, Kevin %A Foroud, Tatiana M %A Kukull, Walter A %A Hannequin, Didier %A Powell, John F %A Nalls, Michael A %A Ritchie, Karen %A Lunetta, Kathryn L %A Kauwe, John S K %A Boerwinkle, Eric %A Riemenschneider, Matthias %A Boada, Merce %A Hiltunen, Mikko %A Martin, Eden R %A Schmidt, Reinhold %A Rujescu, Dan %A Dartigues, Jean-François %A Mayeux, Richard %A Tzourio, Christophe %A Hofman, Albert %A Nöthen, Markus M %A Graff, Caroline %A Psaty, Bruce M %A Haines, Jonathan L %A Lathrop, Mark %A Pericak-Vance, Margaret A %A Launer, Lenore J %A Van Broeckhoven, Christine %A Farrer, Lindsay A %A van Duijn, Cornelia M %A Ramirez, Alfredo %A Seshadri, Sudha %A Schellenberg, Gerard D %A Amouyel, Philippe %A Williams, Julie %K Alzheimer Disease %K Carrier Proteins %K Case-Control Studies %K Genome-Wide Association Study %K Heat-Shock Proteins %K Humans %K Polymorphism, Single Nucleotide %K Receptors, Antigen, B-Cell %X

BACKGROUND: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.

PRINCIPAL FINDINGS: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci.

SIGNIFICANCE: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.

%B PLoS One %V 9 %P e94661 %8 2014 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/24922517?dopt=Abstract %R 10.1371/journal.pone.0094661 %0 Journal Article %J Nat Genet %D 2017 %T Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. %A Sims, Rebecca %A van der Lee, Sven J %A Naj, Adam C %A Bellenguez, Céline %A Badarinarayan, Nandini %A Jakobsdottir, Johanna %A Kunkle, Brian W %A Boland, Anne %A Raybould, Rachel %A Bis, Joshua C %A Martin, Eden R %A Grenier-Boley, Benjamin %A Heilmann-Heimbach, Stefanie %A Chouraki, Vincent %A Kuzma, Amanda B %A Sleegers, Kristel %A Vronskaya, Maria %A Ruiz, Agustin %A Graham, Robert R %A Olaso, Robert %A Hoffmann, Per %A Grove, Megan L %A Vardarajan, Badri N %A Hiltunen, Mikko %A Nöthen, Markus M %A White, Charles C %A Hamilton-Nelson, Kara L %A Epelbaum, Jacques %A Maier, Wolfgang %A Choi, Seung-Hoan %A Beecham, Gary W %A Dulary, Cécile %A Herms, Stefan %A Smith, Albert V %A Funk, Cory C %A Derbois, Céline %A Forstner, Andreas J %A Ahmad, Shahzad %A Li, Hongdong %A Bacq, Delphine %A Harold, Denise %A Satizabal, Claudia L %A Valladares, Otto %A Squassina, Alessio %A Thomas, Rhodri %A Brody, Jennifer A %A Qu, Liming %A Sánchez-Juan, Pascual %A Morgan, Taniesha %A Wolters, Frank J %A Zhao, Yi %A Garcia, Florentino Sanchez %A Denning, Nicola %A Fornage, Myriam %A Malamon, John %A Naranjo, Maria Candida Deniz %A Majounie, Elisa %A Mosley, Thomas H %A Dombroski, Beth %A Wallon, David %A Lupton, Michelle K %A Dupuis, Josée %A Whitehead, Patrice %A Fratiglioni, Laura %A Medway, Christopher %A Jian, Xueqiu %A Mukherjee, Shubhabrata %A Keller, Lina %A Brown, Kristelle %A Lin, Honghuang %A Cantwell, Laura B %A Panza, Francesco %A McGuinness, Bernadette %A Moreno-Grau, Sonia %A Burgess, Jeremy D %A Solfrizzi, Vincenzo %A Proitsi, Petra %A Adams, Hieab H %A Allen, Mariet %A Seripa, Davide %A Pastor, Pau %A Cupples, L Adrienne %A Price, Nathan D %A Hannequin, Didier %A Frank-García, Ana %A Levy, Daniel %A Chakrabarty, Paramita %A Caffarra, Paolo %A Giegling, Ina %A Beiser, Alexa S %A Giedraitis, Vilmantas %A Hampel, Harald %A Garcia, Melissa E %A Wang, Xue %A Lannfelt, Lars %A Mecocci, Patrizia %A Eiriksdottir, Gudny %A Crane, Paul K %A Pasquier, Florence %A Boccardi, Virginia %A Henández, Isabel %A Barber, Robert C %A Scherer, Martin %A Tarraga, Lluis %A Adams, Perrie M %A Leber, Markus %A Chen, Yuning %A Albert, Marilyn S %A Riedel-Heller, Steffi %A Emilsson, Valur %A Beekly, Duane %A Braae, Anne %A Schmidt, Reinhold %A Blacker, Deborah %A Masullo, Carlo %A Schmidt, Helena %A Doody, Rachelle S %A Spalletta, Gianfranco %A Jr, W T Longstreth %A Fairchild, Thomas J %A Bossù, Paola %A Lopez, Oscar L %A Frosch, Matthew P %A Sacchinelli, Eleonora %A Ghetti, Bernardino %A Yang, Qiong %A Huebinger, Ryan M %A Jessen, Frank %A Li, Shuo %A Kamboh, M Ilyas %A Morris, John %A Sotolongo-Grau, Oscar %A Katz, Mindy J %A Corcoran, Chris %A Dunstan, Melanie %A Braddel, Amy %A Thomas, Charlene %A Meggy, Alun %A Marshall, Rachel %A Gerrish, Amy %A Chapman, Jade %A Aguilar, Miquel %A Taylor, Sarah %A Hill, Matt %A Fairén, Mònica Díez %A Hodges, Angela %A Vellas, Bruno %A Soininen, Hilkka %A Kloszewska, Iwona %A Daniilidou, Makrina %A Uphill, James %A Patel, Yogen %A Hughes, Joseph T %A Lord, Jenny %A Turton, James %A Hartmann, Annette M %A Cecchetti, Roberta %A Fenoglio, Chiara %A Serpente, Maria %A Arcaro, Marina %A Caltagirone, Carlo %A Orfei, Maria Donata %A Ciaramella, Antonio %A Pichler, Sabrina %A Mayhaus, Manuel %A Gu, Wei %A Lleo, Alberto %A Fortea, Juan %A Blesa, Rafael %A Barber, Imelda S %A Brookes, Keeley %A Cupidi, Chiara %A Maletta, Raffaele Giovanni %A Carrell, David %A Sorbi, Sandro %A Moebus, Susanne %A Urbano, Maria %A Pilotto, Alberto %A Kornhuber, Johannes %A Bosco, Paolo %A Todd, Stephen %A Craig, David %A Johnston, Janet %A Gill, Michael %A Lawlor, Brian %A Lynch, Aoibhinn %A Fox, Nick C %A Hardy, John %A Albin, Roger L %A Apostolova, Liana G %A Arnold, Steven E %A Asthana, Sanjay %A Atwood, Craig S %A Baldwin, Clinton T %A Barnes, Lisa L %A Barral, Sandra %A Beach, Thomas G %A Becker, James T %A Bigio, Eileen H %A Bird, Thomas D %A Boeve, Bradley F %A Bowen, James D %A Boxer, Adam %A Burke, James R %A Burns, Jeffrey M %A Buxbaum, Joseph D %A Cairns, Nigel J %A Cao, Chuanhai %A Carlson, Chris S %A Carlsson, Cynthia M %A Carney, Regina M %A Carrasquillo, Minerva M %A Carroll, Steven L %A Diaz, Carolina Ceballos %A Chui, Helena C %A Clark, David G %A Cribbs, David H %A Crocco, Elizabeth A %A DeCarli, Charles %A Dick, Malcolm %A Duara, Ranjan %A Evans, Denis A %A Faber, Kelley M %A Fallon, Kenneth B %A Fardo, David W %A Farlow, Martin R %A Ferris, Steven %A Foroud, Tatiana M %A Galasko, Douglas R %A Gearing, Marla %A Geschwind, Daniel H %A Gilbert, John R %A Graff-Radford, Neill R %A Green, Robert C %A Growdon, John H %A Hamilton, Ronald L %A Harrell, Lindy E %A Honig, Lawrence S %A Huentelman, Matthew J %A Hulette, Christine M %A Hyman, Bradley T %A Jarvik, Gail P %A Abner, Erin %A Jin, Lee-Way %A Jun, Gyungah %A Karydas, Anna %A Kaye, Jeffrey A %A Kim, Ronald %A Kowall, Neil W %A Kramer, Joel H %A LaFerla, Frank M %A Lah, James J %A Leverenz, James B %A Levey, Allan I %A Li, Ge %A Lieberman, Andrew P %A Lunetta, Kathryn L %A Lyketsos, Constantine G %A Marson, Daniel C %A Martiniuk, Frank %A Mash, Deborah C %A Masliah, Eliezer %A McCormick, Wayne C %A McCurry, Susan M %A McDavid, Andrew N %A McKee, Ann C %A Mesulam, Marsel %A Miller, Bruce L %A Miller, Carol A %A Miller, Joshua W %A Morris, John C %A Murrell, Jill R %A Myers, Amanda J %A O'Bryant, Sid %A Olichney, John M %A Pankratz, Vernon S %A Parisi, Joseph E %A Paulson, Henry L %A Perry, William %A Peskind, Elaine %A Pierce, Aimee %A Poon, Wayne W %A Potter, Huntington %A Quinn, Joseph F %A Raj, Ashok %A Raskind, Murray %A Reisberg, Barry %A Reitz, Christiane %A Ringman, John M %A Roberson, Erik D %A Rogaeva, Ekaterina %A Rosen, Howard J %A Rosenberg, Roger N %A Sager, Mark A %A Saykin, Andrew J %A Schneider, Julie A %A Schneider, Lon S %A Seeley, William W %A Smith, Amanda G %A Sonnen, Joshua A %A Spina, Salvatore %A Stern, Robert A %A Swerdlow, Russell H %A Tanzi, Rudolph E %A Thornton-Wells, Tricia A %A Trojanowski, John Q %A Troncoso, Juan C %A Van Deerlin, Vivianna M %A Van Eldik, Linda J %A Vinters, Harry V %A Vonsattel, Jean Paul %A Weintraub, Sandra %A Welsh-Bohmer, Kathleen A %A Wilhelmsen, Kirk C %A Williamson, Jennifer %A Wingo, Thomas S %A Woltjer, Randall L %A Wright, Clinton B %A Yu, Chang-En %A Yu, Lei %A Garzia, Fabienne %A Golamaully, Feroze %A Septier, Gislain %A Engelborghs, Sebastien %A Vandenberghe, Rik %A De Deyn, Peter P %A Fernadez, Carmen Muñoz %A Benito, Yoland Aladro %A Thonberg, Håkan %A Forsell, Charlotte %A Lilius, Lena %A Kinhult-Ståhlbom, Anne %A Kilander, Lena %A Brundin, RoseMarie %A Concari, Letizia %A Helisalmi, Seppo %A Koivisto, Anne Maria %A Haapasalo, Annakaisa %A Dermecourt, Vincent %A Fiévet, Nathalie %A Hanon, Olivier %A Dufouil, Carole %A Brice, Alexis %A Ritchie, Karen %A Dubois, Bruno %A Himali, Jayanadra J %A Keene, C Dirk %A Tschanz, JoAnn %A Fitzpatrick, Annette L %A Kukull, Walter A %A Norton, Maria %A Aspelund, Thor %A Larson, Eric B %A Munger, Ron %A Rotter, Jerome I %A Lipton, Richard B %A Bullido, María J %A Hofman, Albert %A Montine, Thomas J %A Coto, Eliecer %A Boerwinkle, Eric %A Petersen, Ronald C %A Alvarez, Victoria %A Rivadeneira, Fernando %A Reiman, Eric M %A Gallo, Maura %A O'Donnell, Christopher J %A Reisch, Joan S %A Bruni, Amalia Cecilia %A Royall, Donald R %A Dichgans, Martin %A Sano, Mary %A Galimberti, Daniela %A St George-Hyslop, Peter %A Scarpini, Elio %A Tsuang, Debby W %A Mancuso, Michelangelo %A Bonuccelli, Ubaldo %A Winslow, Ashley R %A Daniele, Antonio %A Wu, Chuang-Kuo %A Peters, Oliver %A Nacmias, Benedetta %A Riemenschneider, Matthias %A Heun, Reinhard %A Brayne, Carol %A Rubinsztein, David C %A Bras, Jose %A Guerreiro, Rita %A Al-Chalabi, Ammar %A Shaw, Christopher E %A Collinge, John %A Mann, David %A Tsolaki, Magda %A Clarimon, Jordi %A Sussams, Rebecca %A Lovestone, Simon %A O'Donovan, Michael C %A Owen, Michael J %A Behrens, Timothy W %A Mead, Simon %A Goate, Alison M %A Uitterlinden, André G %A Holmes, Clive %A Cruchaga, Carlos %A Ingelsson, Martin %A Bennett, David A %A Powell, John %A Golde, Todd E %A Graff, Caroline %A De Jager, Philip L %A Morgan, Kevin %A Ertekin-Taner, Nilufer %A Combarros, Onofre %A Psaty, Bruce M %A Passmore, Peter %A Younkin, Steven G %A Berr, Claudine %A Gudnason, Vilmundur %A Rujescu, Dan %A Dickson, Dennis W %A Dartigues, Jean-François %A DeStefano, Anita L %A Ortega-Cubero, Sara %A Hakonarson, Hakon %A Campion, Dominique %A Boada, Merce %A Kauwe, John Keoni %A Farrer, Lindsay A %A Van Broeckhoven, Christine %A Ikram, M Arfan %A Jones, Lesley %A Haines, Jonathan L %A Tzourio, Christophe %A Launer, Lenore J %A Escott-Price, Valentina %A Mayeux, Richard %A Deleuze, Jean-Francois %A Amin, Najaf %A Holmans, Peter A %A Pericak-Vance, Margaret A %A Amouyel, Philippe %A van Duijn, Cornelia M %A Ramirez, Alfredo %A Wang, Li-San %A Lambert, Jean-Charles %A Seshadri, Sudha %A Williams, Julie %A Schellenberg, Gerard D %K Adaptor Proteins, Signal Transducing %K Alzheimer Disease %K Amino Acid Sequence %K Case-Control Studies %K Exome %K Gene Expression Profiling %K Gene Frequency %K Genetic Predisposition to Disease %K Genotype %K Humans %K Immunity, Innate %K Linkage Disequilibrium %K Membrane Glycoproteins %K Microglia %K Odds Ratio %K Phospholipase C gamma %K Polymorphism, Single Nucleotide %K Protein Interaction Maps %K Receptors, Immunologic %K Sequence Homology, Amino Acid %X

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.

%B Nat Genet %V 49 %P 1373-1384 %8 2017 Sep %G eng %N 9 %R 10.1038/ng.3916 %0 Journal Article %J Nat Genet %D 2019 %T Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. %A Kunkle, Brian W %A Grenier-Boley, Benjamin %A Sims, Rebecca %A Bis, Joshua C %A Damotte, Vincent %A Naj, Adam C %A Boland, Anne %A Vronskaya, Maria %A van der Lee, Sven J %A Amlie-Wolf, Alexandre %A Bellenguez, Céline %A Frizatti, Aura %A Chouraki, Vincent %A Martin, Eden R %A Sleegers, Kristel %A Badarinarayan, Nandini %A Jakobsdottir, Johanna %A Hamilton-Nelson, Kara L %A Moreno-Grau, Sonia %A Olaso, Robert %A Raybould, Rachel %A Chen, Yuning %A Kuzma, Amanda B %A Hiltunen, Mikko %A Morgan, Taniesha %A Ahmad, Shahzad %A Vardarajan, Badri N %A Epelbaum, Jacques %A Hoffmann, Per %A Boada, Merce %A Beecham, Gary W %A Garnier, Jean-Guillaume %A Harold, Denise %A Fitzpatrick, Annette L %A Valladares, Otto %A Moutet, Marie-Laure %A Gerrish, Amy %A Smith, Albert V %A Qu, Liming %A Bacq, Delphine %A Denning, Nicola %A Jian, Xueqiu %A Zhao, Yi %A Del Zompo, Maria %A Fox, Nick C %A Choi, Seung-Hoan %A Mateo, Ignacio %A Hughes, Joseph T %A Adams, Hieab H %A Malamon, John %A Sanchez-Garcia, Florentino %A Patel, Yogen %A Brody, Jennifer A %A Dombroski, Beth A %A Naranjo, Maria Candida Deniz %A Daniilidou, Makrina %A Eiriksdottir, Gudny %A Mukherjee, Shubhabrata %A Wallon, David %A Uphill, James %A Aspelund, Thor %A Cantwell, Laura B %A Garzia, Fabienne %A Galimberti, Daniela %A Hofer, Edith %A Butkiewicz, Mariusz %A Fin, Bertrand %A Scarpini, Elio %A Sarnowski, Chloe %A Bush, Will S %A Meslage, Stéphane %A Kornhuber, Johannes %A White, Charles C %A Song, Yuenjoo %A Barber, Robert C %A Engelborghs, Sebastiaan %A Sordon, Sabrina %A Voijnovic, Dina %A Adams, Perrie M %A Vandenberghe, Rik %A Mayhaus, Manuel %A Cupples, L Adrienne %A Albert, Marilyn S %A De Deyn, Peter P %A Gu, Wei %A Himali, Jayanadra J %A Beekly, Duane %A Squassina, Alessio %A Hartmann, Annette M %A Orellana, Adelina %A Blacker, Deborah %A Rodriguez-Rodriguez, Eloy %A Lovestone, Simon %A Garcia, Melissa E %A Doody, Rachelle S %A Munoz-Fernadez, Carmen %A Sussams, Rebecca %A Lin, Honghuang %A Fairchild, Thomas J %A Benito, Yolanda A %A Holmes, Clive %A Karamujić-Čomić, Hata %A Frosch, Matthew P %A Thonberg, Håkan %A Maier, Wolfgang %A Roschupkin, Gena %A Ghetti, Bernardino %A Giedraitis, Vilmantas %A Kawalia, Amit %A Li, Shuo %A Huebinger, Ryan M %A Kilander, Lena %A Moebus, Susanne %A Hernandez, Isabel %A Kamboh, M Ilyas %A Brundin, RoseMarie %A Turton, James %A Yang, Qiong %A Katz, Mindy J %A Concari, Letizia %A Lord, Jenny %A Beiser, Alexa S %A Keene, C Dirk %A Helisalmi, Seppo %A Kloszewska, Iwona %A Kukull, Walter A %A Koivisto, Anne Maria %A Lynch, Aoibhinn %A Tarraga, Lluis %A Larson, Eric B %A Haapasalo, Annakaisa %A Lawlor, Brian %A Mosley, Thomas H %A Lipton, Richard B %A Solfrizzi, Vincenzo %A Gill, Michael %A Longstreth, W T %A Montine, Thomas J %A Frisardi, Vincenza %A Diez-Fairen, Monica %A Rivadeneira, Fernando %A Petersen, Ronald C %A Deramecourt, Vincent %A Alvarez, Ignacio %A Salani, Francesca %A Ciaramella, Antonio %A Boerwinkle, Eric %A Reiman, Eric M %A Fiévet, Nathalie %A Rotter, Jerome I %A Reisch, Joan S %A Hanon, Olivier %A Cupidi, Chiara %A Andre Uitterlinden, A G %A Royall, Donald R %A Dufouil, Carole %A Maletta, Raffaele Giovanni %A de Rojas, Itziar %A Sano, Mary %A Brice, Alexis %A Cecchetti, Roberta %A George-Hyslop, Peter St %A Ritchie, Karen %A Tsolaki, Magda %A Tsuang, Debby W %A Dubois, Bruno %A Craig, David %A Wu, Chuang-Kuo %A Soininen, Hilkka %A Avramidou, Despoina %A Albin, Roger L %A Fratiglioni, Laura %A Germanou, Antonia %A Apostolova, Liana G %A Keller, Lina %A Koutroumani, Maria %A Arnold, Steven E %A Panza, Francesco %A Gkatzima, Olymbia %A Asthana, Sanjay %A Hannequin, Didier %A Whitehead, Patrice %A Atwood, Craig S %A Caffarra, Paolo %A Hampel, Harald %A Quintela, Inés %A Carracedo, Angel %A Lannfelt, Lars %A Rubinsztein, David C %A Barnes, Lisa L %A Pasquier, Florence %A Frölich, Lutz %A Barral, Sandra %A McGuinness, Bernadette %A Beach, Thomas G %A Johnston, Janet A %A Becker, James T %A Passmore, Peter %A Bigio, Eileen H %A Schott, Jonathan M %A Bird, Thomas D %A Warren, Jason D %A Boeve, Bradley F %A Lupton, Michelle K %A Bowen, James D %A Proitsi, Petra %A Boxer, Adam %A Powell, John F %A Burke, James R %A Kauwe, John S K %A Burns, Jeffrey M %A Mancuso, Michelangelo %A Buxbaum, Joseph D %A Bonuccelli, Ubaldo %A Cairns, Nigel J %A McQuillin, Andrew %A Cao, Chuanhai %A Livingston, Gill %A Carlson, Chris S %A Bass, Nicholas J %A Carlsson, Cynthia M %A Hardy, John %A Carney, Regina M %A Bras, Jose %A Carrasquillo, Minerva M %A Guerreiro, Rita %A Allen, Mariet %A Chui, Helena C %A Fisher, Elizabeth %A Masullo, Carlo %A Crocco, Elizabeth A %A DeCarli, Charles %A Bisceglio, Gina %A Dick, Malcolm %A Ma, Li %A Duara, Ranjan %A Graff-Radford, Neill R %A Evans, Denis A %A Hodges, Angela %A Faber, Kelley M %A Scherer, Martin %A Fallon, Kenneth B %A Riemenschneider, Matthias %A Fardo, David W %A Heun, Reinhard %A Farlow, Martin R %A Kölsch, Heike %A Ferris, Steven %A Leber, Markus %A Foroud, Tatiana M %A Heuser, Isabella %A Galasko, Douglas R %A Giegling, Ina %A Gearing, Marla %A Hüll, Michael %A Geschwind, Daniel H %A Gilbert, John R %A Morris, John %A Green, Robert C %A Mayo, Kevin %A Growdon, John H %A Feulner, Thomas %A Hamilton, Ronald L %A Harrell, Lindy E %A Drichel, Dmitriy %A Honig, Lawrence S %A Cushion, Thomas D %A Huentelman, Matthew J %A Hollingworth, Paul %A Hulette, Christine M %A Hyman, Bradley T %A Marshall, Rachel %A Jarvik, Gail P %A Meggy, Alun %A Abner, Erin %A Menzies, Georgina E %A Jin, Lee-Way %A Leonenko, Ganna %A Real, Luis M %A Jun, Gyungah R %A Baldwin, Clinton T %A Grozeva, Detelina %A Karydas, Anna %A Russo, Giancarlo %A Kaye, Jeffrey A %A Kim, Ronald %A Jessen, Frank %A Kowall, Neil W %A Vellas, Bruno %A Kramer, Joel H %A Vardy, Emma %A LaFerla, Frank M %A Jöckel, Karl-Heinz %A Lah, James J %A Dichgans, Martin %A Leverenz, James B %A Mann, David %A Levey, Allan I %A Pickering-Brown, Stuart %A Lieberman, Andrew P %A Klopp, Norman %A Lunetta, Kathryn L %A Wichmann, H-Erich %A Lyketsos, Constantine G %A Morgan, Kevin %A Marson, Daniel C %A Brown, Kristelle %A Martiniuk, Frank %A Medway, Christopher %A Mash, Deborah C %A Nöthen, Markus M %A Masliah, Eliezer %A Hooper, Nigel M %A McCormick, Wayne C %A Daniele, Antonio %A McCurry, Susan M %A Bayer, Anthony %A McDavid, Andrew N %A Gallacher, John %A McKee, Ann C %A van den Bussche, Hendrik %A Mesulam, Marsel %A Brayne, Carol %A Miller, Bruce L %A Riedel-Heller, Steffi %A Miller, Carol A %A Miller, Joshua W %A Al-Chalabi, Ammar %A Morris, John C %A Shaw, Christopher E %A Myers, Amanda J %A Wiltfang, Jens %A O'Bryant, Sid %A Olichney, John M %A Alvarez, Victoria %A Parisi, Joseph E %A Singleton, Andrew B %A Paulson, Henry L %A Collinge, John %A Perry, William R %A Mead, Simon %A Peskind, Elaine %A Cribbs, David H %A Rossor, Martin %A Pierce, Aimee %A Ryan, Natalie S %A Poon, Wayne W %A Nacmias, Benedetta %A Potter, Huntington %A Sorbi, Sandro %A Quinn, Joseph F %A Sacchinelli, Eleonora %A Raj, Ashok %A Spalletta, Gianfranco %A Raskind, Murray %A Caltagirone, Carlo %A Bossù, Paola %A Orfei, Maria Donata %A Reisberg, Barry %A Clarke, Robert %A Reitz, Christiane %A Smith, A David %A Ringman, John M %A Warden, Donald %A Roberson, Erik D %A Wilcock, Gordon %A Rogaeva, Ekaterina %A Bruni, Amalia Cecilia %A Rosen, Howard J %A Gallo, Maura %A Rosenberg, Roger N %A Ben-Shlomo, Yoav %A Sager, Mark A %A Mecocci, Patrizia %A Saykin, Andrew J %A Pastor, Pau %A Cuccaro, Michael L %A Vance, Jeffery M %A Schneider, Julie A %A Schneider, Lori S %A Slifer, Susan %A Seeley, William W %A Smith, Amanda G %A Sonnen, Joshua A %A Spina, Salvatore %A Stern, Robert A %A Swerdlow, Russell H %A Tang, Mitchell %A Tanzi, Rudolph E %A Trojanowski, John Q %A Troncoso, Juan C %A Van Deerlin, Vivianna M %A Van Eldik, Linda J %A Vinters, Harry V %A Vonsattel, Jean Paul %A Weintraub, Sandra %A Welsh-Bohmer, Kathleen A %A Wilhelmsen, Kirk C %A Williamson, Jennifer %A Wingo, Thomas S %A Woltjer, Randall L %A Wright, Clinton B %A Yu, Chang-En %A Yu, Lei %A Saba, Yasaman %A Pilotto, Alberto %A Bullido, María J %A Peters, Oliver %A Crane, Paul K %A Bennett, David %A Bosco, Paola %A Coto, Eliecer %A Boccardi, Virginia %A De Jager, Phil L %A Lleo, Alberto %A Warner, Nick %A Lopez, Oscar L %A Ingelsson, Martin %A Deloukas, Panagiotis %A Cruchaga, Carlos %A Graff, Caroline %A Gwilliam, Rhian %A Fornage, Myriam %A Goate, Alison M %A Sánchez-Juan, Pascual %A Kehoe, Patrick G %A Amin, Najaf %A Ertekin-Taner, Nilifur %A Berr, Claudine %A Debette, Stephanie %A Love, Seth %A Launer, Lenore J %A Younkin, Steven G %A Dartigues, Jean-François %A Corcoran, Chris %A Ikram, M Arfan %A Dickson, Dennis W %A Nicolas, Gaël %A Campion, Dominique %A Tschanz, JoAnn %A Schmidt, Helena %A Hakonarson, Hakon %A Clarimon, Jordi %A Munger, Ron %A Schmidt, Reinhold %A Farrer, Lindsay A %A Van Broeckhoven, Christine %A C O'Donovan, Michael %A DeStefano, Anita L %A Jones, Lesley %A Haines, Jonathan L %A Deleuze, Jean-Francois %A Owen, Michael J %A Gudnason, Vilmundur %A Mayeux, Richard %A Escott-Price, Valentina %A Psaty, Bruce M %A Ramirez, Alfredo %A Wang, Li-San %A Ruiz, Agustin %A van Duijn, Cornelia M %A Holmans, Peter A %A Seshadri, Sudha %A Williams, Julie %A Amouyel, Phillippe %A Schellenberg, Gerard D %A Lambert, Jean-Charles %A Pericak-Vance, Margaret A %X

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

%B Nat Genet %V 51 %P 414-430 %8 2019 Mar %G eng %N 3 %R 10.1038/s41588-019-0358-2