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Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates A?, tau, immunity and lipid processing.

ABSTRACT: 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 A? 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?×?10-7), 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.

SUBMITTER: Kunkle BW

PROVIDER: S-EPMC6463297 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.

Kunkle Brian W BW Grenier-Boley Benjamin B Sims Rebecca R Bis Joshua C JC Damotte Vincent V Naj Adam C AC Boland Anne A Vronskaya Maria M van der Lee Sven J SJ Amlie-Wolf Alexandre A Bellenguez Céline C Frizatti Aura A Chouraki Vincent V Martin Eden R ER Sleegers Kristel K Badarinarayan Nandini N Jakobsdottir Johanna J Hamilton-Nelson Kara L KL Moreno-Grau Sonia S Olaso Robert R Raybould Rachel R Chen Yuning Y Kuzma Amanda B AB Hiltunen Mikko M Morgan Taniesha T Ahmad Shahzad S Vardarajan Badri N BN Epelbaum Jacques J Hoffmann Per P Boada Merce M Beecham Gary W GW Garnier Jean-Guillaume JG Harold Denise D Fitzpatrick Annette L AL Valladares Otto O Moutet Marie-Laure ML Gerrish Amy A Smith Albert V AV Qu Liming L Bacq Delphine D Denning Nicola N Jian Xueqiu X Zhao Yi Y Del Zompo Maria M Fox Nick C NC Choi Seung-Hoan SH Mateo Ignacio I Hughes Joseph T JT Adams Hieab H HH Malamon John J Sanchez-Garcia Florentino F Patel Yogen Y Brody Jennifer A JA Dombroski Beth A BA Naranjo Maria Candida Deniz MCD Daniilidou Makrina M Eiriksdottir Gudny G Mukherjee Shubhabrata S Wallon David D Uphill James J Aspelund Thor T Cantwell Laura B LB Garzia Fabienne F Galimberti Daniela D Hofer Edith E Butkiewicz Mariusz M Fin Bertrand B Scarpini Elio E Sarnowski Chloe C Bush Will S WS Meslage Stéphane S Kornhuber Johannes J White Charles C CC Song Yuenjoo Y Barber Robert C RC Engelborghs Sebastiaan S Sordon Sabrina S Voijnovic Dina D Adams Perrie M PM Vandenberghe Rik R Mayhaus Manuel M Cupples L Adrienne LA Albert Marilyn S MS De Deyn Peter P PP Gu Wei W Himali Jayanadra J JJ Beekly Duane D Squassina Alessio A Hartmann Annette M AM Orellana Adelina A Blacker Deborah D Rodriguez-Rodriguez Eloy E Lovestone Simon S Garcia Melissa E ME Doody Rachelle S RS Munoz-Fernadez Carmen C Sussams Rebecca R Lin Honghuang H Fairchild Thomas J TJ Benito Yolanda A YA Holmes Clive C Karamujić-Čomić Hata H Frosch Matthew P MP Thonberg Hakan H Maier Wolfgang W Roshchupkin Gennady G Ghetti Bernardino B Giedraitis Vilmantas V Kawalia Amit A Li Shuo S Huebinger Ryan M RM Kilander Lena L Moebus Susanne S Hernández Isabel I Kamboh M Ilyas MI Brundin RoseMarie R Turton James J Yang Qiong Q Katz Mindy J MJ Concari Letizia L Lord Jenny J Beiser Alexa S AS Keene C Dirk CD Helisalmi Seppo S Kloszewska Iwona I Kukull Walter A WA Koivisto Anne Maria AM Lynch Aoibhinn A Tarraga Lluís L Larson Eric B EB Haapasalo Annakaisa A Lawlor Brian B Mosley Thomas H TH Lipton Richard B RB Solfrizzi Vincenzo V Gill Michael M Longstreth W T WT Montine Thomas J TJ Frisardi Vincenza V Diez-Fairen Monica M Rivadeneira Fernando F Petersen Ronald C RC Deramecourt Vincent V Alvarez Ignacio I Salani Francesca F Ciaramella Antonio A Boerwinkle Eric E Reiman Eric M EM Fievet Nathalie N Rotter Jerome I JI Reisch Joan S JS Hanon Olivier O Cupidi Chiara C Andre Uitterlinden A G AG Royall Donald R DR Dufouil Carole C Maletta Raffaele Giovanni RG de Rojas Itziar I Sano Mary M Brice Alexis A Cecchetti Roberta R George-Hyslop Peter St PS Ritchie Karen K Tsolaki Magda M Tsuang Debby W DW Dubois Bruno B Craig David D Wu Chuang-Kuo CK Soininen Hilkka H Avramidou Despoina D Albin Roger L RL Fratiglioni Laura L Germanou Antonia A Apostolova Liana G LG Keller Lina L Koutroumani Maria M Arnold Steven E SE Panza Francesco F Gkatzima Olymbia O Asthana Sanjay S Hannequin Didier D Whitehead Patrice P Atwood Craig S CS Caffarra Paolo P Hampel Harald H Quintela Inés I Carracedo Ángel Á Lannfelt Lars L Rubinsztein David C DC Barnes Lisa L LL Pasquier Florence F Frölich Lutz L Barral Sandra S McGuinness Bernadette B Beach Thomas G TG Johnston Janet A JA Becker James T JT Passmore Peter P Bigio Eileen H EH Schott Jonathan M JM Bird Thomas D TD Warren Jason D JD Boeve Bradley F BF Lupton Michelle K MK Bowen James D JD Proitsi Petra P Boxer Adam A Powell John F JF Burke James R JR Kauwe John S K JSK Burns Jeffrey M JM Mancuso Michelangelo M Buxbaum Joseph D JD Bonuccelli Ubaldo U Cairns Nigel J NJ McQuillin Andrew A Cao Chuanhai C Livingston Gill G Carlson Chris S CS Bass Nicholas J NJ Carlsson Cynthia M CM Hardy John J Carney Regina M RM Bras Jose J Carrasquillo Minerva M MM Guerreiro Rita R Allen Mariet M Chui Helena C HC Fisher Elizabeth E Masullo Carlo C Crocco Elizabeth A EA DeCarli Charles C Bisceglio Gina G Dick Malcolm M Ma Li L Duara Ranjan R Graff-Radford Neill R NR Evans Denis A DA Hodges Angela A Faber Kelley M KM Scherer Martin M Fallon Kenneth B KB Riemenschneider Matthias M Fardo David W DW Heun Reinhard R Farlow Martin R MR Kölsch Heike H Ferris Steven S Leber Markus M Foroud Tatiana M TM Heuser Isabella I Galasko Douglas R DR Giegling Ina I Gearing Marla M Hüll Michael M Geschwind Daniel H DH Gilbert John R JR Morris John J Green Robert C RC Mayo Kevin K Growdon John H JH Feulner Thomas T Hamilton Ronald L RL Harrell Lindy E LE Drichel Dmitriy D Honig Lawrence S LS Cushion Thomas D TD Huentelman Matthew J MJ Hollingworth Paul P Hulette Christine M CM Hyman Bradley T BT Marshall Rachel R Jarvik Gail P GP Meggy Alun A Abner Erin E Menzies Georgina E GE Jin Lee-Way LW Leonenko Ganna G Real Luis M LM Jun Gyungah R GR Baldwin Clinton T CT Grozeva Detelina D Karydas Anna A Russo Giancarlo G Kaye Jeffrey A JA Kim Ronald R Jessen Frank F Kowall Neil W NW Vellas Bruno B Kramer Joel H JH Vardy Emma E LaFerla Frank M FM Jöckel Karl-Heinz KH Lah James J JJ Dichgans Martin M Leverenz James B JB Mann David D Levey Allan I AI Pickering-Brown Stuart S Lieberman Andrew P AP Klopp Norman N Lunetta Kathryn L KL Wichmann H-Erich HE Lyketsos Constantine G CG Morgan Kevin K Marson Daniel C DC Brown Kristelle K Martiniuk Frank F Medway Christopher C Mash Deborah C DC Nöthen Markus M MM Masliah Eliezer E Hooper Nigel M NM McCormick Wayne C WC Daniele Antonio A McCurry Susan M SM Bayer Anthony A McDavid Andrew N AN Gallacher John J McKee Ann C AC van den Bussche Hendrik H Mesulam Marsel M Brayne Carol C Miller Bruce L BL Riedel-Heller Steffi S Miller Carol A CA Miller Joshua W JW Al-Chalabi Ammar A Morris John C JC Shaw Christopher E CE Myers Amanda J AJ Wiltfang Jens J O'Bryant Sid S Olichney John M JM Alvarez Victoria V Parisi Joseph E JE Singleton Andrew B AB Paulson Henry L HL Collinge John J Perry William R WR Mead Simon S Peskind Elaine E Cribbs David H DH Rossor Martin M Pierce Aimee A Ryan Natalie S NS Poon Wayne W WW Nacmias Benedetta B Potter Huntington H Sorbi Sandro S Quinn Joseph F JF Sacchinelli Eleonora E Raj Ashok A Spalletta Gianfranco G Raskind Murray M Caltagirone Carlo C Bossù Paola P Orfei Maria Donata MD Reisberg Barry B Clarke Robert R Reitz Christiane C Smith A David AD Ringman John M JM Warden Donald D Roberson Erik D ED Wilcock Gordon G Rogaeva Ekaterina E Bruni Amalia Cecilia AC Rosen Howard J HJ Gallo Maura M Rosenberg Roger N RN Ben-Shlomo Yoav Y Sager Mark A MA Mecocci Patrizia P Saykin Andrew J AJ Pastor Pau P Cuccaro Michael L ML Vance Jeffery M JM Schneider Julie A JA Schneider Lori S LS Slifer Susan S Seeley William W WW Smith Amanda G AG Sonnen Joshua A JA Spina Salvatore S Stern Robert A RA Swerdlow Russell H RH Tang Mitchell M Tanzi Rudolph E RE 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 Saba Yasaman Y Pilotto Alberto A Bullido Maria J MJ Peters Oliver O Crane Paul K PK Bennett David D Bosco Paola P Coto Eliecer E Boccardi Virginia V De Jager Phil L PL Lleo Alberto A Warner Nick N Lopez Oscar L OL Ingelsson Martin M Deloukas Panagiotis P Cruchaga Carlos C Graff Caroline C Gwilliam Rhian R Fornage Myriam M Goate Alison M AM Sanchez-Juan Pascual P Kehoe Patrick G PG Amin Najaf N Ertekin-Taner Nilifur N Berr Claudine C Debette Stéphanie S Debette Stéphanie S Love Seth S Launer Lenore J LJ Younkin Steven G SG Dartigues Jean-Francois JF Corcoran Chris C Ikram M Arfan MA Dickson Dennis W DW Nicolas Gael G Campion Dominique D Tschanz JoAnn J Schmidt Helena H Hakonarson Hakon H Clarimon Jordi J Munger Ron R Schmidt Reinhold R Farrer Lindsay A LA Van Broeckhoven Christine C C O'Donovan Michael M DeStefano Anita L AL Jones Lesley L Haines Jonathan L JL Deleuze Jean-Francois JF Owen Michael J MJ Gudnason Vilmundur V Mayeux Richard R Escott-Price Valentina V Psaty Bruce M BM Ramirez Alfredo A Wang Li-San LS Ruiz Agustin A van Duijn Cornelia M CM Holmans Peter A PA Seshadri Sudha S Williams Julie J Amouyel Phillippe P Schellenberg Gerard D GD Lambert Jean-Charles JC Pericak-Vance Margaret A MA

Nature genetics 20190228 3

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. Fin ...[more]

PMID: 30820047

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Project description:Identifying genetic risk factors underpinning different aspects of Alzheimer's disease has the potential to provide important insights into pathogenesis. Moving away from simple case-control definitions, there is considerable interest in using quantitative endophenotypes, such as those derived from imaging as outcome measures. Previous genome-wide association studies of imaging-derived biomarkers in sporadic late-onset Alzheimer's disease focused only on phenotypes derived from single imaging modalities. In contrast, we computed a novel multi-modal neuroimaging phenotype comprising cortical amyloid burden and bilateral hippocampal volume. Both imaging biomarkers were used as input to a disease progression modelling algorithm, which estimates the biomarkers' long-term evolution curves from population-based longitudinal data. Among other parameters, the algorithm computes the shift in time required to optimally align a subjects' biomarker trajectories with these population curves. This time shift serves as a disease progression score and it was used as a quantitative trait in a discovery genome-wide association study with n = 944 subjects from the Alzheimer's Disease Neuroimaging Initiative database diagnosed as Alzheimer's disease, mild cognitive impairment or healthy at the time of imaging. We identified a genome-wide significant locus implicating LCORL (rs6850306, chromosome 4; P = 1.03 × 10-8). The top variant rs6850306 was found to act as an expression quantitative trait locus for LCORL in brain tissue. The clinical role of rs6850306 in conversion from healthy ageing to mild cognitive impairment or Alzheimer's disease was further validated in an independent cohort comprising healthy, older subjects from the National Alzheimer's Coordinating Center database. Specifically, possession of a minor allele at rs6850306 was protective against conversion from mild cognitive impairment to Alzheimer's disease in the National Alzheimer's Coordinating Center cohort (hazard ratio = 0.593, 95% confidence interval = 0.387-0.907, n = 911, PBonf = 0.032), in keeping with the negative direction of effect reported in the genome-wide association study (βdisease progression score = -0.07 ± 0.01). The implicated locus is linked to genes with known connections to Alzheimer's disease pathophysiology and other neurodegenerative diseases. Using multimodal imaging phenotypes in association studies may assist in unveiling the genetic drivers of the onset and progression of complex diseases.

Dataset Information

Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates A?, tau, immunity and lipid processing.

Publications

Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.

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