Abstract
APOE ε4, 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 ε4+ (10 352 cases and 9207 controls) and APOE ε4- (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 ε4 status. Suggestive associations (P<1 × 10-4) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ε4+: 1250 cases and 536 controls; APOE ε4-: 718 cases and 1699 controls). Among APOE ε4- 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 ε4+ subjects (CR1 and CLU) or APOE ε4- 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 ε4 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.
| Original language | English |
|---|---|
| Pages (from-to) | 108-117 |
| Number of pages | 10 |
| Journal | Molecular Psychiatry |
| Volume | 21 |
| Issue number | 1 |
| DOIs | |
| State | Published - 1 Jan 2016 |
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In: Molecular Psychiatry, Vol. 21, No. 1, 01.01.2016, p. 108-117.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - A novel Alzheimer disease locus located near the gene encoding tau protein
AU - Jun, G.
AU - Ibrahim-Verbaas, C. A.
AU - Vronskaya, M.
AU - Lambert, J. C.
AU - Chung, J.
AU - Naj, A. C.
AU - Kunkle, B. W.
AU - Wang, L. S.
AU - Bis, J. C.
AU - Bellenguez, C.
AU - Harold, D.
AU - Lunetta, K. L.
AU - Destefano, A. L.
AU - Grenier-Boley, B.
AU - Sims, R.
AU - Beecham, G. W.
AU - Smith, A. V.
AU - Chouraki, V.
AU - Hamilton-Nelson, K. L.
AU - Ikram, M. A.
AU - Fievet, N.
AU - Denning, N.
AU - Martin, E. R.
AU - Schmidt, H.
AU - Kamatani, Y.
AU - Dunstan, M. L.
AU - Valladares, O.
AU - Laza, A. R.
AU - Zelenika, D.
AU - Ramirez, A.
AU - Foroud, T. M.
AU - Choi, S. H.
AU - Boland, A.
AU - Becker, T.
AU - Kukull, W. A.
AU - Van Der Lee, S. J.
AU - Pasquier, F.
AU - Cruchaga, C.
AU - Beekly, D.
AU - Fitzpatrick, A. L.
AU - Hanon, O.
AU - Gill, M.
AU - Barber, R.
AU - Gudnason, V.
AU - Campion, D.
AU - Love, S.
AU - Bennett, D. A.
AU - Amin, N.
AU - Berr, C.
AU - Tsolaki, Magda
AU - Buxbaum, J. D.
AU - Lopez, O. L.
AU - Deramecourt, V.
AU - Fox, N. C.
AU - Cantwell, L. B.
AU - Tárraga, L.
AU - Dufouil, C.
AU - Hardy, J.
AU - Crane, P. K.
AU - Eiriksdottir, G.
AU - Hannequin, D.
AU - Clarke, R.
AU - Evans, D.
AU - Mosley, T. H.
AU - Letenneur, L.
AU - Brayne, C.
AU - Maier, W.
AU - De Jager, P.
AU - Emilsson, V.
AU - Dartigues, J. F.
AU - Hampel, H.
AU - Kamboh, M. I.
AU - De Bruijn, R. F.A.G.
AU - Tzourio, C.
AU - Pastor, P.
AU - Larson, E. B.
AU - Rotter, J. I.
AU - O'Donovan, M. C.
AU - Montine, T. J.
AU - Nalls, M. A.
AU - Mead, S.
AU - Reiman, E. M.
AU - Jonsson, P. V.
AU - Holmes, C.
AU - St George-Hyslop, P. H.
AU - Boada, M.
AU - Passmore, P.
AU - Wendland, J. R.
AU - Schmidt, R.
AU - Morgan, K.
AU - Winslow, A. R.
AU - Powell, J. F.
AU - Carasquillo, M.
AU - Younkin, S. G.
AU - Jakobsdóttir, J.
AU - Kauwe, J. S.K.
AU - Wilhelmsen, K. C.
AU - Rujescu, D.
AU - Nöthen, M. M.
AU - Hofman, A.
AU - Jones, L.
AU - Haines, J. L.
AU - Psaty, B. M.
AU - Van Broeckhoven, C.
AU - Holmans, P.
AU - Launer, L. J.
AU - Mayeux, R.
AU - Lathrop, M.
AU - Goate, A. M.
AU - Escott-Price, V.
AU - Seshadri, S.
AU - Pericak-Vance, M. A.
AU - Amouyel, P.
AU - Williams, J.
AU - Van Duijn, C. M.
AU - Schellenberg, G. D.
AU - Farrer, L. A.
AU - Adams, Perrie M.
AU - Albert, Marilyn S.
AU - Albin, Roger L.
AU - Apostolova, Liana G.
AU - Arnold, Steven E.
AU - Asthana, Sanjay
AU - Atwood, Craig S.
AU - Baldwin, Clinton T.
AU - Barmada, Michjael M.
AU - Barnes, Lisa L.
AU - Beach, Thomas G.
AU - Bigio, Eileen H.
AU - Bird, Thomas D.
AU - Blacker, Deborah
AU - Boeve, Bradley F.
AU - Bowen, James D.
AU - Boxer, Adam
AU - Burke, James R.
AU - Cairns, Nigel J.
AU - Cao, Chuanhai
AU - Carlson, Chris S.
AU - Carlsson, Cynthia M.
AU - Carney, Regina M.
AU - Carrasquillo, Minerva M.
AU - Carroll, Steven L.
AU - Chui, Helena C.
AU - Clark, David G.
AU - Corneveaux, Jason
AU - Cribbs, David H.
AU - Crocco, Elizabeth A.
AU - DeCarli, Charles
AU - DeKosky, Steven T.
AU - Yesim Demirci, F.
AU - Dick, Malcolm
AU - Dickson, Dennis W.
AU - Doody, Rachelle S.
AU - Duara, Ranjan
AU - Ertekin-Taner, Nilufer
AU - Faber, Kelley M.
AU - Fairchild, Thomas J.
AU - Fallon, Kenneth B.
AU - Farlow, Martin R.
AU - Ferris, Steven
AU - Frosch, Matthew P.
AU - Galasko, Douglas R.
AU - Gearing, Marla
AU - Geschwind, Daniel H.
AU - Ghetti, Bernardino
AU - Gilbert, John R.
AU - Glass, Jonathan D.
AU - Graff-Radford, Neill R.
AU - Green, Robert C.
AU - Growdon, John H.
AU - Hakonarson, Hakon
AU - Hamilton, Ronald L.
AU - Harrell, Lindy E.
AU - Head, Elizabeth
AU - Honig, Lawrence S.
AU - Huebinger, Ryan M.
AU - Huentelman, Matthew J.
AU - Hulette, Christine M.
AU - Hyman, Bradley T.
AU - Jarvik, Gail P.
AU - Jicha, Gregory A.
AU - Jin, Lee Way
AU - Karydas, Anna
AU - Kaye, Jeffrey A.
AU - Kim, Ronald
AU - Koo, Edward H.
AU - Kowall, Neil W.
AU - Kramer, Joel H.
AU - LaFerla, Frank M.
AU - Lah, James J.
AU - Leverenz, James B.
AU - Levey, Allan I.
AU - Li, Ge
AU - Lieberman, Andrew P.
AU - Lin, Chiao Feng
AU - Lyketsos, Constantine G.
AU - Mack, Wendy J.
AU - Marson, Daniel C.
AU - Martiniuk, Frank
AU - Mash, Deborah C.
AU - Masliah, Eliezer
AU - McCormick, Wayne C.
AU - McCurry, Susan M.
AU - McDavid, Andrew N.
AU - McKee, Ann C.
AU - Mesulam, Marsel
AU - Miller, Bruce L.
AU - Miller, Carol A.
AU - Miller, Joshua W.
AU - Morris, John C.
AU - Mukherjee, Shubhabrata
AU - Murrell, Jill R.
AU - Myers, Amanda J.
AU - O'Bryant, Sid
AU - Olichney, John M.
AU - Pankratz, Vernon S.
AU - Parisi, Joseph E.
AU - Partch, Amanda
AU - Paulson, Henry L.
AU - Perry, William
AU - Peskind, Elaine
AU - Petersen, Ronald C.
AU - Pierce, Aimee
AU - Poon, Wayne W.
AU - Potter, Huntington
AU - Quinn, Joseph F.
AU - Raj, Ashok
AU - Raskind, Murray
AU - Reisberg, Barry
AU - Reisch, Joan S.
AU - Reitz, Christiane
AU - Ringman, John M.
AU - Roberson, Erik D.
AU - Rogaeva, Ekaterina
AU - Rosen, Howard J.
AU - Rosenberg, Roger N.
AU - Royall, Donald R.
AU - Sager, Mark A.
AU - Sano, Mary
AU - Saykin, Andrew J.
AU - Schneider, Julie A.
AU - Schneider, Lon S.
AU - Seeley, William W.
AU - Smith, Amanda G.
AU - Sonnen, Joshua A.
AU - Spina, Salvatore
AU - Stern, Robert A.
AU - Tanzi, Rudolph E.
AU - Thornton-Wells, Tricia A.
AU - Trojanowski, John Q.
AU - Troncoso, Juan C.
AU - Tsuang, Debby W.
AU - Van Deerlin, Vivianna M.
AU - Van Eldik, Linda J.
AU - Vardarajan, Badri N.
AU - Vinters, Harry V.
AU - Vonsattel, Jean Paul
AU - Weintraub, Sandra
AU - Welsh-Bohmer, Kathleen A.
AU - Williamson, Jennifer
AU - Wishnek, Sarah
AU - Woltjer, Randall L.
AU - Wright, Clinton B.
AU - Wu, Chuang Kuo
AU - Yu, Chang En
AU - Yu, Lei
AU - Thomas, Charlene
AU - Gerrish, Amy
AU - Chapman, Jade
AU - Stretton, Alexandra
AU - Morgan, Angharad
AU - Oldham, Harriet
AU - Owen, Michael J.
AU - Kehoe, Patrick G.
AU - Medway, Christopher
AU - Brown, Kristelle
AU - Lord, Jenny
AU - Turton, James
AU - Hooper, Nigel M.
AU - Vardy, Emma
AU - Warren, Jason D.
AU - Schott, Jonathan M.
AU - Uphill, James
AU - Hollingworth, Paul
AU - Ryan, Natalie
AU - Rossor, Martin
AU - Collinge, John
AU - Ben-Shlomo, Yoav
AU - Makrina, Daniilidou
AU - Gkatzima, Olymbia
AU - Lupton, Michelle
AU - Koutroumani, Maria
AU - Avramidou, Despoina
AU - Germanou, Antonia
AU - Jessen, Frank
AU - Riedel-Heller, Steffi
AU - Dichgans, Martin
AU - Heun, Reiner
AU - Kölsch, Heike
AU - Schürmann, Britta
AU - Herold, Christine
AU - Lacour, André
AU - Drichel, Dmitriy
AU - Hoffmann, Per
AU - Kornhuber, Johannes
AU - Gu, Wei
AU - Feulner, Thomas
AU - Mayhaus, Manuel
AU - Pichler, Sabrina
AU - Riemenschneider, Matthias
AU - van den Bussche, Hendrik
AU - Lawlor, Brian
AU - Lynch, Aoibhinn
AU - Mann, David
AU - Smith, A. David
AU - Warden, Donald
AU - Wilcock, Gordon
AU - Heuser, Isabella
AU - Wiltfang, Jens
AU - Frölich, Lutz
AU - Hüll, Michael
AU - Mayo, Kevin
AU - Livingston, Gill
AU - Bass, Nicholas J.
AU - Gurling, Hugh
AU - McQuillin, Andrew
AU - Gwilliam, Rhian
AU - Deloukas, Panagiotis
AU - Al-Chalabi, Ammar
AU - Shaw, Christopher E.
AU - Singleton, Andrew B.
AU - Guerreiro, Rita
AU - Russo, Giancarlo
AU - Jöckel, Karl Heinz
AU - Moebus, Susanne
AU - Klopp, Norman
AU - Wichmann, H. Erich
AU - Ma, Li
AU - Bisceglio, Gina
AU - Fisher, Elizabeth
AU - Warner, Nick
AU - Pickering-Brown, Stuart
AU - Craig, David
AU - Johnston, Janet A.
AU - McGuinness, Bernadette
AU - Todd, Stephen
AU - Rubinsztein, David C.
AU - Lovestone, Simon
AU - Bayer, Anthony
AU - Gallacher, John
AU - Proitsi, Petroula
AU - Ortega-Cubero, Sara
N1 - Publisher Copyright: © 2016 Macmillan Publishers Limited All rights reserved.
PY - 2016/1/1
Y1 - 2016/1/1
N2 - APOE ε4, 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 ε4+ (10 352 cases and 9207 controls) and APOE ε4- (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 ε4 status. Suggestive associations (P<1 × 10-4) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ε4+: 1250 cases and 536 controls; APOE ε4-: 718 cases and 1699 controls). Among APOE ε4- 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 ε4+ subjects (CR1 and CLU) or APOE ε4- 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 ε4 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.
AB - APOE ε4, 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 ε4+ (10 352 cases and 9207 controls) and APOE ε4- (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 ε4 status. Suggestive associations (P<1 × 10-4) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ε4+: 1250 cases and 536 controls; APOE ε4-: 718 cases and 1699 controls). Among APOE ε4- 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 ε4+ subjects (CR1 and CLU) or APOE ε4- 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 ε4 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.
UR - http://www.scopus.com/inward/record.url?scp=84948671541&partnerID=8YFLogxK
U2 - 10.1038/mp.2015.23
DO - 10.1038/mp.2015.23
M3 - Article
C2 - 25778476
AN - SCOPUS:84948671541
SN - 1359-4184
VL - 21
SP - 108
EP - 117
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 1
ER -