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Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease

V. Escott-Price,C. Bellenguez,Li-San Wang,S. Choi,D. Harold,L. Jones,P. Holmans,A. Gerrish,Alexey Vedernikov,A. Richards,A. Destefano,J. Lambert,C. Ibrahim-Verbaas,A. Naj,R. Sims,G. Jun,J. Bis,G. Beecham,B. Grenier‐Boley,G. Russo,T. Thornton-Wells,N. Denning,A. Smith,V. Chouraki,C. Thomas,M. Ikram,D. Zélénika,B. Vardarajan,Y. Kamatani,Chiao-Feng Lin,H. Schmidt,B. Kunkle,M. Dunstan,M. Vronskaya,Andrew D. Johnson,A. Ruiz,M. Bihoreau,C. Reitz,F. Pasquier,P. Hollingworth,O. Hanon,A. Fitzpatrick,J. Buxbaum,D. Campion,P. Crane,C. Baldwin,T. Becker,V. Gudnason,C. Cruchaga,D. Craig,N. Amin,C. Berr,O. Lopez,P. D. De Jager,V. Deramecourt,J. Johnston,D. Evans,S. Lovestone,L. Letenneur,I. Hernández,D. Rubinsztein,G. Eiriksdottir,K. Sleegers,A. Goate,N. Fievet,M. Huentelman,M. Gill,K. Brown,M. Kamboh,L. Keller,P. Barberger‐Gateau,B. McGuinness,E. Larson,A. Myers,C. Dufouil,S. Todd,D. Wallon,S. Love,E. Rogaeva,J. Gallacher,P. George-Hyslop,J. Clarimón,A. Lleó,A. Bayer,D. Tsuang,Lei Yu,M. Tsolaki,P. Bossù,G. Spalletta,P. Proitsi,J. Collinge,S. Sorbi,Florentino Sanchez Garcia,Nick C Fox,J. Hardy,M. Naranjo,P. Bosco,R. Clarke,C. Brayne,D. Galimberti,E. Scarpini,U. Bonuccelli,M. Mancuso,G. Siciliano,S. Moebus,P. Mecocci,M. Zompo,W. Maier,H. Hampel,A. Pilotto,A. Frank‐García,F. Panza,V. Solfrizzi,P. Caffarra,B. Nacmias,W. Perry,M. Mayhaus,L. Lannfelt,H. Hakonarson,S. Pichler,M. Carrasquillo,M. Ingelsson,D. Beekly,V. Álvarez,F. Zou,O. Valladares,S. Younkin,E. Coto,K. Hamilton-Nelson,W. Gu,C. Razquín,P. Pastor,I. Mateo,M. Owen,K. Faber,P. Jonsson,O. Combarros,M. O’Donovan,L. Cantwell,H. Soininen,D. Blacker,S. Mead,T. Mosley,D. Bennett,T. Harris,L. Fratiglioni,C. Holmes,R. F. de Bruijn,P. Passmore,T. Montine,K. Bettens,J. Rotter,A. Brice,K. Morgan,T. Foroud,W. Kukull,D. Hannequin,J. Powell,M. Nalls,K. Ritchie,K. Lunetta,J. Kauwe,E. Boerwinkle,M. Riemenschneider,M. Boada,M. Hiltunen,E. Martin,R. Schmidt,D. Rujescu,J. Dartigues,R. Mayeux,C. Tzourio,A. Hofman,M. Nöthen,C. Graff,B. Psaty,J. Haines,M. Lathrop,M. Pericak-Vance,L. Launer,C. van Broeckhoven,L. Farrer,C. V. van Duijn,A. Ramírez,S. Seshadri,G. Schellenberg,P. Amouyel,Julie Williams

Published 2014 in PLoS ONE

ABSTRACT

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.

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