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PLoS One DOI:10.1371/journal.pone.0094661

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

Publication TypeJournal Article
Year of Publication2014
AuthorsEscott-Price, V, Bellenguez, C, San Wang, L-, Choi, S-H, Harold, D, Jones, L, Holmans, P, Gerrish, A, Vedernikov, A, Richards, A, DeStefano, AL, Lambert, J-C, Ibrahim-Verbaas, CA, Naj, AC, Sims, R, Jun, G, Bis, JC, Beecham, GW, Grenier-Boley, B, Russo, G, Thornton-Wells, TA, Denning, N, Smith, AV, Chouraki, V, Thomas, C, M Ikram, A, Zelenika, D, Vardarajan, BN, Kamatani, Y, Lin, C-F, Schmidt, H, Kunkle, B, Dunstan, ML, Vronskaya, M, Johnson, AD, Ruiz, A, Bihoreau, M-T, Reitz, C, Pasquier, F, Hollingworth, P, Hanon, O, Fitzpatrick, AL, Buxbaum, JD, Campion, D, Crane, PK, Baldwin, C, Becker, T, Gudnason, V, Cruchaga, C, Craig, D, Amin, N, Berr, C, Lopez, OL, De Jager, PL, Deramecourt, V, Johnston, JA, Evans, D, Lovestone, S, Letenneur, L, Hernández, I, Rubinsztein, DC, Eiriksdottir, G, Sleegers, K, Goate, AM, Fiévet, N, Huentelman, MJ, Gill, M, Brown, K, M Kamboh, I, Keller, L, Barberger-Gateau, P, McGuinness, B, Larson, EB, Myers, AJ, Dufouil, C, Todd, S, Wallon, D, Love, S, Rogaeva, E, Gallacher, J, St George-Hyslop, P, Clarimon, J, Lleo, A, Bayer, A, Tsuang, DW, Yu, L, Tsolaki, M, Bossù, P, Spalletta, G, Proitsi, P, Collinge, J, Sorbi, S, Garcia, FSanchez, Fox, NC, Hardy, J, Naranjo, MCandida De, Bosco, P, Clarke, R, Brayne, C, Galimberti, D, Scarpini, E, Bonuccelli, U, Mancuso, M, Siciliano, G, Moebus, S, Mecocci, P, Del Zompo, M, Maier, W, Hampel, H, Pilotto, A, Frank-García, A, Panza, F, Solfrizzi, V, Caffarra, P, Nacmias, B, Perry, W, Mayhaus, M, Lannfelt, L, Hakonarson, H, Pichler, S, Carrasquillo, MM, Ingelsson, M, Beekly, D, Alvarez, V, Zou, F, Valladares, O, Younkin, SG, Coto, E, Hamilton-Nelson, KL, Gu, W, Razquin, C, Pastor, P, Mateo, I, Owen, MJ, Faber, KM, Jonsson, PV, Combarros, O, O'Donovan, MC, Cantwell, LB, Soininen, H, Blacker, D, Mead, S, Mosley, TH, Bennett, DA, Harris, TB, Fratiglioni, L, Holmes, C, de Bruijn, RFAG, Passmore, P, Montine, TJ, Bettens, K, Rotter, JI, Brice, A, Morgan, K, Foroud, TM, Kukull, WA, Hannequin, D, Powell, JF, Nalls, MA, Ritchie, K, Lunetta, KL, Kauwe, JSK, Boerwinkle, E, Riemenschneider, M, Boada, M, Hiltunen, M, Martin, ER, Schmidt, R, Rujescu, D, Dartigues, J-F, Mayeux, R, Tzourio, C, Hofman, A, Nöthen, MM, Graff, C, Psaty, BM, Haines, JL, Lathrop, M, Pericak-Vance, MA, Launer, LJ, Van Broeckhoven, C, Farrer, LA, van Duijn, CM, Ramirez, A, Seshadri, S, Schellenberg, GD, Amouyel, P, Williams, J
Corporate AuthorsUnited Kingdom Brain Expression Consortium, Cardiovascular Health Study (CHS)
JournalPLoS One
Volume9
Issue6
Pagese94661
Date Published2014
ISSN1932-6203
KeywordsAlzheimer Disease, Carrier Proteins, Case-Control Studies, Genome-Wide Association Study, Heat-Shock Proteins, Humans, Polymorphism, Single Nucleotide, Receptors, Antigen, B-Cell
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.

URLhttp://dx.plos.org/10.1371/journal.pone.0094661
DOI10.1371/journal.pone.0094661
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24922517?dopt=Abstract

Alternate JournalPLoS ONE
PubMed ID24922517
PubMed Central IDPMC4055488
Grant ListMH60451 / MH / NIMH NIH HHS / United States
MR/K013041/1 / / Medical Research Council / United Kingdom
P50AG005133 / AG / NIA NIH HHS / United States
MC_U123192748 / / Medical Research Council / United Kingdom
P50 AG008671 / AG / NIA NIH HHS / United States
RC2-HL102419 / HL / NHLBI NIH HHS / United States
P30 AG010129 / AG / NIA NIH HHS / United States
U01 HG006375 / HG / NHGRI NIH HHS / United States
AG027058 / AG / NIA NIH HHS / United States
AG15928 / AG / NIA NIH HHS / United States
T32 GM008151 / GM / NIGMS NIH HHS / United States
RF1 AG015819 / AG / NIA NIH HHS / United States
P50 AG005142 / AG / NIA NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States
K24HL038444 / HL / NHLBI NIH HHS / United States
R01 HL096917 / HL / NHLBI NIH HHS / United States
MC_U123160651 / / Medical Research Council / United Kingdom
P30 AG010124 / AG / NIA NIH HHS / United States
167 / / Alzheimer's Society / United Kingdom
HL105756 / HL / NHLBI NIH HHS / United States
U01 AG016976 / AG / NIA NIH HHS / United States
P50 AG005681 / AG / NIA NIH HHS / United States
P30 AG013846 / AG / NIA NIH HHS / United States
R01 AG017917 / AG / NIA NIH HHS / United States
AG033193 / AG / NIA NIH HHS / United States
U01 AG024904 / AG / NIA NIH HHS / United States
HL093029 / HL / NHLBI NIH HHS / United States
HL087652 / HL / NHLBI NIH HHS / United States
P01 AG03991 / AG / NIA NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
RC2 AG036535 / AG / NIA NIH HHS / United States
MC_U137686857 / / Medical Research Council / United Kingdom
G0902227 / / Medical Research Council / United Kingdom
P50 AG005136 / AG / NIA NIH HHS / United States
AG010491 / AG / NIA NIH HHS / United States
NS39764 / NS / NINDS NIH HHS / United States
UL1 TR001108 / TR / NCATS NIH HHS / United States
089703 / / Wellcome Trust / United Kingdom
MR/L501517/1 / / Medical Research Council / United Kingdom
AG041718 / AG / NIA NIH HHS / United States
AG08122 / AG / NIA NIH HHS / United States
UC2 HL103 / HL / NHLBI NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
P30 AG010161 / AG / NIA NIH HHS / United States
AG030653 / AG / NIA NIH HHS / United States
AG027944 / AG / NIA NIH HHS / United States
P50 AG025688 / AG / NIA NIH HHS / United States
R01 AG019085 / AG / NIA NIH HHS / United States
P50 AG008671; / AG / NIA NIH HHS / United States
164 / / Alzheimer's Society / United Kingdom
K01 AG030514 / AG / NIA NIH HHS / United States
P50 AG005133 / AG / NIA NIH HHS / United States
U01 AG006781 / AG / NIA NIH HHS / United States
R01 AG041797 / AG / NIA NIH HHS / United States
R01 AG034504 / AG / NIA NIH HHS / United States
R01 AG041232 / AG / NIA NIH HHS / United States
R01 AG037212 / AG / NIA NIH HHS / United States
N01-AG-12100 / AG / NIA NIH HHS / United States
AG034504 / AG / NIA NIH HHS / United States
DK063491 / DK / NIDDK NIH HHS / United States
HL080295 / HL / NHLBI NIH HHS / United States
AG20098 / AG / NIA NIH HHS / United States
MR/L010305/1 / / Medical Research Council / United Kingdom
095317 / / Wellcome Trust / United Kingdom
100140 / / Wellcome Trust / United Kingdom
AG019757 / AG / NIA NIH HHS / United States
AG023629 / AG / NIA NIH HHS / United States
081864 / / Wellcome Trust / United Kingdom
AG021547 / AG / NIA NIH HHS / United States
U01 AG049505 / AG / NIA NIH HHS / United States