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

G. Jun, C. A. Ibrahim-Verbaas, M. Vronskaya, J. C. Lambert, J. Chung, A. C. Naj, B. W. Kunkle, L. S. Wang, J. C. Bis, C. Bellenguez, D. Harold, K. L. Lunetta, A. L. Destefano, B. Grenier-Boley, R. Sims, G. W. Beecham, A. V. Smith, V. Chouraki, K. L. Hamilton-Nelson, M. A. Ikram & 334 others N. Fievet, N. Denning, E. R. Martin, H. Schmidt, Y. Kamatani, M. L. Dunstan, O. Valladares, A. R. Laza, D. Zelenika, A. Ramirez, T. M. Foroud, S. H. Choi, A. Boland, T. Becker, W. A. Kukull, S. J. Van Der Lee, F. Pasquier, C. Cruchaga, D. Beekly, A. L. Fitzpatrick, O. Hanon, M. Gill, Robert Clinton Barber, V. Gudnason, D. Campion, S. Love, D. A. Bennett, N. Amin, C. Berr, Magda Tsolaki, J. D. Buxbaum, O. L. Lopez, V. Deramecourt, N. C. Fox, L. B. Cantwell, L. Tárraga, C. Dufouil, J. Hardy, P. K. Crane, G. Eiriksdottir, D. Hannequin, R. Clarke, D. Evans, T. H. Mosley, L. Letenneur, C. Brayne, W. Maier, P. De Jager, V. Emilsson, J. F. Dartigues, H. Hampel, M. I. Kamboh, R. F.A.G. De Bruijn, C. Tzourio, P. Pastor, E. B. Larson, J. I. Rotter, M. C. O'Donovan, T. J. Montine, M. A. Nalls, S. Mead, E. M. Reiman, P. V. Jonsson, C. Holmes, P. H. St George-Hyslop, M. Boada, P. Passmore, J. R. Wendland, R. Schmidt, K. Morgan, A. R. Winslow, J. F. Powell, M. Carasquillo, S. G. Younkin, J. Jakobsdóttir, J. S.K. Kauwe, K. C. Wilhelmsen, D. Rujescu, M. M. Nöthen, A. Hofman, L. Jones, J. L. Haines, B. M. Psaty, C. Van Broeckhoven, P. Holmans, L. J. Launer, R. Mayeux, M. Lathrop, A. M. Goate, V. Escott-Price, S. Seshadri, M. A. Pericak-Vance, P. Amouyel, J. Williams, C. M. Van Duijn, G. D. Schellenberg, L. A. Farrer, Perrie M. Adams, Marilyn S. Albert, Roger L. Albin, Liana G. Apostolova, Steven E. Arnold, Sanjay Asthana, Craig S. Atwood, Clinton T. Baldwin, Michjael M. Barmada, Lisa L. Barnes, Thomas G. Beach, James T. Becker, Eileen H. Bigio, Thomas D. Bird, Deborah Blacker, Bradley F. Boeve, James D. Bowen, Adam Boxer, James R. Burke, Nigel J. Cairns, Chuanhai Cao, Chris S. Carlson, Cynthia M. Carlsson, Regina M. Carney, Minerva M. Carrasquillo, Steven L. Carroll, Helena C. Chui, David G. Clark, Jason Corneveaux, David H. Cribbs, Elizabeth A. Crocco, Philip L. De Jager, Charles DeCarli, Steven T. DeKosky, F. Yesim Demirci, Malcolm Dick, Dennis W. Dickson, Rachelle S. Doody, Ranjan Duara, Nilufer Ertekin-Taner, Kelley M. Faber, Thomas J. Fairchild, Kenneth B. Fallon, Martin R. Farlow, Steven Ferris, Matthew P. Frosch, Douglas R. Galasko, Marla Gearing, Daniel H. Geschwind, Bernardino Ghetti, John R. Gilbert, Jonathan D. Glass, Neill R. Graff-Radford, Robert C. Green, John H. Growdon, Hakon Hakonarson, Ronald L. Hamilton, Lindy E. Harrell, Elizabeth Head, Lawrence S. Honig, Ryan M. Huebinger, Matthew J. Huentelman, Christine M. Hulette, Bradley T. Hyman, Gail P. Jarvik, Gregory A. Jicha, Lee Way Jin, Anna Karydas, Jeffrey A. Kaye, Ronald Kim, Edward H. Koo, Neil W. Kowall, Joel H. Kramer, Frank M. LaFerla, James J. Lah, James B. Leverenz, Allan I. Levey, Ge Li, Andrew P. Lieberman, Chiao Feng Lin, Constantine G. Lyketsos, Wendy J. Mack, Daniel C. Marson, Frank Martiniuk, Deborah C. Mash, Eliezer Masliah, Wayne C. McCormick, Susan M. McCurry, Andrew N. McDavid, Ann C. McKee, Marsel Mesulam, Bruce L. Miller, Carol A. Miller, Joshua W. Miller, John C. Morris, Shubhabrata Mukherjee, Jill R. Murrell, Amanda J. Myers, Sidney O'Bryant, John M. Olichney, Vernon S. Pankratz, Joseph E. Parisi, Amanda Partch, Henry L. Paulson, William Perry, Elaine Peskind, Ronald C. Petersen, Aimee Pierce, Wayne W. Poon, Huntington Potter, Joseph F. Quinn, Ashok Raj, Murray Raskind, Barry Reisberg, Joan S. Reisch, Christiane Reitz, John M. Ringman, Erik D. Roberson, Ekaterina Rogaeva, Howard J. Rosen, Roger N. Rosenberg, Donald R. Royall, Mark A. Sager, Mary Sano, Andrew J. Saykin, Julie A. Schneider, Lon S. Schneider, William W. Seeley, Amanda G. Smith, Joshua A. Sonnen, Salvatore Spina, Robert A. Stern, Rudolph E. Tanzi, Tricia A. Thornton-Wells, John Q. Trojanowski, Juan C. Troncoso, Debby W. Tsuang, Vivianna M. Van Deerlin, Linda J. Van Eldik, Badri N. Vardarajan, Harry V. Vinters, Jean Paul Vonsattel, Sandra Weintraub, Kathleen A. Welsh-Bohmer, Jennifer Williamson, Sarah Wishnek, Randall L. Woltjer, Clinton B. Wright, Chuang Kuo Wu, Chang En Yu, Lei Yu, Charlene Thomas, Amy Gerrish, Jade Chapman, Alexandra Stretton, Angharad Morgan, Harriet Oldham, Michael J. Owen, Patrick G. Kehoe, Christopher Medway, Kristelle Brown, Jenny Lord, James Turton, Nigel M. Hooper, Emma Vardy, Jason D. Warren, Jonathan M. Schott, James Uphill, Paul Hollingworth, Natalie Ryan, Martin Rossor, John Collinge, Yoav Ben-Shlomo, Daniilidou Makrina, Olymbia Gkatzima, Michelle Lupton, Maria Koutroumani, Despoina Avramidou, Antonia Germanou, Frank Jessen, Steffi Riedel-Heller, Martin Dichgans, Reiner Heun, Heike Kölsch, Britta Schürmann, Christine Herold, André Lacour, Dmitriy Drichel, Per Hoffmann, Johannes Kornhuber, Wei Gu, Thomas Feulner, Manuel Mayhaus, Sabrina Pichler, Matthias Riemenschneider, Hendrik van den Bussche, Brian Lawlor, Aoibhinn Lynch, David Mann, A. David Smith, Donald Warden, Gordon Wilcock, Isabella Heuser, Jens Wiltfang, Lutz Frölich, Michael Hüll, Kevin Mayo, Gill Livingston, Nicholas J. Bass, Hugh Gurling, Andrew McQuillin, Rhian Gwilliam, Panagiotis Deloukas, Ammar Al-Chalabi, Christopher E. Shaw, Andrew B. Singleton, Rita Guerreiro, Giancarlo Russo, Karl Heinz Jöckel, Susanne Moebus, Norman Klopp, H. Erich Wichmann, Li Ma, Gina Bisceglio, Elizabeth Fisher, Nick Warner, Stuart Pickering-Brown, David Craig, Janet A. Johnston, Bernadette McGuinness, Stephen Todd, David C. Rubinsztein, Simon Lovestone, Anthony Bayer, John Gallacher, Petroula Proitsi, Sara Ortega-Cubero

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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 languageEnglish
Pages (from-to)108-117
Number of pages10
JournalMolecular Psychiatry
Volume21
Issue number1
DOIs
StatePublished - 1 Jan 2016

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tau Proteins
Single Nucleotide Polymorphism
Alzheimer Disease
Genes
Exons
Genome-Wide Association Study
Frontal Lobe
Genome
Temporal Lobe
Frontotemporal Dementia
Chromosomes, Human, Pair 17
Quantitative Trait Loci
Masks
Genomics
Meta-Analysis
Hippocampus
Chromosomes
Alleles
Genotype

Cite this

Jun, G., Ibrahim-Verbaas, C. A., Vronskaya, M., Lambert, J. C., Chung, J., Naj, A. C., ... Ortega-Cubero, S. (2016). A novel Alzheimer disease locus located near the gene encoding tau protein. Molecular Psychiatry, 21(1), 108-117. https://doi.org/10.1038/mp.2015.23
Jun, G. ; Ibrahim-Verbaas, C. A. ; Vronskaya, M. ; Lambert, J. C. ; Chung, J. ; Naj, A. C. ; Kunkle, B. W. ; Wang, L. S. ; Bis, J. C. ; Bellenguez, C. ; Harold, D. ; Lunetta, K. L. ; Destefano, A. L. ; Grenier-Boley, B. ; Sims, R. ; Beecham, G. W. ; Smith, A. V. ; Chouraki, V. ; Hamilton-Nelson, K. L. ; Ikram, M. A. ; Fievet, N. ; Denning, N. ; Martin, E. R. ; Schmidt, H. ; Kamatani, Y. ; Dunstan, M. L. ; Valladares, O. ; Laza, A. R. ; Zelenika, D. ; Ramirez, A. ; Foroud, T. M. ; Choi, S. H. ; Boland, A. ; Becker, T. ; Kukull, W. A. ; Van Der Lee, S. J. ; Pasquier, F. ; Cruchaga, C. ; Beekly, D. ; Fitzpatrick, A. L. ; Hanon, O. ; Gill, M. ; Barber, Robert Clinton ; Gudnason, V. ; Campion, D. ; Love, S. ; Bennett, D. A. ; Amin, N. ; Berr, C. ; Tsolaki, Magda ; Buxbaum, J. D. ; Lopez, O. L. ; Deramecourt, V. ; Fox, N. C. ; Cantwell, L. B. ; Tárraga, L. ; Dufouil, C. ; Hardy, J. ; Crane, P. K. ; Eiriksdottir, G. ; Hannequin, D. ; Clarke, R. ; Evans, D. ; Mosley, T. H. ; Letenneur, L. ; Brayne, C. ; Maier, W. ; De Jager, P. ; Emilsson, V. ; Dartigues, J. F. ; Hampel, H. ; Kamboh, M. I. ; De Bruijn, R. F.A.G. ; Tzourio, C. ; Pastor, P. ; Larson, E. B. ; Rotter, J. I. ; O'Donovan, M. C. ; Montine, T. J. ; Nalls, M. A. ; Mead, S. ; Reiman, E. M. ; Jonsson, P. V. ; Holmes, C. ; St George-Hyslop, P. H. ; Boada, M. ; Passmore, P. ; Wendland, J. R. ; Schmidt, R. ; Morgan, K. ; Winslow, A. R. ; Powell, J. F. ; Carasquillo, M. ; Younkin, S. G. ; Jakobsdóttir, J. ; Kauwe, J. S.K. ; Wilhelmsen, K. C. ; Rujescu, D. ; Nöthen, M. M. ; Hofman, A. ; Jones, L. ; Haines, J. L. ; Psaty, B. M. ; Van Broeckhoven, C. ; Holmans, P. ; Launer, L. J. ; Mayeux, R. ; Lathrop, M. ; Goate, A. M. ; Escott-Price, V. ; Seshadri, S. ; Pericak-Vance, M. A. ; Amouyel, P. ; Williams, J. ; Van Duijn, C. M. ; Schellenberg, G. D. ; Farrer, L. A. ; Adams, Perrie M. ; Albert, Marilyn S. ; Albin, Roger L. ; Apostolova, Liana G. ; Arnold, Steven E. ; Asthana, Sanjay ; Atwood, Craig S. ; Baldwin, Clinton T. ; Barmada, Michjael M. ; Barnes, Lisa L. ; Beach, Thomas G. ; Becker, James T. ; Bigio, Eileen H. ; Bird, Thomas D. ; Blacker, Deborah ; Boeve, Bradley F. ; Bowen, James D. ; Boxer, Adam ; Burke, James R. ; Cairns, Nigel J. ; Cao, Chuanhai ; Carlson, Chris S. ; Carlsson, Cynthia M. ; Carney, Regina M. ; Carrasquillo, Minerva M. ; Carroll, Steven L. ; Chui, Helena C. ; Clark, David G. ; Corneveaux, Jason ; Cribbs, David H. ; Crocco, Elizabeth A. ; De Jager, Philip L. ; DeCarli, Charles ; DeKosky, Steven T. ; Yesim Demirci, F. ; Dick, Malcolm ; Dickson, Dennis W. ; Doody, Rachelle S. ; Duara, Ranjan ; Ertekin-Taner, Nilufer ; Faber, Kelley M. ; Fairchild, Thomas J. ; Fallon, Kenneth B. ; Farlow, Martin R. ; Ferris, Steven ; Frosch, Matthew P. ; Galasko, Douglas R. ; Gearing, Marla ; Geschwind, Daniel H. ; Ghetti, Bernardino ; Gilbert, John R. ; Glass, Jonathan D. ; Graff-Radford, Neill R. ; Green, Robert C. ; Growdon, John H. ; Hakonarson, Hakon ; Hamilton, Ronald L. ; Harrell, Lindy E. ; Head, Elizabeth ; Honig, Lawrence S. ; Huebinger, Ryan M. ; Huentelman, Matthew J. ; Hulette, Christine M. ; Hyman, Bradley T. ; Jarvik, Gail P. ; Jicha, Gregory A. ; Jin, Lee Way ; Karydas, Anna ; Kaye, Jeffrey A. ; Kim, Ronald ; Koo, Edward H. ; Kowall, Neil W. ; Kramer, Joel H. ; LaFerla, Frank M. ; Lah, James J. ; Leverenz, James B. ; Levey, Allan I. ; Li, Ge ; Lieberman, Andrew P. ; Lin, Chiao Feng ; Lyketsos, Constantine G. ; Mack, Wendy J. ; Marson, Daniel C. ; Martiniuk, Frank ; Mash, Deborah C. ; Masliah, Eliezer ; McCormick, Wayne C. ; McCurry, Susan M. ; McDavid, Andrew N. ; McKee, Ann C. ; Mesulam, Marsel ; Miller, Bruce L. ; Miller, Carol A. ; Miller, Joshua W. ; Morris, John C. ; Mukherjee, Shubhabrata ; Murrell, Jill R. ; Myers, Amanda J. ; O'Bryant, Sidney ; Olichney, John M. ; Pankratz, Vernon S. ; Parisi, Joseph E. ; Partch, Amanda ; Paulson, Henry L. ; Perry, William ; Peskind, Elaine ; Petersen, Ronald C. ; Pierce, Aimee ; Poon, Wayne W. ; Potter, Huntington ; Quinn, Joseph F. ; Raj, Ashok ; Raskind, Murray ; Reisberg, Barry ; Reisch, Joan S. ; Reitz, Christiane ; Ringman, John M. ; Roberson, Erik D. ; Rogaeva, Ekaterina ; Rosen, Howard J. ; Rosenberg, Roger N. ; Royall, Donald R. ; Sager, Mark A. ; Sano, Mary ; Saykin, Andrew J. ; Schneider, Julie A. ; Schneider, Lon S. ; Seeley, William W. ; Smith, Amanda G. ; Sonnen, Joshua A. ; Spina, Salvatore ; Stern, Robert A. ; Tanzi, Rudolph E. ; Thornton-Wells, Tricia A. ; Trojanowski, John Q. ; Troncoso, Juan C. ; Tsuang, Debby W. ; Van Deerlin, Vivianna M. ; Van Eldik, Linda J. ; Vardarajan, Badri N. ; Vinters, Harry V. ; Vonsattel, Jean Paul ; Weintraub, Sandra ; Welsh-Bohmer, Kathleen A. ; Williamson, Jennifer ; Wishnek, Sarah ; Woltjer, Randall L. ; Wright, Clinton B. ; Wu, Chuang Kuo ; Yu, Chang En ; Yu, Lei ; Thomas, Charlene ; Gerrish, Amy ; Chapman, Jade ; Stretton, Alexandra ; Morgan, Angharad ; Oldham, Harriet ; Owen, Michael J. ; Kehoe, Patrick G. ; Medway, Christopher ; Brown, Kristelle ; Lord, Jenny ; Turton, James ; Hooper, Nigel M. ; Vardy, Emma ; Warren, Jason D. ; Schott, Jonathan M. ; Uphill, James ; Hollingworth, Paul ; Ryan, Natalie ; Rossor, Martin ; Collinge, John ; Ben-Shlomo, Yoav ; Makrina, Daniilidou ; Gkatzima, Olymbia ; Lupton, Michelle ; Koutroumani, Maria ; Avramidou, Despoina ; Germanou, Antonia ; Jessen, Frank ; Riedel-Heller, Steffi ; Dichgans, Martin ; Heun, Reiner ; Kölsch, Heike ; Schürmann, Britta ; Herold, Christine ; Lacour, André ; Drichel, Dmitriy ; Hoffmann, Per ; Kornhuber, Johannes ; Gu, Wei ; Feulner, Thomas ; Mayhaus, Manuel ; Pichler, Sabrina ; Riemenschneider, Matthias ; van den Bussche, Hendrik ; Lawlor, Brian ; Lynch, Aoibhinn ; Mann, David ; Smith, A. David ; Warden, Donald ; Wilcock, Gordon ; Heuser, Isabella ; Wiltfang, Jens ; Frölich, Lutz ; Hüll, Michael ; Mayo, Kevin ; Livingston, Gill ; Bass, Nicholas J. ; Gurling, Hugh ; McQuillin, Andrew ; Gwilliam, Rhian ; Deloukas, Panagiotis ; Al-Chalabi, Ammar ; Shaw, Christopher E. ; Singleton, Andrew B. ; Guerreiro, Rita ; Russo, Giancarlo ; Jöckel, Karl Heinz ; Moebus, Susanne ; Klopp, Norman ; Wichmann, H. Erich ; Ma, Li ; Bisceglio, Gina ; Fisher, Elizabeth ; Warner, Nick ; Pickering-Brown, Stuart ; Craig, David ; Johnston, Janet A. ; McGuinness, Bernadette ; Todd, Stephen ; Rubinsztein, David C. ; Lovestone, Simon ; Bayer, Anthony ; Gallacher, John ; Proitsi, Petroula ; Ortega-Cubero, Sara. / A novel Alzheimer disease locus located near the gene encoding tau protein. In: Molecular Psychiatry. 2016 ; Vol. 21, No. 1. pp. 108-117.
@article{d03dc405a7274f4e979aaf91c7a55cbc,
title = "A novel Alzheimer disease locus located near the gene encoding tau protein",
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.",
author = "G. Jun and Ibrahim-Verbaas, {C. A.} and M. Vronskaya and Lambert, {J. C.} and J. Chung and Naj, {A. C.} and Kunkle, {B. W.} and Wang, {L. S.} and Bis, {J. C.} and C. Bellenguez and D. Harold and Lunetta, {K. L.} and Destefano, {A. L.} and B. Grenier-Boley and R. Sims and Beecham, {G. W.} and Smith, {A. V.} and V. Chouraki and Hamilton-Nelson, {K. L.} and Ikram, {M. A.} and N. Fievet and N. Denning and Martin, {E. R.} and H. Schmidt and Y. Kamatani and Dunstan, {M. L.} and O. Valladares and Laza, {A. R.} and D. Zelenika and A. Ramirez and Foroud, {T. M.} and Choi, {S. H.} and A. Boland and T. Becker and Kukull, {W. A.} and {Van Der Lee}, {S. J.} and F. Pasquier and C. Cruchaga and D. Beekly and Fitzpatrick, {A. L.} and O. Hanon and M. Gill and Barber, {Robert Clinton} and V. Gudnason and D. Campion and S. Love and Bennett, {D. A.} and N. Amin and C. Berr and Magda Tsolaki and Buxbaum, {J. D.} and Lopez, {O. L.} and V. Deramecourt and Fox, {N. C.} and Cantwell, {L. B.} and L. T{\'a}rraga and C. Dufouil and J. Hardy and Crane, {P. K.} and G. Eiriksdottir and D. Hannequin and R. Clarke and D. Evans and Mosley, {T. H.} and L. Letenneur and C. Brayne and W. Maier and {De Jager}, P. and V. Emilsson and Dartigues, {J. F.} and H. Hampel and Kamboh, {M. I.} and {De Bruijn}, {R. F.A.G.} and C. Tzourio and P. Pastor and Larson, {E. B.} and Rotter, {J. I.} and O'Donovan, {M. C.} and Montine, {T. J.} and Nalls, {M. A.} and S. Mead and Reiman, {E. M.} and Jonsson, {P. V.} and C. Holmes and {St George-Hyslop}, {P. H.} and M. Boada and P. Passmore and Wendland, {J. R.} and R. Schmidt and K. Morgan and Winslow, {A. R.} and Powell, {J. F.} and M. Carasquillo and Younkin, {S. G.} and J. Jakobsd{\'o}ttir and Kauwe, {J. S.K.} and Wilhelmsen, {K. C.} and D. Rujescu and N{\"o}then, {M. M.} and A. Hofman and L. Jones and Haines, {J. L.} and Psaty, {B. M.} and {Van Broeckhoven}, C. and P. Holmans and Launer, {L. J.} and R. Mayeux and M. Lathrop and Goate, {A. M.} and V. Escott-Price and S. Seshadri and Pericak-Vance, {M. A.} and P. Amouyel and J. Williams and {Van Duijn}, {C. M.} and Schellenberg, {G. D.} and Farrer, {L. A.} and Adams, {Perrie M.} and Albert, {Marilyn S.} and Albin, {Roger L.} and Apostolova, {Liana G.} and Arnold, {Steven E.} and Sanjay Asthana and Atwood, {Craig S.} and Baldwin, {Clinton T.} and Barmada, {Michjael M.} and Barnes, {Lisa L.} and Beach, {Thomas G.} and Becker, {James T.} and Bigio, {Eileen H.} and Bird, {Thomas D.} and Deborah Blacker and Boeve, {Bradley F.} and Bowen, {James D.} and Adam Boxer and Burke, {James R.} and Cairns, {Nigel J.} and Chuanhai Cao and Carlson, {Chris S.} and Carlsson, {Cynthia M.} and Carney, {Regina M.} and Carrasquillo, {Minerva M.} and Carroll, {Steven L.} and Chui, {Helena C.} and Clark, {David G.} and Jason Corneveaux and Cribbs, {David H.} and Crocco, {Elizabeth A.} and {De Jager}, {Philip L.} and Charles DeCarli and DeKosky, {Steven T.} and {Yesim Demirci}, F. and Malcolm Dick and Dickson, {Dennis W.} and Doody, {Rachelle S.} and Ranjan Duara and Nilufer Ertekin-Taner and Faber, {Kelley M.} and Fairchild, {Thomas J.} and Fallon, {Kenneth B.} and Farlow, {Martin R.} and Steven Ferris and Frosch, {Matthew P.} and Galasko, {Douglas R.} and Marla Gearing and Geschwind, {Daniel H.} and Bernardino Ghetti and Gilbert, {John R.} and Glass, {Jonathan D.} and Graff-Radford, {Neill R.} and Green, {Robert C.} and Growdon, {John H.} and Hakon Hakonarson and Hamilton, {Ronald L.} and Harrell, {Lindy E.} and Elizabeth Head and Honig, {Lawrence S.} and Huebinger, {Ryan M.} and Huentelman, {Matthew J.} and Hulette, {Christine M.} and Hyman, {Bradley T.} and Jarvik, {Gail P.} and Jicha, {Gregory A.} and Jin, {Lee Way} and Anna Karydas and Kaye, {Jeffrey A.} and Ronald Kim and Koo, {Edward H.} and Kowall, {Neil W.} and Kramer, {Joel H.} and LaFerla, {Frank M.} and Lah, {James J.} and Leverenz, {James B.} and Levey, {Allan I.} and Ge Li and Lieberman, {Andrew P.} and Lin, {Chiao Feng} and Lyketsos, {Constantine G.} and Mack, {Wendy J.} and Marson, {Daniel C.} and Frank Martiniuk and Mash, {Deborah C.} and Eliezer Masliah and McCormick, {Wayne C.} and McCurry, {Susan M.} and McDavid, {Andrew N.} and McKee, {Ann C.} and Marsel Mesulam and Miller, {Bruce L.} and Miller, {Carol A.} and Miller, {Joshua W.} and Morris, {John C.} and Shubhabrata Mukherjee and Murrell, {Jill R.} and Myers, {Amanda J.} and Sidney O'Bryant and Olichney, {John M.} and Pankratz, {Vernon S.} and Parisi, {Joseph E.} and Amanda Partch and Paulson, {Henry L.} and William Perry and Elaine Peskind and Petersen, {Ronald C.} and Aimee Pierce and Poon, {Wayne W.} and Huntington Potter and Quinn, {Joseph F.} and Ashok Raj and Murray Raskind and Barry Reisberg and Reisch, {Joan S.} and Christiane Reitz and Ringman, {John M.} and Roberson, {Erik D.} and Ekaterina Rogaeva and Rosen, {Howard J.} and Rosenberg, {Roger N.} and Royall, {Donald R.} and Sager, {Mark A.} and Mary Sano and Saykin, {Andrew J.} and Schneider, {Julie A.} and Schneider, {Lon S.} and Seeley, {William W.} and Smith, {Amanda G.} and Sonnen, {Joshua A.} and Salvatore Spina and Stern, {Robert A.} and Tanzi, {Rudolph E.} and Thornton-Wells, {Tricia A.} and Trojanowski, {John Q.} and Troncoso, {Juan C.} and Tsuang, {Debby W.} and {Van Deerlin}, {Vivianna M.} and {Van Eldik}, {Linda J.} and Vardarajan, {Badri N.} and Vinters, {Harry V.} and Vonsattel, {Jean Paul} and Sandra Weintraub and Welsh-Bohmer, {Kathleen A.} and Jennifer Williamson and Sarah Wishnek and Woltjer, {Randall L.} and Wright, {Clinton B.} and Wu, {Chuang Kuo} and Yu, {Chang En} and Lei Yu and Charlene Thomas and Amy Gerrish and Jade Chapman and Alexandra Stretton and Angharad Morgan and Harriet Oldham and Owen, {Michael J.} and Kehoe, {Patrick G.} and Christopher Medway and Kristelle Brown and Jenny Lord and James Turton and Hooper, {Nigel M.} and Emma Vardy and Warren, {Jason D.} and Schott, {Jonathan M.} and James Uphill and Paul Hollingworth and Natalie Ryan and Martin Rossor and John Collinge and Yoav Ben-Shlomo and Daniilidou Makrina and Olymbia Gkatzima and Michelle Lupton and Maria Koutroumani and Despoina Avramidou and Antonia Germanou and Frank Jessen and Steffi Riedel-Heller and Martin Dichgans and Reiner Heun and Heike K{\"o}lsch and Britta Sch{\"u}rmann and Christine Herold and Andr{\'e} Lacour and Dmitriy Drichel and Per Hoffmann and Johannes Kornhuber and Wei Gu and Thomas Feulner and Manuel Mayhaus and Sabrina Pichler and Matthias Riemenschneider and {van den Bussche}, Hendrik and Brian Lawlor and Aoibhinn Lynch and David Mann and Smith, {A. David} and Donald Warden and Gordon Wilcock and Isabella Heuser and Jens Wiltfang and Lutz Fr{\"o}lich and Michael H{\"u}ll and Kevin Mayo and Gill Livingston and Bass, {Nicholas J.} and Hugh Gurling and Andrew McQuillin and Rhian Gwilliam and Panagiotis Deloukas and Ammar Al-Chalabi and Shaw, {Christopher E.} and Singleton, {Andrew B.} and Rita Guerreiro and Giancarlo Russo and J{\"o}ckel, {Karl Heinz} and Susanne Moebus and Norman Klopp and Wichmann, {H. Erich} and Li Ma and Gina Bisceglio and Elizabeth Fisher and Nick Warner and Stuart Pickering-Brown and David Craig and Johnston, {Janet A.} and Bernadette McGuinness and Stephen Todd and Rubinsztein, {David C.} and Simon Lovestone and Anthony Bayer and John Gallacher and Petroula Proitsi and Sara Ortega-Cubero",
year = "2016",
month = "1",
day = "1",
doi = "10.1038/mp.2015.23",
language = "English",
volume = "21",
pages = "108--117",
journal = "Molecular Psychiatry",
issn = "1359-4184",
publisher = "Nature Publishing Group",
number = "1",

}

Jun, G, Ibrahim-Verbaas, CA, Vronskaya, M, Lambert, JC, Chung, J, Naj, AC, Kunkle, BW, Wang, LS, 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, Fievet, N, Denning, N, Martin, ER, Schmidt, H, Kamatani, Y, Dunstan, ML, Valladares, O, Laza, AR, Zelenika, D, Ramirez, A, Foroud, TM, Choi, SH, Boland, A, Becker, T, Kukull, WA, Van Der Lee, SJ, Pasquier, F, Cruchaga, C, Beekly, D, Fitzpatrick, AL, Hanon, O, Gill, M, Barber, RC, 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, JF, 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, Adams, PM, Albert, MS, Albin, RL, Apostolova, LG, Arnold, SE, Asthana, S, Atwood, CS, Baldwin, CT, Barmada, MM, Barnes, LL, Beach, TG, Becker, JT, Bigio, EH, Bird, TD, Blacker, D, Boeve, BF, Bowen, JD, Boxer, A, Burke, JR, Cairns, NJ, Cao, C, Carlson, CS, Carlsson, CM, Carney, RM, Carrasquillo, MM, Carroll, SL, Chui, HC, Clark, DG, Corneveaux, J, Cribbs, DH, Crocco, EA, De Jager, PL, DeCarli, C, DeKosky, ST, Yesim Demirci, F, Dick, M, Dickson, DW, Doody, RS, Duara, R, Ertekin-Taner, N, Faber, KM, Fairchild, TJ, Fallon, KB, Farlow, MR, Ferris, S, Frosch, MP, Galasko, DR, Gearing, M, Geschwind, DH, Ghetti, B, Gilbert, JR, Glass, JD, Graff-Radford, NR, Green, RC, Growdon, JH, Hakonarson, H, Hamilton, RL, Harrell, LE, Head, E, Honig, LS, Huebinger, RM, Huentelman, MJ, Hulette, CM, Hyman, BT, Jarvik, GP, Jicha, GA, Jin, LW, Karydas, A, Kaye, JA, Kim, R, Koo, EH, Kowall, NW, Kramer, JH, LaFerla, FM, Lah, JJ, Leverenz, JB, Levey, AI, Li, G, Lieberman, AP, Lin, CF, Lyketsos, CG, Mack, WJ, Marson, DC, Martiniuk, F, Mash, DC, Masliah, E, McCormick, WC, McCurry, SM, McDavid, AN, McKee, AC, Mesulam, M, Miller, BL, Miller, CA, Miller, JW, Morris, JC, Mukherjee, S, Murrell, JR, Myers, AJ, O'Bryant, S, Olichney, JM, Pankratz, VS, Parisi, JE, Partch, A, Paulson, HL, Perry, W, Peskind, E, Petersen, RC, Pierce, A, Poon, WW, Potter, H, Quinn, JF, Raj, A, Raskind, M, Reisberg, B, Reisch, JS, Reitz, C, Ringman, JM, Roberson, ED, Rogaeva, E, Rosen, HJ, Rosenberg, RN, Royall, DR, Sager, MA, Sano, M, Saykin, AJ, Schneider, JA, Schneider, LS, Seeley, WW, Smith, AG, Sonnen, JA, Spina, S, Stern, RA, Tanzi, RE, Thornton-Wells, TA, Trojanowski, JQ, Troncoso, JC, Tsuang, DW, Van Deerlin, VM, Van Eldik, LJ, Vardarajan, BN, Vinters, HV, Vonsattel, JP, Weintraub, S, Welsh-Bohmer, KA, Williamson, J, Wishnek, S, Woltjer, RL, Wright, CB, Wu, CK, Yu, CE, Yu, L, Thomas, C, Gerrish, A, Chapman, J, Stretton, A, Morgan, A, Oldham, H, Owen, MJ, Kehoe, PG, Medway, C, Brown, K, Lord, J, Turton, J, Hooper, NM, Vardy, E, Warren, JD, Schott, JM, Uphill, J, Hollingworth, P, Ryan, N, Rossor, M, Collinge, J, Ben-Shlomo, Y, Makrina, D, Gkatzima, O, Lupton, M, Koutroumani, M, Avramidou, D, Germanou, A, Jessen, F, Riedel-Heller, S, Dichgans, M, Heun, R, Kölsch, H, Schürmann, B, Herold, C, Lacour, A, Drichel, D, Hoffmann, P, Kornhuber, J, Gu, W, Feulner, T, Mayhaus, M, Pichler, S, Riemenschneider, M, van den Bussche, H, Lawlor, B, Lynch, A, Mann, D, Smith, AD, Warden, D, Wilcock, G, Heuser, I, Wiltfang, J, Frölich, L, Hüll, M, Mayo, K, Livingston, G, Bass, NJ, Gurling, H, McQuillin, A, Gwilliam, R, Deloukas, P, Al-Chalabi, A, Shaw, CE, Singleton, AB, Guerreiro, R, Russo, G, Jöckel, KH, Moebus, S, Klopp, N, Wichmann, HE, Ma, L, Bisceglio, G, Fisher, E, Warner, N, Pickering-Brown, S, Craig, D, Johnston, JA, McGuinness, B, Todd, S, Rubinsztein, DC, Lovestone, S, Bayer, A, Gallacher, J, Proitsi, P & Ortega-Cubero, S 2016, 'A novel Alzheimer disease locus located near the gene encoding tau protein', Molecular Psychiatry, vol. 21, no. 1, pp. 108-117. https://doi.org/10.1038/mp.2015.23

A novel Alzheimer disease locus located near the gene encoding tau protein. / Jun, G.; Ibrahim-Verbaas, C. A.; Vronskaya, M.; Lambert, J. C.; Chung, J.; Naj, A. C.; Kunkle, B. W.; Wang, L. S.; Bis, J. C.; Bellenguez, C.; Harold, D.; Lunetta, K. L.; Destefano, A. L.; Grenier-Boley, B.; Sims, R.; Beecham, G. W.; Smith, A. V.; Chouraki, V.; Hamilton-Nelson, K. L.; Ikram, M. A.; Fievet, N.; Denning, N.; Martin, E. R.; Schmidt, H.; Kamatani, Y.; Dunstan, M. L.; Valladares, O.; Laza, A. R.; Zelenika, D.; Ramirez, A.; Foroud, T. M.; Choi, S. H.; Boland, A.; Becker, T.; Kukull, W. A.; Van Der Lee, S. J.; Pasquier, F.; Cruchaga, C.; Beekly, D.; Fitzpatrick, A. L.; Hanon, O.; Gill, M.; Barber, Robert Clinton; Gudnason, V.; Campion, D.; Love, S.; Bennett, D. A.; Amin, N.; Berr, C.; Tsolaki, Magda; Buxbaum, J. D.; Lopez, O. L.; Deramecourt, V.; Fox, N. C.; Cantwell, L. B.; Tárraga, L.; Dufouil, C.; Hardy, J.; Crane, P. K.; Eiriksdottir, G.; Hannequin, D.; Clarke, R.; Evans, D.; Mosley, T. H.; Letenneur, L.; Brayne, C.; Maier, W.; De Jager, P.; Emilsson, V.; Dartigues, J. F.; Hampel, H.; Kamboh, M. I.; De Bruijn, R. F.A.G.; Tzourio, C.; Pastor, P.; Larson, E. B.; Rotter, J. I.; O'Donovan, M. C.; Montine, T. J.; Nalls, M. A.; Mead, S.; Reiman, E. M.; Jonsson, P. V.; Holmes, C.; St George-Hyslop, P. H.; Boada, M.; Passmore, P.; Wendland, J. R.; Schmidt, R.; Morgan, K.; Winslow, A. R.; Powell, J. F.; Carasquillo, M.; Younkin, S. G.; Jakobsdóttir, J.; Kauwe, J. S.K.; Wilhelmsen, K. C.; Rujescu, D.; Nöthen, M. M.; Hofman, A.; Jones, L.; Haines, J. L.; Psaty, B. M.; Van Broeckhoven, C.; Holmans, P.; Launer, L. J.; Mayeux, R.; Lathrop, M.; Goate, A. M.; Escott-Price, V.; Seshadri, S.; Pericak-Vance, M. A.; Amouyel, P.; Williams, J.; Van Duijn, C. M.; Schellenberg, G. D.; Farrer, L. A.; Adams, Perrie M.; Albert, Marilyn S.; Albin, Roger L.; Apostolova, Liana G.; Arnold, Steven E.; Asthana, Sanjay; Atwood, Craig S.; Baldwin, Clinton T.; Barmada, Michjael M.; Barnes, Lisa L.; Beach, Thomas G.; Becker, James T.; Bigio, Eileen H.; Bird, Thomas D.; Blacker, Deborah; Boeve, Bradley F.; Bowen, James D.; Boxer, Adam; Burke, James R.; Cairns, Nigel J.; Cao, Chuanhai; Carlson, Chris S.; Carlsson, Cynthia M.; Carney, Regina M.; Carrasquillo, Minerva M.; Carroll, Steven L.; Chui, Helena C.; Clark, David G.; Corneveaux, Jason; Cribbs, David H.; Crocco, Elizabeth A.; De Jager, Philip L.; DeCarli, Charles; DeKosky, Steven T.; Yesim Demirci, F.; Dick, Malcolm; Dickson, Dennis W.; Doody, Rachelle S.; Duara, Ranjan; Ertekin-Taner, Nilufer; Faber, Kelley M.; Fairchild, Thomas J.; Fallon, Kenneth B.; Farlow, Martin R.; Ferris, Steven; Frosch, Matthew P.; Galasko, Douglas R.; Gearing, Marla; Geschwind, Daniel H.; Ghetti, Bernardino; Gilbert, John R.; Glass, Jonathan D.; Graff-Radford, Neill R.; Green, Robert C.; Growdon, John H.; Hakonarson, Hakon; Hamilton, Ronald L.; Harrell, Lindy E.; Head, Elizabeth; Honig, Lawrence S.; Huebinger, Ryan M.; Huentelman, Matthew J.; Hulette, Christine M.; Hyman, Bradley T.; Jarvik, Gail P.; Jicha, Gregory A.; Jin, Lee Way; Karydas, Anna; Kaye, Jeffrey A.; Kim, Ronald; Koo, Edward H.; Kowall, Neil W.; Kramer, Joel H.; LaFerla, Frank M.; Lah, James J.; Leverenz, James B.; Levey, Allan I.; Li, Ge; Lieberman, Andrew P.; Lin, Chiao Feng; Lyketsos, Constantine G.; Mack, Wendy J.; Marson, Daniel C.; Martiniuk, Frank; Mash, Deborah C.; Masliah, Eliezer; McCormick, Wayne C.; McCurry, Susan M.; McDavid, Andrew N.; McKee, Ann C.; Mesulam, Marsel; Miller, Bruce L.; Miller, Carol A.; Miller, Joshua W.; Morris, John C.; Mukherjee, Shubhabrata; Murrell, Jill R.; Myers, Amanda J.; O'Bryant, Sidney; Olichney, John M.; Pankratz, Vernon S.; Parisi, Joseph E.; Partch, Amanda; Paulson, Henry L.; Perry, William; Peskind, Elaine; Petersen, Ronald C.; Pierce, Aimee; Poon, Wayne W.; Potter, Huntington; Quinn, Joseph F.; Raj, Ashok; Raskind, Murray; Reisberg, Barry; Reisch, Joan S.; Reitz, Christiane; Ringman, John M.; Roberson, Erik D.; Rogaeva, Ekaterina; Rosen, Howard J.; Rosenberg, Roger N.; Royall, Donald R.; Sager, Mark A.; Sano, Mary; Saykin, Andrew J.; Schneider, Julie A.; Schneider, Lon S.; Seeley, William W.; Smith, Amanda G.; Sonnen, Joshua A.; Spina, Salvatore; Stern, Robert A.; Tanzi, Rudolph E.; Thornton-Wells, Tricia A.; Trojanowski, John Q.; Troncoso, Juan C.; Tsuang, Debby W.; Van Deerlin, Vivianna M.; Van Eldik, Linda J.; Vardarajan, Badri N.; Vinters, Harry V.; Vonsattel, Jean Paul; Weintraub, Sandra; Welsh-Bohmer, Kathleen A.; Williamson, Jennifer; Wishnek, Sarah; Woltjer, Randall L.; Wright, Clinton B.; Wu, Chuang Kuo; Yu, Chang En; Yu, Lei; Thomas, Charlene; Gerrish, Amy; Chapman, Jade; Stretton, Alexandra; Morgan, Angharad; Oldham, Harriet; Owen, Michael J.; Kehoe, Patrick G.; Medway, Christopher; Brown, Kristelle; Lord, Jenny; Turton, James; Hooper, Nigel M.; Vardy, Emma; Warren, Jason D.; Schott, Jonathan M.; Uphill, James; Hollingworth, Paul; Ryan, Natalie; Rossor, Martin; Collinge, John; Ben-Shlomo, Yoav; Makrina, Daniilidou; Gkatzima, Olymbia; Lupton, Michelle; Koutroumani, Maria; Avramidou, Despoina; Germanou, Antonia; Jessen, Frank; Riedel-Heller, Steffi; Dichgans, Martin; Heun, Reiner; Kölsch, Heike; Schürmann, Britta; Herold, Christine; Lacour, André; Drichel, Dmitriy; Hoffmann, Per; Kornhuber, Johannes; Gu, Wei; Feulner, Thomas; Mayhaus, Manuel; Pichler, Sabrina; Riemenschneider, Matthias; van den Bussche, Hendrik; Lawlor, Brian; Lynch, Aoibhinn; Mann, David; Smith, A. David; Warden, Donald; Wilcock, Gordon; Heuser, Isabella; Wiltfang, Jens; Frölich, Lutz; Hüll, Michael; Mayo, Kevin; Livingston, Gill; Bass, Nicholas J.; Gurling, Hugh; McQuillin, Andrew; Gwilliam, Rhian; Deloukas, Panagiotis; Al-Chalabi, Ammar; Shaw, Christopher E.; Singleton, Andrew B.; Guerreiro, Rita; Russo, Giancarlo; Jöckel, Karl Heinz; Moebus, Susanne; Klopp, Norman; Wichmann, H. Erich; Ma, Li; Bisceglio, Gina; Fisher, Elizabeth; Warner, Nick; Pickering-Brown, Stuart; Craig, David; Johnston, Janet A.; McGuinness, Bernadette; Todd, Stephen; Rubinsztein, David C.; Lovestone, Simon; Bayer, Anthony; Gallacher, John; Proitsi, Petroula; Ortega-Cubero, Sara.

In: Molecular Psychiatry, Vol. 21, No. 1, 01.01.2016, p. 108-117.

Research output: Contribution to journalArticleResearchpeer-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, Robert Clinton

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 - Becker, James T.

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.

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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

VL - 21

SP - 108

EP - 117

JO - Molecular Psychiatry

JF - Molecular Psychiatry

SN - 1359-4184

IS - 1

ER -

Jun G, Ibrahim-Verbaas CA, Vronskaya M, Lambert JC, Chung J, Naj AC et al. A novel Alzheimer disease locus located near the gene encoding tau protein. Molecular Psychiatry. 2016 Jan 1;21(1):108-117. https://doi.org/10.1038/mp.2015.23