CHS Home | Welcome New Investigators | Directory | Contact Us

 

You are here

Home

A novel Alzheimer disease locus located near the gene encoding tau protein.

Friday,2015-04-17 13:47 America/Los_Angeles — zdrager
TitleA novel Alzheimer disease locus located near the gene encoding tau protein.
Publication TypeJournal Article
Year of Publication2016
AuthorsJun, G, Ibrahim-Verbaas, CA, Vronskaya, M, Lambert, J-C, Chung, J, Naj, AC, Kunkle, BW, Wang, L-S, Bis, JC, Bellenguez, C, Harold, D, Lunetta, KL, DeStefano, AL, Grenier-Boley, B, Sims, R, Beecham, GW, Smith, AV, Chouraki, V, Hamilton-Nelson, KL, Ikram, MA, Fiévet, N, Denning, N, Martin, ER, Schmidt, H, Kamatani, Y, Dunstan, ML, Valladares, O, Laza, AR, Zelenika, D, Ramirez, A, Foroud, TM, Choi, S-H, Boland, A, Becker, T, Kukull, WA, van der Lee, SJ, Pasquier, F, Cruchaga, C, Beekly, D, Fitzpatrick, AL, Hanon, O, Gill, M, Barber, R, Gudnason, V, Campion, D, Love, S, Bennett, DA, Amin, N, Berr, C, Tsolaki, M, Buxbaum, JD, Lopez, OL, Deramecourt, V, Fox, NC, Cantwell, LB, Tárraga, L, Dufouil, C, Hardy, J, Crane, PK, Eiriksdottir, G, Hannequin, D, Clarke, R, Evans, D, Mosley, TH, Letenneur, L, Brayne, C, Maier, W, De Jager, P, Emilsson, V, Dartigues, J-F, Hampel, H, Kamboh, MI, de Bruijn, RFAG, Tzourio, C, Pastor, P, Larson, EB, Rotter, JI, O'Donovan, MC, Montine, TJ, Nalls, MA, Mead, S, Reiman, EM, Jonsson, PV, Holmes, C, St George-Hyslop, PH, Boada, M, Passmore, P, Wendland, JR, Schmidt, R, Morgan, K, Winslow, AR, Powell, JF, Carasquillo, M, Younkin, SG, Jakobsdóttir, J, Kauwe, JSK, Wilhelmsen, KC, Rujescu, D, Nöthen, MM, Hofman, A, Jones, L, Haines, JL, Psaty, BM, Van Broeckhoven, C, Holmans, P, Launer, LJ, Mayeux, R, Lathrop, M, Goate, AM, Escott-Price, V, Seshadri, S, Pericak-Vance, MA, Amouyel, P, Williams, J, van Duijn, CM, Schellenberg, GD, Farrer, LA
Corporate/Institutional AuthorsIGAP Consortium
JournalMol Psychiatry
Volume21
Issue1
Pagination108-17
Date Published2016 Jan
ISSN1476-5578
KeywordsAlzheimer Disease, Apolipoprotein E4, Chromosomes, Human, Pair 17, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, tau Proteins
Abstract<p>APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P<1 × 10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE ɛ4-: 718 cases and 1699 controls). Among APOE ɛ4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10(-9)). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ɛ4+ subjects (CR1 and CLU) or APOE ɛ4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P ⩽ 1.3 × 10(-8)), frontal cortex (P ⩽ 1.3 × 10(-9)) and temporal cortex (P⩽1.2 × 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10(-6)) and temporal cortex (P=2.6 × 10(-6)). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ɛ4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.</p>
DOI10.1038/mp.2015.23
Alternate JournalMol. Psychiatry
PubMed ID25778476
PubMed Central IDPMC4573764
Grant List081864 / / Wellcome Trust / United Kingdom
089701 / / Wellcome Trust / United Kingdom
089703 / / Wellcome Trust / United Kingdom
167 / / Alzheimer's Society / United Kingdom
AG010491 / AG / NIA NIH HHS / United States
AG019757 / AG / NIA NIH HHS / United States
AG021547 / AG / NIA NIH HHS / United States
AG025688 / AG / NIA NIH HHS / United States
AG027944 / AG / NIA NIH HHS / United States
AG030653 / AG / NIA NIH HHS / United States
AG031287 / AG / NIA NIH HHS / United States
AG033040 / AG / NIA NIH HHS / United States
AG033193 / AG / NIA NIH HHS / United States
AG034504 / AG / NIA NIH HHS / United States
AG041718 / AG / NIA NIH HHS / United States
AG05128 / AG / NIA NIH HHS / United States
AG08122 / AG / NIA NIH HHS / United States
DK063491 / DK / NIDDK NIH HHS / United States
HHSN268200625226C / / PHS HHS / United States
HHSN268200800007C / / PHS HHS / United States
HHSN268201200036C / / PHS HHS / United States
HL093029 / HL / NHLBI NIH HHS / United States
K01 AG030514 / AG / NIA NIH HHS / United States
K24HL038444 / HL / NHLBI NIH HHS / United States
MC_U123192748 / / Medical Research Council / United Kingdom
MO1RR00096 / RR / NCRR NIH HHS / United States
MR/L501529/1 / / Medical Research Council / United Kingdom
N01-HC-25195 / HC / NHLBI NIH HHS / United States
N01-HC-55015 / HC / NHLBI NIH HHS / United States
N01-HC-55016 / HC / NHLBI NIH HHS / United States
N01-HC-55018 / HC / NHLBI NIH HHS / United States
N01-HC-55019 / HC / NHLBI NIH HHS / United States
N01-HC-55020 / HC / NHLBI NIH HHS / United States
N01-HC-55021 / HC / NHLBI NIH HHS / United States
N01-HC-55022 / HC / NHLBI NIH HHS / United States
N01HC55222 / HC / NHLBI NIH HHS / United States
N01HC85079 / HC / NHLBI NIH HHS / United States
N01HC85080 / HC / NHLBI NIH HHS / United States
N01HC85081 / HC / NHLBI NIH HHS / United States
N01HC85082 / HC / NHLBI NIH HHS / United States
N01HC85083 / HC / NHLBI NIH HHS / United States
N01HC85086 / HC / NHLBI NIH HHS / United States
N02-HL-6-4278 / HL / NHLBI NIH HHS / United States
NIMH MH60451 / / PHS HHS / United States
NS39764 / NS / NINDS NIH HHS / United States
P01 AG002219 / AG / NIA NIH HHS / United States
P01 AG003991 / AG / NIA NIH HHS / United States
P01 AG019724 / AG / NIA NIH HHS / United States
P01 AG019724 / AG / NIA NIH HHS / United States
P01 AG03991 / AG / NIA NIH HHS / United States
P30 AG008017 / AG / NIA NIH HHS / United States
P30 AG008051 / AG / NIA NIH HHS / United States
P30 AG010124 / AG / NIA NIH HHS / United States
P30 AG010124 / AG / NIA NIH HHS / United States
P30 AG010129 / AG / NIA NIH HHS / United States
P30 AG010161 / AG / NIA NIH HHS / United States
P30 AG010161 / AG / NIA NIH HHS / United States
P30 AG012300 / AG / NIA NIH HHS / United States
P30 AG013846 / AG / NIA NIH HHS / United States
P30 AG013846 / AG / NIA NIH HHS / United States
P30 AG013854 / AG / NIA NIH HHS / United States
P30 AG019610 / AG / NIA NIH HHS / United States
P30 AG028377 / AG / NIA NIH HHS / United States
P30 AG028383 / AG / NIA NIH HHS / United States
P30 AG08051 / AG / NIA NIH HHS / United States
P30 AG10133 / AG / NIA NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
P30 ES013508 / ES / NIEHS NIH HHS / United States
P50 AG005131 / AG / NIA NIH HHS / United States
P50 AG005131 / AG / NIA NIH HHS / United States
P50 AG005133 / AG / NIA NIH HHS / United States
P50 AG005133 / AG / NIA NIH HHS / United States
P50 AG005134 / AG / NIA NIH HHS / United States
P50 AG005134 / AG / NIA NIH HHS / United States
P50 AG005136 / AG / NIA NIH HHS / United States
P50 AG005136 / AG / NIA NIH HHS / United States
P50 AG005138 / AG / NIA NIH HHS / United States
P50 AG005142 / AG / NIA NIH HHS / United States
P50 AG005142 / AG / NIA NIH HHS / United States
P50 AG005146 / AG / NIA NIH HHS / United States
P50 AG005681 / AG / NIA NIH HHS / United States
P50 AG005681 / AG / NIA NIH HHS / United States
P50 AG008671 / AG / NIA NIH HHS / United States
P50 AG008702 / AG / NIA NIH HHS / United States
P50 AG016570 / AG / NIA NIH HHS / United States
P50 AG016573 / AG / NIA NIH HHS / United States
P50 AG016574 / AG / NIA NIH HHS / United States
P50 AG016575 / AG / NIA NIH HHS / United States
P50 AG016576 / AG / NIA NIH HHS / United States
P50 AG016577 / AG / NIA NIH HHS / United States
P50 AG016582 / AG / NIA NIH HHS / United States
P50 AG023501 / AG / NIA NIH HHS / United States
P50 AG025688 / AG / NIA NIH HHS / United States
R01 AG017173 / AG / NIA NIH HHS / United States
R01 AG017917 / AG / NIA NIH HHS / United States
R01 AG019085 / AG / NIA NIH HHS / United States
R01 AG019085 / AG / NIA NIH HHS / United States
R01 AG020688 / AG / NIA NIH HHS / United States
R01 AG025259 / AG / NIA NIH HHS / United States
R01 AG025259 / AG / NIA NIH HHS / United States
R01 AG026916 / AG / NIA NIH HHS / United States
R01 AG027944 / AG / NIA NIH HHS / United States
R01 AG031581 / AG / NIA NIH HHS / United States
R01 AG033193 / AG / NIA NIH HHS / United States
R01 AG033193 / AG / NIA NIH HHS / United States
R01 AG15819 / AG / NIA NIH HHS / United States
R01 AG16495 / AG / NIA NIH HHS / United States
R01 AG17917 / AG / NIA NIH HHS / United States
R01 AG30146 / AG / NIA NIH HHS / United States
R01 CA129769 / CA / NCI NIH HHS / United States
R01 MH080295 / MH / NIMH NIH HHS / United States
R01 NS059873 / NS / NINDS NIH HHS / United States
R01 NS080820 / NS / NINDS NIH HHS / United States
R01 NS17950 / NS / NINDS NIH HHS / United States
R01-HL087641 / HL / NHLBI NIH HHS / United States
R01-HL093029 / HL / NHLBI NIH HHS / United States
R01AG023629 / AG / NIA NIH HHS / United States
R01AG027058 / AG / NIA NIH HHS / United States
R01AG033193 / AG / NIA NIH HHS / United States
R01AG15928 / AG / NIA NIH HHS / United States
R01AG20098 / AG / NIA NIH HHS / United States
R01AG33193 / AG / NIA NIH HHS / United States
R01HL087652 / HL / NHLBI NIH HHS / United States
R01HL103612 / HL / NHLBI NIH HHS / United States
R01HL105756 / HL / NHLBI NIH HHS / United States
R01HL120393 / HL / NHLBI NIH HHS / United States
R37 AG015473 / AG / NIA NIH HHS / United States
RC2 AG036528 / AG / NIA NIH HHS / United States
RC2 AG036528 / AG / NIA NIH HHS / United States
RC2 AG036535 / AG / NIA NIH HHS / United States
RC2-HL102419 / HL / NHLBI NIH HHS / United States
RF1 AG015819 / AG / NIA NIH HHS / United States
U01 AG016976 / AG / NIA NIH HHS / United States
U01 AG016976 / AG / NIA NIH HHS / United States
U01 AG024904 / AG / NIA NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States
U01 AG046139 / AG / NIA NIH HHS / United States
U01 AG049505 / AG / NIA NIH HHS / United States
U01 AG10483 / AG / NIA NIH HHS / United States
U01 HG006375 / HG / NHGRI NIH HHS / United States
U01 HL096917 / HL / NHLBI NIH HHS / United States
U01-HG004402 / HG / NHGRI NIH HHS / United States
U01HL080295 / HL / NHLBI NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States
U24 AG026390 / AG / NIA NIH HHS / United States
U24 AG026395 / AG / NIA NIH HHS / United States
U24-AG041689 / AG / NIA NIH HHS / United States
U24AG026395 / AG / NIA NIH HHS / United States
UC2 HL103010 / HL / NHLBI NIH HHS / United States
UL1 RR029893 / RR / NCRR NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
UL1 TR001108 / TR / NCATS NIH HHS / United States
UL1RR025005 / RR / NCRR NIH HHS / United States
UL1RR02777 / RR / NCRR NIH HHS / United States
UL1TR000124 / TR / NCATS NIH HHS / United States
UO1 AG06781 / AG / NIA NIH HHS / United States
UO1 HG004610 / HG / NHGRI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
/ / Medical Research Council / United Kingdom
/ / Wellcome Trust / United Kingdom

© 2001 - 2020 CHS Coordinating Center University of Washington, Seattle, WA

Privacy | Terms