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. 2014 Jun 12;9(6):e94661.
doi: 10.1371/journal.pone.0094661. eCollection 2014.

Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease

Valentina Escott-Price  1 , Céline Bellenguez  2 , Li-San Wang  3 , Seung-Hoan Choi  4 , Denise Harold  1 , Lesley Jones  1 , Peter Holmans  1 , Amy Gerrish  1 , Alexey Vedernikov  1 , Alexander Richards  1 , Anita L DeStefano  4 , Jean-Charles Lambert  2 , Carla A Ibrahim-Verbaas  5 , Adam C Naj  6 , Rebecca Sims  1 , Gyungah Jun  7 , Joshua C Bis  8 , Gary W Beecham  9 , Benjamin Grenier-Boley  2 , Giancarlo Russo  10 , Tricia A Thornton-Wells  11 , Nicola Denning  1 , Albert V Smith  12 , Vincent Chouraki  13 , Charlene Thomas  1 , M Arfan Ikram  14 , Diana Zelenika  15 , Badri N Vardarajan  16 , Yoichiro Kamatani  17 , Chiao-Feng Lin  3 , Helena Schmidt  18 , Brian Kunkle  19 , Melanie L Dunstan  1 , Maria Vronskaya  1 ; United Kingdom Brain Expression Consortium; Andrew D Johnson  20 , Agustin Ruiz  21 , Marie-Thérèse Bihoreau  15 , Christiane Reitz  22 , Florence Pasquier  23 , Paul Hollingworth  1 , Olivier Hanon  24 , Annette L Fitzpatrick  25 , Joseph D Buxbaum  26 , Dominique Campion  27 , Paul K Crane  28 , Clinton Baldwin  29 , Tim Becker  30 , Vilmundur Gudnason  12 , Carlos Cruchaga  31 , David Craig  32 , Najaf Amin  33 , Claudine Berr  34 , Oscar L Lopez  35 , Philip L De Jager  36 , Vincent Deramecourt  23 , Janet A Johnston  32 , Denis Evans  37 , Simon Lovestone  38 , Luc Letenneur  39 , Isabel Hernández  21 , David C Rubinsztein  40 , Gudny Eiriksdottir  41 , Kristel Sleegers  42 , Alison M Goate  31 , Nathalie Fiévet  43 , Matthew J Huentelman  44 , Michael Gill  45 , Kristelle Brown  46 , M Ilyas Kamboh  47 , Lina Keller  48 , Pascale Barberger-Gateau  38 , Bernadette McGuinness  32 , Eric B Larson  49 , Amanda J Myers  50 , Carole Dufouil  39 , Stephen Todd  32 , David Wallon  27 , Seth Love  51 , Ekaterina Rogaeva  52 , John Gallacher  53 , Peter St George-Hyslop  54 , Jordi Clarimon  55 , Alberto Lleo  55 , Anthony Bayer  53 , Debby W Tsuang  56 , Lei Yu  57 , Magda Tsolaki  58 , Paola Bossù  59 , Gianfranco Spalletta  59 , Petra Proitsi  38 , John Collinge  60 , Sandro Sorbi  61 , Florentino Sanchez Garcia  62 , Nick C Fox  63 , John Hardy  64 , Maria Candida Deniz Naranjo  62 , Paolo Bosco  65 , Robert Clarke  66 , Carol Brayne  67 , Daniela Galimberti  68 , Elio Scarpini  68 , Ubaldo Bonuccelli  69 , Michelangelo Mancuso  69 , Gabriele Siciliano  69 , Susanne Moebus  70 , Patrizia Mecocci  71 , Maria Del Zompo  72 , Wolfgang Maier  73 , Harald Hampel  74 , Alberto Pilotto  75 , Ana Frank-García  76 , Francesco Panza  77 , Vincenzo Solfrizzi  77 , Paolo Caffarra  78 , Benedetta Nacmias  61 , William Perry  9 , Manuel Mayhaus  79 , Lars Lannfelt  80 , Hakon Hakonarson  81 , Sabrina Pichler  79 , Minerva M Carrasquillo  82 , Martin Ingelsson  80 , Duane Beekly  83 , Victoria Alvarez  84 , Fanggeng Zou  82 , Otto Valladares  3 , Steven G Younkin  82 , Eliecer Coto  84 , Kara L Hamilton-Nelson  19 , Wei Gu  85 , Cristina Razquin  86 , Pau Pastor  87 , Ignacio Mateo  88 , Michael J Owen  1 , Kelley M Faber  89 , Palmi V Jonsson  90 , Onofre Combarros  88 , Michael C O'Donovan  1 , Laura B Cantwell  3 , Hilkka Soininen  91 , Deborah Blacker  92 , Simon Mead  60 , Thomas H Mosley Jr  93 , David A Bennett  94 , Tamara B Harris  95 , Laura Fratiglioni  96 , Clive Holmes  97 , Renee F A G de Bruijn  98 , Peter Passmore  32 , Thomas J Montine  99 , Karolien Bettens  42 , Jerome I Rotter  100 , Alexis Brice  101 , Kevin Morgan  46 , Tatiana M Foroud  89 , Walter A Kukull  102 , Didier Hannequin  27 , John F Powell  38 , Michael A Nalls  103 , Karen Ritchie  104 , Kathryn L Lunetta  4 , John S K Kauwe  105 , Eric Boerwinkle  106 , Matthias Riemenschneider  85 , Mercè Boada  107 , Mikko Hiltunen  91 , Eden R Martin  9 , Reinhold Schmidt  108 , Dan Rujescu  109 , Jean-François Dartigues  110 , Richard Mayeux  22 , Christophe Tzourio  111 , Albert Hofman  14 , Markus M Nöthen  112 , Caroline Graff  113 , Bruce M Psaty  114 , Jonathan L Haines  115 , Mark Lathrop  116 , Margaret A Pericak-Vance  9 , Lenore J Launer  95 , Christine Van Broeckhoven  42 , Lindsay A Farrer  117 , Cornelia M van Duijn  118 , Alfredo Ramirez  119 , Sudha Seshadri  120 , Gerard D Schellenberg  3 , Philippe Amouyel  121 , Julie Williams  1 ; Cardiovascular Health Study (CHS)
Collaborators, Affiliations

Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease

Valentina Escott-Price et al. 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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Conflict of interest statement

Competing Interests: Bruce M. Psaty serves on the DSMB for a clinical trial of a device funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Figure 1
Figure 1. Linkage disequilibrium structure of TP53INP1 gene.
The SNPs which are significant at 10−4 level are circled in red.
Figure 2
Figure 2. Linkage disequilibrium structure of IGHV1-67 gene ±5 kb.
The SNPs which are significant at 10−4 level are circled in red.
Figure 3
Figure 3. Manhattan plot of gene-wide p-values in the Stage 1 dataset and combined gene-wide p-values where Stage 2 data are available.
Each dot represents a gene, genes in blue lie within the previously reported– associated regions.
See this image and copyright information in PMC

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