Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease.
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ABSTRACT:
SUBMITTER: Sims R
PROVIDER: S-EPMC5669039 | biostudies-literature | 2017 Sep
REPOSITORIES: biostudies-literature
Publications
Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease.
Sims Rebecca R van der Lee Sven J SJ Naj Adam C AC Bellenguez Céline C Badarinarayan Nandini N Jakobsdottir Johanna J Kunkle Brian W BW Boland Anne A Raybould Rachel R Bis Joshua C JC Martin Eden R ER Grenier-Boley Benjamin B Heilmann-Heimbach Stefanie S Chouraki Vincent V Kuzma Amanda B AB Sleegers Kristel K Vronskaya Maria M Ruiz Agustin A Graham Robert R RR Olaso Robert R Hoffmann Per P Grove Megan L ML Vardarajan Badri N BN Hiltunen Mikko M Nöthen Markus M MM White Charles C CC Hamilton-Nelson Kara L KL Epelbaum Jacques J Maier Wolfgang W Choi Seung-Hoan SH Beecham Gary W GW Dulary Cécile C Herms Stefan S Smith Albert V AV Funk Cory C CC Derbois Céline C Forstner Andreas J AJ Ahmad Shahzad S Li Hongdong H Bacq Delphine D Harold Denise D Satizabal Claudia L CL Valladares Otto O Squassina Alessio A Thomas Rhodri R Brody Jennifer A JA Qu Liming L Sánchez-Juan Pascual P Morgan Taniesha T Wolters Frank J FJ Zhao Yi Y Garcia Florentino Sanchez FS Denning Nicola N Fornage Myriam M Malamon John J Naranjo Maria Candida Deniz MCD Majounie Elisa E Mosley Thomas H TH Dombroski Beth B Wallon David D Lupton Michelle K MK Dupuis Josée J Whitehead Patrice P Fratiglioni Laura L Medway Christopher C Jian Xueqiu X Mukherjee Shubhabrata S Keller Lina L Brown Kristelle K Lin Honghuang H Cantwell Laura B LB Panza Francesco F McGuinness Bernadette B Moreno-Grau Sonia S Burgess Jeremy D JD Solfrizzi Vincenzo V Proitsi Petra P Adams Hieab H HH Allen Mariet M Seripa Davide D Pastor Pau P Cupples L Adrienne LA Price Nathan D ND Hannequin Didier D Frank-García Ana A Levy Daniel D Chakrabarty Paramita P Caffarra Paolo P Giegling Ina I Beiser Alexa S AS Giedraitis Vilmantas V Hampel Harald H Garcia Melissa E ME Wang Xue X Lannfelt Lars L Mecocci Patrizia P Eiriksdottir Gudny G Crane Paul K PK Pasquier Florence F Boccardi Virginia V Henández Isabel I Barber Robert C RC Scherer Martin M Tarraga Lluis L Adams Perrie M PM Leber Markus M Chen Yuning Y Albert Marilyn S MS Riedel-Heller Steffi S Emilsson Valur V Beekly Duane D Braae Anne A Schmidt Reinhold R Blacker Deborah D Masullo Carlo C Schmidt Helena H Doody Rachelle S RS Spalletta Gianfranco G Longstreth W T WT Fairchild Thomas J TJ Bossù Paola P Lopez Oscar L OL Frosch Matthew P MP Sacchinelli Eleonora E Ghetti Bernardino B Yang Qiong Q Huebinger Ryan M RM Jessen Frank F Li Shuo S Kamboh M Ilyas MI Morris John J Sotolongo-Grau Oscar O Katz Mindy J MJ Corcoran Chris C Dunstan Melanie M Braddel Amy A Thomas Charlene C Meggy Alun A Marshall Rachel R Gerrish Amy A Chapman Jade J Aguilar Miquel M Taylor Sarah S Hill Matt M Fairén Mònica Díez MD Hodges Angela A Vellas Bruno B Soininen Hilkka H Kloszewska Iwona I Daniilidou Makrina M Uphill James J Patel Yogen Y Hughes Joseph T JT Lord Jenny J Turton James J Hartmann Annette M AM Cecchetti Roberta R Fenoglio Chiara C Serpente Maria M Arcaro Marina M Caltagirone Carlo C Orfei Maria Donata MD Ciaramella Antonio A Pichler Sabrina S Mayhaus Manuel M Gu Wei W Lleó Alberto A Fortea Juan J Blesa Rafael R Barber Imelda S IS Brookes Keeley K Cupidi Chiara C Maletta Raffaele Giovanni RG Carrell David D Sorbi Sandro S Moebus Susanne S Urbano Maria M Pilotto Alberto A Kornhuber Johannes J Bosco Paolo P Todd Stephen S Craig David D Johnston Janet J Gill Michael M Lawlor Brian B Lynch Aoibhinn A Fox Nick C NC Hardy John J Albin Roger L RL Apostolova Liana G LG Arnold Steven E SE Asthana Sanjay S Atwood Craig S CS Baldwin Clinton T CT Barnes Lisa L LL Barral Sandra S Beach Thomas G TG Becker James T JT Bigio Eileen H EH Bird Thomas D TD Boeve Bradley F BF Bowen James D JD Boxer Adam A Burke James R JR Burns Jeffrey M JM Buxbaum Joseph D JD Cairns Nigel J NJ Cao Chuanhai C Carlson Chris S CS Carlsson Cynthia M CM Carney Regina M RM Carrasquillo Minerva M MM Carroll Steven L SL Diaz Carolina Ceballos CC Chui Helena C HC Clark David G DG Cribbs David H DH Crocco Elizabeth A EA DeCarli Charles C Dick Malcolm M Duara Ranjan R Evans Denis A DA Faber Kelley M KM Fallon Kenneth B KB Fardo David W DW Farlow Martin R MR Ferris Steven S Foroud Tatiana M TM Galasko Douglas R DR Gearing Marla M Geschwind Daniel H DH Gilbert John R JR Graff-Radford Neill R NR Green Robert C RC Growdon John H JH Hamilton Ronald L RL Harrell Lindy E LE Honig Lawrence S LS Huentelman Matthew J MJ Hulette Christine M CM Hyman Bradley T BT Jarvik Gail P GP Abner Erin E Jin Lee-Way LW Jun Gyungah G Karydas Anna A Kaye Jeffrey A JA Kim Ronald R Kowall Neil W NW Kramer Joel H JH LaFerla Frank M FM Lah James J JJ Leverenz James B JB Levey Allan I AI Li Ge G Lieberman Andrew P AP Lunetta Kathryn L KL Lyketsos Constantine G CG Marson Daniel C DC Martiniuk Frank F Mash Deborah C DC Masliah Eliezer E McCormick Wayne C WC McCurry Susan M SM McDavid Andrew N AN McKee Ann C AC Mesulam Marsel M Miller Bruce L BL Miller Carol A CA Miller Joshua W JW Morris John C JC Murrell Jill R JR Myers Amanda J AJ O'Bryant Sid S Olichney John M JM Pankratz Vernon S VS Parisi Joseph E JE Paulson Henry L HL Perry William W Peskind Elaine E Pierce Aimee A Poon Wayne W WW Potter Huntington H Quinn Joseph F JF Raj Ashok A Raskind Murray M Reisberg Barry B Reitz Christiane C Ringman John M JM Roberson Erik D ED Rogaeva Ekaterina E Rosen Howard J HJ Rosenberg Roger N RN Sager Mark A MA Saykin Andrew J AJ Schneider Julie A JA Schneider Lon S LS Seeley William W WW Smith Amanda G AG Sonnen Joshua A JA Spina Salvatore S Stern Robert A RA Swerdlow Russell H RH Tanzi Rudolph E RE Thornton-Wells Tricia A TA Trojanowski John Q JQ Troncoso Juan C JC Van Deerlin Vivianna M VM Van Eldik Linda J LJ Vinters Harry V HV Vonsattel Jean Paul JP Weintraub Sandra S Welsh-Bohmer Kathleen A KA Wilhelmsen Kirk C KC Williamson Jennifer J Wingo Thomas S TS Woltjer Randall L RL Wright Clinton B CB Yu Chang-En CE Yu Lei L Garzia Fabienne F Golamaully Feroze F Septier Gislain G Engelborghs Sebastien S Vandenberghe Rik R De Deyn Peter P PP Fernadez Carmen Muñoz CM Benito Yoland Aladro YA Thonberg Hakan H Forsell Charlotte C Lilius Lena L Kinhult-Stählbom Anne A Kilander Lena L Brundin RoseMarie R Concari Letizia L Helisalmi Seppo S Koivisto Anne Maria AM Haapasalo Annakaisa A Dermecourt Vincent V Fievet Nathalie N Hanon Olivier O Dufouil Carole C Brice Alexis A Ritchie Karen K Dubois Bruno B Himali Jayanadra J JJ Keene C Dirk CD Tschanz JoAnn J Fitzpatrick Annette L AL Kukull Walter A WA Norton Maria M Aspelund Thor T Larson Eric B EB Munger Ron R Rotter Jerome I JI Lipton Richard B RB Bullido María J MJ Hofman Albert A Montine Thomas J TJ Coto Eliecer E Boerwinkle Eric E Petersen Ronald C RC Alvarez Victoria V Rivadeneira Fernando F Reiman Eric M EM Gallo Maura M O'Donnell Christopher J CJ Reisch Joan S JS Bruni Amalia Cecilia AC Royall Donald R DR Dichgans Martin M Sano Mary M Galimberti Daniela D St George-Hyslop Peter P Scarpini Elio E Tsuang Debby W DW Mancuso Michelangelo M Bonuccelli Ubaldo U Winslow Ashley R AR Daniele Antonio A Wu Chuang-Kuo CK Peters Oliver O Nacmias Benedetta B Riemenschneider Matthias M Heun Reinhard R Brayne Carol C Rubinsztein David C DC Bras Jose J Guerreiro Rita R Al-Chalabi Ammar A Shaw Christopher E CE Collinge John J Mann David D Tsolaki Magda M Clarimón Jordi J Sussams Rebecca R Lovestone Simon S O'Donovan Michael C MC Owen Michael J MJ Behrens Timothy W TW Mead Simon S Goate Alison M AM Uitterlinden Andre G AG Holmes Clive C Cruchaga Carlos C Ingelsson Martin M Bennett David A DA Powell John J Golde Todd E TE Graff Caroline C De Jager Philip L PL Morgan Kevin K Ertekin-Taner Nilufer N Combarros Onofre O Psaty Bruce M BM Passmore Peter P Younkin Steven G SG Berr Claudine C Gudnason Vilmundur V Rujescu Dan D Dickson Dennis W DW Dartigues Jean-François JF DeStefano Anita L AL Ortega-Cubero Sara S Hakonarson Hakon H Campion Dominique D Boada Merce M Kauwe John Keoni JK Farrer Lindsay A LA Van Broeckhoven Christine C Ikram M Arfan MA Jones Lesley L Haines Jonathan L JL Tzourio Christophe C Launer Lenore J LJ Escott-Price Valentina V Mayeux Richard R Deleuze Jean-François JF Amin Najaf N Holmans Peter A PA Pericak-Vance Margaret A MA Amouyel Philippe P van Duijn Cornelia M CM Ramirez Alfredo A Wang Li-San LS Lambert Jean-Charles JC Seshadri Sudha S Williams Julie J Schellenberg Gerard D GD
Nature genetics 20170717 9
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<sup>-4</sup>) 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<sup>-8</sup>) using imputed genotypes. We ob ...[more]
