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

TitleGene-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
Paginatione94661
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.
DOI10.1371/journal.pone.0094661
Alternate JournalPLoS One
PubMed ID24922517
PubMed Central IDPMC4055488
Grant ListUC2 HL103 / HL / NHLBI NIH HHS / United States
P50 AG008671; / AG / NIA NIH HHS / United States
P30 AG013854 / AG / NIA NIH HHS / United States
N01HC55020 / HL / NHLBI NIH HHS / United States
167 / ALZS_ / Alzheimer's Society / United Kingdom
P50 MH060451 / MH / NIMH NIH HHS / United States
K01 AG030514 / AG / NIA NIH HHS / United States
MH60451 / MH / NIMH NIH HHS / United States
P50AG005133 / AG / NIA NIH HHS / United States
RC2 HL102419 / HL / NHLBI NIH HHS / United States
P30 AG010124 / AG / NIA NIH HHS / United States
P50 AG023501 / AG / NIA NIH HHS / United States
RC2-HL102419 / HL / NHLBI NIH HHS / United States
U01 HG006375 / HG / NHGRI NIH HHS / United States
UC2 HL103010 / HL / NHLBI NIH HHS / United States
AG027058 / AG / NIA NIH HHS / United States
M01 RR000096 / RR / NCRR NIH HHS / United States
RC2 AG036528 / AG / NIA NIH HHS / United States
AG15928 / AG / NIA NIH HHS / United States
P30 AG028377 / AG / NIA NIH HHS / United States
MC_U137686857 / MRC_ / Medical Research Council / United Kingdom
R01 NS017950 / NS / NINDS NIH HHS / United States
N01AG12100 / AG / NIA NIH HHS / United States
T32 GM008151 / GM / NIGMS NIH HHS / United States
RF1 AG015819 / AG / NIA NIH HHS / United States
G0902227 / MRC_ / Medical Research Council / United Kingdom
P50 AG008671 / AG / NIA NIH HHS / United States
N01HC55018 / HL / NHLBI NIH HHS / United States
P50 AG005142 / AG / NIA NIH HHS / United States
R01 AG016495 / AG / NIA NIH HHS / United States
MC_U123192748 / MRC_ / Medical Research Council / United Kingdom
UL1 RR025005 / RR / NCRR NIH HHS / United States
P50 AG005131 / AG / NIA NIH HHS / United States
R01 AG015928 / AG / NIA NIH HHS / United States
P50 AG005128 / AG / NIA NIH HHS / United States
P30 AG010133 / AG / NIA NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States
R01 AG031581 / AG / NIA NIH HHS / United States
K24HL038444 / HL / NHLBI NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
R01 HL096917 / HL / NHLBI NIH HHS / United States
P50 AG016574 / AG / NIA NIH HHS / United States
P50 AG005146 / AG / NIA NIH HHS / United States
U01 HL096917 / HL / NHLBI NIH HHS / United States
R01 AG019085 / AG / NIA NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States
HL105756 / HL / NHLBI NIH HHS / United States
R01 AG030146 / AG / NIA NIH HHS / United States
HHSN268200800007C / HL / NHLBI NIH HHS / United States
U01 AG024904 / AG / NIA NIH HHS / United States
P50 AG008702 / AG / NIA NIH HHS / United States
MR/L010305/1 / MRC_ / Medical Research Council / United Kingdom
UL1 RR029893 / RR / NCRR NIH HHS / United States
R56 AG020098 / AG / NIA NIH HHS / United States
U01 AG016976 / AG / NIA NIH HHS / United States
P50 NS039764 / NS / NINDS NIH HHS / United States
P01 AG003991 / AG / NIA NIH HHS / United States
P30 AG008051 / AG / NIA NIH HHS / United States
P50 AG005681 / AG / NIA NIH HHS / United States
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U24 AG056270 / AG / NIA NIH HHS / United States
R01 AG017917 / AG / NIA NIH HHS / United States
AG033193 / AG / NIA NIH HHS / United States
164 / ALZS_ / Alzheimer's Society / United Kingdom
R01 HL087652 / HL / NHLBI NIH HHS / United States
N01HC55022 / HL / NHLBI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
N01HC55222 / HL / NHLBI NIH HHS / United States
R01 MH080295 / MH / NIMH NIH HHS / United States
U01 HG004402 / HG / NHGRI 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
RC2 AG036535 / AG / NIA NIH HHS / United States
P50 AG005136 / AG / NIA NIH HHS / United States
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AG010491 / AG / NIA NIH HHS / United States
NS39764 / NS / NINDS NIH HHS / United States
UL1 TR001108 / TR / NCATS NIH HHS / United States
R01 HL093029 / HL / NHLBI NIH HHS / United States
P30 AG012300 / AG / NIA NIH HHS / United States
N01HC85086 / HL / NHLBI NIH HHS / United States
089703 / WT_ / Wellcome Trust / United Kingdom
R01 HL105756 / HL / NHLBI NIH HHS / United States
AG041718 / AG / NIA NIH HHS / United States
AG08122 / AG / NIA NIH HHS / United States
MR/K013041/1 / MRC_ / Medical Research Council / United Kingdom
P50 AG016573 / AG / NIA NIH HHS / United States
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AG030653 / AG / NIA NIH HHS / United States
R37 AG015473 / AG / NIA NIH HHS / United States
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P01 AG002219 / AG / NIA NIH HHS / United States
R01 HL080295 / HL / NHLBI NIH HHS / United States
U01 AG006781 / AG / NIA NIH HHS / United States
R01 AG041797 / AG / NIA NIH HHS / United States
P01 AG010491 / AG / NIA NIH HHS / United States
R01 AG033040 / AG / NIA NIH HHS / United States
R01 AG034504 / AG / NIA NIH HHS / United States
P50 AG005138 / AG / NIA NIH HHS / United States
R01 AG037212 / AG / NIA NIH HHS / United States
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R01 AG041232 / AG / NIA NIH HHS / United States
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N01-AG-12100 / AG / NIA NIH HHS / United States
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AG034504 / AG / NIA NIH HHS / United States
R01 AG017173 / AG / NIA NIH HHS / United States
R01 AG025259 / AG / NIA NIH HHS / United States
DK063491 / DK / NIDDK NIH HHS / United States
U01 HG004610 / HG / NHGRI NIH HHS / United States
/ WT_ / Wellcome Trust / United Kingdom
P30 AG010129 / AG / NIA NIH HHS / United States
P30 AG019610 / AG / NIA NIH HHS / United States
P50 AG016582 / AG / NIA NIH HHS / United States
HL080295 / HL / NHLBI NIH HHS / United States
R01 AG041718 / AG / NIA NIH HHS / United States
AG20098 / AG / NIA NIH HHS / United States
N01HC85079 / HL / NHLBI NIH HHS / United States
N01HC55021 / HL / NHLBI NIH HHS / United States
R01 AG023629 / AG / NIA NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
095317 / WT_ / Wellcome Trust / United Kingdom
100140 / WT_ / Wellcome Trust / United Kingdom
P30 AG028383 / AG / NIA NIH HHS / United States
R01 AG027058 / AG / NIA NIH HHS / United States
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AG023629 / AG / NIA NIH HHS / United States
R01 AG026916 / AG / NIA NIH HHS / United States
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R01 NS059873 / NS / NINDS NIH HHS / United States
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R56 AG023629 / AG / NIA NIH HHS / United States
MR/L501517/1 / MRC_ / Medical Research Council / United Kingdom
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