Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease

Adam C. Naj; Gyungah Jun; Gary W. Beecham; Li San Wang; Badri Narayan Vardarajan; Jacqueline Buros; Paul J. Gallins; Joseph D. Buxbaum; Gail P. Jarvik; Paul K. Crane; Eric B. Larson; Thomas D. Bird; Bradley F. Boeve; Neill R. Graff-Radford; Philip L. De Jager; Denis Evans; Julie A. Schneider; Minerva M. Carrasquillo; Nilufer Ertekin-Taner; Steven G. Younkin; Carlos Cruchaga; John S.K. Kauwe; Petra Nowotny; Patricia Kramer; John Hardy; Matthew J. Huentelman; Amanda J. Myers; Michael M. Barmada; F. Yesim Demirci; Clinton T. Baldwin; Robert C. Green; Ekaterina Rogaeva; Peter St George-Hyslop; Steven E. Arnold; Robert Barber; Thomas Beach; Eileen H. Bigio; James D. Bowen; Adam Boxer; James R. Burke; Nigel J. Cairns; Chris S. Carlson; Regina M. Carney; Steven L. Carroll; Helena C. Chui; David G. Clark; Jason Corneveaux; Carl W. Cotman; Jeffrey L. Cummings; Charles Decarli; Steven T. Dekosky; Ramon Diaz-Arrastia; Malcolm Dick; Dennis W. Dickson; William G. Ellis; Kelley M. Faber; Kenneth B. Fallon; Martin R. Farlow; Steven Ferris; Matthew P. Frosch; Douglas R. Galasko; Mary Ganguli; Marla Gearing; Daniel H. Geschwind; Bernardino Ghetti; John R. Gilbert; Sid Gilman; Bruno Giordani; Jonathan D. Glass; John H. Growdon; Ronald L. Hamilton; Lindy E. Harrell; Elizabeth Head; Lawrence S. Honig; Christine M. Hulette; Bradley T. Hyman; Gregory A. Jicha; Lee Way Jin; Nancy Johnson; Jason Karlawish; Anna Karydas; Jeffrey A. Kaye; Ronald Kim; Edward H. Koo; Neil W. Kowall; James J. Lah; Allan I. Levey; Andrew P. Lieberman; Oscar L. Lopez; 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; Joseph E. Parisi; Daniel P. Perl; Elaine Peskind; Ronald C. Petersen; Wayne W. Poon; Joseph F. Quinn; Ruchita A. Rajbhandary; Murray Raskind; Barry Reisberg; John M. Ringman; Erik D. Roberson; Roger N. Rosenberg; Mary Sano; Lon S. Schneider; William Seeley; Michael L. Shelanski; Michael A. Slifer; Charles D. Smith; Joshua A. Sonnen; Salvatore Spina; Robert A. Stern; Rudolph E. Tanzi; John Q. Trojanowski; Juan C. Troncoso; Vivianna M. Van Deerlin; Harry V. Vinters; Jean Paul Vonsattel; Sandra Weintraub; Kathleen A. Welsh-Bohmer; Jennifer Williamson; Randall L. Woltjer; Laura B. Cantwell; Beth A. Dombroski; Duane Beekly; Kathryn L. Lunetta; Eden R. Martin; M. Ilyas Kamboh; Andrew J. Saykin; Eric M. Reiman; David A. Bennett; John C. Morris; Thomas J. Montine; Alison M. Goate; Deborah Blacker; Debby W. Tsuang; Hakon Hakonarson; Walter A. Kukull; Tatiana M. Foroud; Jonathan L. Haines; Richard Mayeux; Margaret A. Pericak-Vance; Lindsay A. Farrer; Gerard D. Schellenberg

doi:10.1038/ng.801

Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease

Adam C. Naj, Gyungah Jun, Gary W. Beecham, Li San Wang, Badri Narayan Vardarajan, Jacqueline Buros, Paul J. Gallins, Joseph D. Buxbaum, Gail P. Jarvik, Paul K. Crane, Eric B. Larson, Thomas D. Bird, Bradley F. Boeve, Neill R. Graff-Radford, Philip L. De Jager, Denis Evans, Julie A. Schneider, Minerva M. Carrasquillo, Nilufer Ertekin-Taner, Steven G. YounkinCarlos Cruchaga, John S.K. Kauwe, Petra Nowotny, Patricia Kramer, John Hardy, Matthew J. Huentelman, Amanda J. Myers, Michael M. Barmada, F. Yesim Demirci, Clinton T. Baldwin, Robert C. Green, Ekaterina Rogaeva, Peter St George-Hyslop, Steven E. Arnold, Robert Barber, Thomas Beach, Eileen H. Bigio, James D. Bowen, Adam Boxer, James R. Burke, Nigel J. Cairns, Chris S. Carlson, Regina M. Carney, Steven L. Carroll, Helena C. Chui, David G. Clark, Jason Corneveaux, Carl W. Cotman, Jeffrey L. Cummings, Charles Decarli, Steven T. Dekosky, Ramon Diaz-Arrastia, Malcolm Dick, Dennis W. Dickson, William G. Ellis, Kelley M. Faber, Kenneth B. Fallon, Martin R. Farlow, Steven Ferris, Matthew P. Frosch, Douglas R. Galasko, Mary Ganguli, Marla Gearing, Daniel H. Geschwind, Bernardino Ghetti, John R. Gilbert, Sid Gilman, Bruno Giordani, Jonathan D. Glass, John H. Growdon, Ronald L. Hamilton, Lindy E. Harrell, Elizabeth Head, Lawrence S. Honig, Christine M. Hulette, Bradley T. Hyman, Gregory A. Jicha, Lee Way Jin, Nancy Johnson, Jason Karlawish, Anna Karydas, Jeffrey A. Kaye, Ronald Kim, Edward H. Koo, Neil W. Kowall, James J. Lah, Allan I. Levey, Andrew P. Lieberman, Oscar L. Lopez, 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, Joseph E. Parisi, Daniel P. Perl, Elaine Peskind, Ronald C. Petersen, Wayne W. Poon, Joseph F. Quinn, Ruchita A. Rajbhandary, Murray Raskind, Barry Reisberg, John M. Ringman, Erik D. Roberson, Roger N. Rosenberg, Mary Sano, Lon S. Schneider, William Seeley, Michael L. Shelanski, Michael A. Slifer, Charles D. Smith, Joshua A. Sonnen, Salvatore Spina, Robert A. Stern, Rudolph E. Tanzi, John Q. Trojanowski, Juan C. Troncoso, Vivianna M. Van Deerlin, Harry V. Vinters, Jean Paul Vonsattel, Sandra Weintraub, Kathleen A. Welsh-Bohmer, Jennifer Williamson, Randall L. Woltjer, Laura B. Cantwell, Beth A. Dombroski, Duane Beekly, Kathryn L. Lunetta, Eden R. Martin, M. Ilyas Kamboh, Andrew J. Saykin, Eric M. Reiman, David A. Bennett, John C. Morris, Thomas J. Montine, Alison M. Goate, Deborah Blacker, Debby W. Tsuang, Hakon Hakonarson, Walter A. Kukull, Tatiana M. Foroud, Jonathan L. Haines, Richard Mayeux, Margaret A. Pericak-Vance, Lindsay A. Farrer, Gerard D. Schellenberg

Research output: Contribution to journal › Article › peer-review

1569 Scopus citations

Abstract

The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P M) = 1.7 × 10 ^-9, joint analysis P (P J) = 1.7 × 10 ^-9; stages 1, 2 and 3, P M = 8.2 × 10 ^-12), CD2AP (rs9349407; stages 1, 2 and 3, P M = 8.6 × 10 ^-9), EPHA1 (rs11767557; stages 1, 2 and 3, P M = 6.0 × 10 ^-10) and CD33 (rs3865444; stages 1, 2 and 3, P M = 1.6 × 10 ^-9). We also replicated previous associations at CR1 (rs6701713; P M = 4.6 × 10 ^-10, P J = 5.2 × 10 ^-11), CLU (rs1532278; P M = 8.3 × 10 ^-8, P J = 1.9 × 10 ^-8), BIN1 (rs7561528; P M = 4.0 × 10 ^-14, P J = 5.2 × 10 ^-14) and PICALM (rs561655; P M = 7.0 × 10 ^-11, P J = 1.0 × 10 ^-10), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.

Original language	English
Pages (from-to)	436-443
Number of pages	8
Journal	Nature Genetics
Volume	43
Issue number	5
DOIs	https://doi.org/10.1038/ng.801
State	Published - May 2011

Bibliographical note

Funding Information:
The National Institutes of Health, National Institute on Aging (NIH-NIA) supported this work through the following grants: ADGC, U01 AG032984, RC2 AG036528; NACC, U01 AG016976; NCRAD, U24 AG021886; NIA LOAD, U24 AG026395, U24 AG026390; Boston University, P30 AG013846, R01 HG02213, K24 AG027841, U01 AG10483, R01 CA129769, R01 MH080295, R01 AG009029, R01 AG017173, R01 AG025259; Columbia University, P50 AG008702, R37 AG015473; Duke University, P30 AG028377; Emory University, AG025688; Indiana University, P30 AG10133; Johns Hopkins University, P50 AG005146, R01 AG020688; Massachusetts General Hospital, P50 AG005134; Mayo Clinic, P50 AG016574; Mount Sinai School of Medicine, P50 AG005138, P01 AG002219; New York University, P30 AG08051, MO1RR00096, and UL1 RR029893; Northwestern University, P30 AG013854; Oregon Health & Science University, P30 AG008017, R01 AG026916; Rush University, P30 AG010161, R01 AG019085, R01 AG15819, R01 AG17917, R01 AG30146; University of Alabama at Birmingham, P50 AG016582, UL1RR02777; University of Arizona/TGEN, P30 AG019610, R01 AG031581, R01 NS059873; University of California, Davis, P30 AG010129; University of California, Irvine, P50 AG016573, P50, P50 AG016575, P50 AG016576, P50 AG016577; University of California, Los Angeles, P50 AG016570; University of California, San Diego, P50 AG005131; University of California, San Francisco, P50 AG023501, P01 AG019724; University of Kentucky, P30 AG028383; University of Michigan, P50 AG008671; University of Pennsylvania, P30 AG010124; University of Pittsburgh, P50 AG005133, AG030653; University of Southern California, P50 AG005142; University of Texas Southwestern, P30 AG012300; University of Miami, R01 AG027944, AG010491, AG027944, AG021547, AG019757; University of Washington, P50 AG005136, UO1 AG06781, UO1 HG004610; Vanderbilt University, R01 AG019085; and Washington University, P50 AG005681, P01 AG03991. ADNI Funding for ADNI is through the Northern California Institute for Research and Education by grants from Abbott, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare, GlaxoSmithKline, Innogenetics, Johnson and Johnson, Eli Lilly and Co., Medpace, Inc., Merck and Co., Inc., Novartis AG, Pfizer Inc., F. Hoffman-La Roche, Schering-Plough, Synarc, Inc., Alzheimer’s Association, Alzheimer’s Drug Discovery Foundation, the Dana Foundation, and by the National Institute of Biomedical Imaging and Bioengineering and NIA grants U01 AG024904, RC2 AG036535, K01 AG030514. We thank C. Phelps, M. Morrison-Bogorad and M. Miller from NIA who are ex-officio ADGC members. Support was also from the Alzheimer’s Association (LAF, IIRG-08-89720; MP-V, IIRG-05-14147) and the Veterans Affairs Administration. P.S.-H. is supported by Wellcome Trust, Howard Hughes Medical Institute, and the Canadian Institute of Health Research.

Funding

The National Institutes of Health, National Institute on Aging (NIH-NIA) supported this work through the following grants: ADGC, U01 AG032984, RC2 AG036528; NACC, U01 AG016976; NCRAD, U24 AG021886; NIA LOAD, U24 AG026395, U24 AG026390; Boston University, P30 AG013846, R01 HG02213, K24 AG027841, U01 AG10483, R01 CA129769, R01 MH080295, R01 AG009029, R01 AG017173, R01 AG025259; Columbia University, P50 AG008702, R37 AG015473; Duke University, P30 AG028377; Emory University, AG025688; Indiana University, P30 AG10133; Johns Hopkins University, P50 AG005146, R01 AG020688; Massachusetts General Hospital, P50 AG005134; Mayo Clinic, P50 AG016574; Mount Sinai School of Medicine, P50 AG005138, P01 AG002219; New York University, P30 AG08051, MO1RR00096, and UL1 RR029893; Northwestern University, P30 AG013854; Oregon Health & Science University, P30 AG008017, R01 AG026916; Rush University, P30 AG010161, R01 AG019085, R01 AG15819, R01 AG17917, R01 AG30146; University of Alabama at Birmingham, P50 AG016582, UL1RR02777; University of Arizona/TGEN, P30 AG019610, R01 AG031581, R01 NS059873; University of California, Davis, P30 AG010129; University of California, Irvine, P50 AG016573, P50, P50 AG016575, P50 AG016576, P50 AG016577; University of California, Los Angeles, P50 AG016570; University of California, San Diego, P50 AG005131; University of California, San Francisco, P50 AG023501, P01 AG019724; University of Kentucky, P30 AG028383; University of Michigan, P50 AG008671; University of Pennsylvania, P30 AG010124; University of Pittsburgh, P50 AG005133, AG030653; University of Southern California, P50 AG005142; University of Texas Southwestern, P30 AG012300; University of Miami, R01 AG027944, AG010491, AG027944, AG021547, AG019757; University of Washington, P50 AG005136, UO1 AG06781, UO1 HG004610; Vanderbilt University, R01 AG019085; and Washington University, P50 AG005681, P01 AG03991. ADNI Funding for ADNI is through the Northern California Institute for Research and Education by grants from Abbott, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare, GlaxoSmithKline, Innogenetics, Johnson and Johnson, Eli Lilly and Co., Medpace, Inc., Merck and Co., Inc., Novartis AG, Pfizer Inc., F. Hoffman-La Roche, Schering-Plough, Synarc, Inc., Alzheimer’s Association, Alzheimer’s Drug Discovery Foundation, the Dana Foundation, and by the National Institute of Biomedical Imaging and Bioengineering and NIA grants U01 AG024904, RC2 AG036535, K01 AG030514. We thank C. Phelps, M. Morrison-Bogorad and M. Miller from NIA who are ex-officio ADGC members. Support was also from the Alzheimer’s Association (LAF, IIRG-08-89720; MP-V, IIRG-05-14147) and the Veterans Affairs Administration. P.S.-H. is supported by Wellcome Trust, Howard Hughes Medical Institute, and the Canadian Institute of Health Research.

Funders	Funder number
ADGC	RC2 AG036528, U01 AG032984
Alzheimer’s Association, and Cure Alzheimer’s Fund
AstraZeneca
Canadian Health Research Institute
Eisai Global Clinical Development
Eli Lilly and Co., Medpace, Inc.
Merck and Company Inc
NCRAD	U24 AG021886
NIA/NIH
Pfizer Inc., F. Hoffman-La Roche
Synarc, Inc.
University of Arizona/TGEN	P30 AG019610, R01 NS059873, R01 AG031581
The George Washington University	P50 AG005681, P01 AG03991
National Institutes of Health (NIH)
Howard Hughes Medical Institute
National Institute on Aging	U24 AG026395, U24 AG026390, R01AG015819
National Institute on Aging
National Institute of Biomedical Imaging and Bioengineering	RC2 AG036535, U01 AG024904, K01 AG030514
National Institute of Biomedical Imaging and Bioengineering
Mayo Clinic Rochester	P50 AG016574
Mayo Clinic Rochester
Charles A Dana Foundation
Abbott Laboratories
Bristol-Myers Squibb
Alzheimer's Drug Discovery Foundation
Genentech Incorporated
Johnson and Johnson Pharmaceutical Research and Development
Novartis
Massachusetts General Hospital	P50 AG005134
Massachusetts General Hospital
North Carolina GlaxoSmithKline Foundation
University of Southern California	P50 AG005142
University of Southern California
Columbia University	P50 AG008702, R37 AG015473
Columbia University
Duke-Kunshan University	P30 AG028377
Duke-Kunshan University
Vanderbilt Digestive Diseases Research Center, Vanderbilt University Medical Center
Oregon Health and Science University	P30 AG008017, R01 AG026916
Oregon Health and Science University
Miami Clinical and Translational Science Institute, University of Miami	AG027944, AG021547, R01 AG027944, AG010491, AG019757
Miami Clinical and Translational Science Institute, University of Miami
York University, New York, New York, USA bbbUniversity of Rochester, Rochester, New York	UL1 RR029893, P30 AG08051, MO1RR00096
York University, New York, New York, USA bbbUniversity of Rochester, Rochester, New York
University of Southern Indiana	P30 AG10133
University of Southern Indiana
GE Healthcare
The Pennsylvania State University	P30 AG010124
The Pennsylvania State University
University Research Committee, Emory University	AG025688
University Research Committee, Emory University
Northwestern Polytechnical University	P30 AG013854
Northwestern Polytechnical University
Schering Plough Co
Boston University School of Public Health/Boston University Medical Campus	K24 AG027841, P30 AG013846, R01 AG009029, U01 AG10483, R01 AG017173, R01 MH080295, R01 AG025259, R01 CA129769, R01 HG02213
Boston University School of Public Health/Boston University Medical Campus
University of California, Los Angeles	P50 AG016570
University of California, Los Angeles
Michigan Retirement Research Center, University of Michigan	P50 AG008671
Michigan Retirement Research Center, University of Michigan
Icahn School of Medicine at Mount Sinai	P01 AG002219, P50 AG005138
Icahn School of Medicine at Mount Sinai
DoD Alzheimer's Disease Neuroimaging Initiative
University of Kentucky	P30 AG028383
University of Kentucky
University of California Davis	P30 AG010129
University of California Davis
The George Washington University	P50 AG005136, UO1 AG06781, UO1 HG004610
The George Washington University
The Johns Hopkins University	R01 AG020688, P50 AG005146
The Johns Hopkins University
University of California San Diego Health	P50 AG023501, P01 AG019724, P50 AG005131
University of California San Diego Health
University of Texas Southwestern Medical Center	P30 AG012300
University of Texas Southwestern Medical Center
University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh	AG030653, P50 AG005133
University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh
University of California Irvine	P50 AG016577, P50 AG016576, P50 AG016575, P50 AG016573
University of California Irvine
Rush University	R01 AG15819, R01 AG30146, P30 AG010161, R01 AG17917, R01 AG019085
Rush University
Wellcome Trust
University of Alabama	P50 AG016582, UL1RR02777
University of Alabama
National Association for Colitis and Crohn's Disease	U01 AG016976
National Association for Colitis and Crohn's Disease
Elan Corporation
Innogenetics
Bayer Schering

ASJC Scopus subject areas

Genetics

Access to Document

10.1038/ng.801

Cite this

Naj, A. C., Jun, G., Beecham, G. W., Wang, L. S., Vardarajan, B. N., Buros, J., Gallins, P. J., Buxbaum, J. D., Jarvik, G. P., Crane, P. K., Larson, E. B., Bird, T. D., Boeve, B. F., Graff-Radford, N. R., De Jager, P. L., Evans, D., Schneider, J. A., Carrasquillo, M. M., Ertekin-Taner, N., ... Schellenberg, G. D. (2011). Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nature Genetics, 43(5), 436-443. https://doi.org/10.1038/ng.801

@article{5bf4a112a2514468960ef3ae1af7fb1e,

title = "Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease",

abstract = "The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P M) = 1.7 × 10 -9, joint analysis P (P J) = 1.7 × 10 -9; stages 1, 2 and 3, P M = 8.2 × 10 -12), CD2AP (rs9349407; stages 1, 2 and 3, P M = 8.6 × 10 -9), EPHA1 (rs11767557; stages 1, 2 and 3, P M = 6.0 × 10 -10) and CD33 (rs3865444; stages 1, 2 and 3, P M = 1.6 × 10 -9). We also replicated previous associations at CR1 (rs6701713; P M = 4.6 × 10 -10, P J = 5.2 × 10 -11), CLU (rs1532278; P M = 8.3 × 10 -8, P J = 1.9 × 10 -8), BIN1 (rs7561528; P M = 4.0 × 10 -14, P J = 5.2 × 10 -14) and PICALM (rs561655; P M = 7.0 × 10 -11, P J = 1.0 × 10 -10), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.",

author = "Naj, {Adam C.} and Gyungah Jun and Beecham, {Gary W.} and Wang, {Li San} and Vardarajan, {Badri Narayan} and Jacqueline Buros and Gallins, {Paul J.} and Buxbaum, {Joseph D.} and Jarvik, {Gail P.} and Crane, {Paul K.} and Larson, {Eric B.} and Bird, {Thomas D.} and Boeve, {Bradley F.} and Graff-Radford, {Neill R.} and {De Jager}, {Philip L.} and Denis Evans and Schneider, {Julie A.} and Carrasquillo, {Minerva M.} and Nilufer Ertekin-Taner and Younkin, {Steven G.} and Carlos Cruchaga and Kauwe, {John S.K.} and Petra Nowotny and Patricia Kramer and John Hardy and Huentelman, {Matthew J.} and Myers, {Amanda J.} and Barmada, {Michael M.} and Demirci, {F. Yesim} and Baldwin, {Clinton T.} and Green, {Robert C.} and Ekaterina Rogaeva and George-Hyslop, {Peter St} and Arnold, {Steven E.} and Robert Barber and Thomas Beach and Bigio, {Eileen H.} and Bowen, {James D.} and Adam Boxer and Burke, {James R.} and Cairns, {Nigel J.} and Carlson, {Chris S.} and Carney, {Regina M.} and Carroll, {Steven L.} and Chui, {Helena C.} and Clark, {David G.} and Jason Corneveaux and Cotman, {Carl W.} and Cummings, {Jeffrey L.} and Charles Decarli and Dekosky, {Steven T.} and Ramon Diaz-Arrastia and Malcolm Dick and Dickson, {Dennis W.} and Ellis, {William G.} and Faber, {Kelley M.} and Fallon, {Kenneth B.} and Farlow, {Martin R.} and Steven Ferris and Frosch, {Matthew P.} and Galasko, {Douglas R.} and Mary Ganguli and Marla Gearing and Geschwind, {Daniel H.} and Bernardino Ghetti and Gilbert, {John R.} and Sid Gilman and Bruno Giordani and Glass, {Jonathan D.} and Growdon, {John H.} and Hamilton, {Ronald L.} and Harrell, {Lindy E.} and Elizabeth Head and Honig, {Lawrence S.} and Hulette, {Christine M.} and Hyman, {Bradley T.} and Jicha, {Gregory A.} and Jin, {Lee Way} and Nancy Johnson and Jason Karlawish and Anna Karydas and Kaye, {Jeffrey A.} and Ronald Kim and Koo, {Edward H.} and Kowall, {Neil W.} and Lah, {James J.} and Levey, {Allan I.} and Lieberman, {Andrew P.} and Lopez, {Oscar L.} 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 Parisi, {Joseph E.} and Perl, {Daniel P.} and Elaine Peskind and Petersen, {Ronald C.} and Poon, {Wayne W.} and Quinn, {Joseph F.} and Rajbhandary, {Ruchita A.} and Murray Raskind and Barry Reisberg and Ringman, {John M.} and Roberson, {Erik D.} and Rosenberg, {Roger N.} and Mary Sano and Schneider, {Lon S.} and William Seeley and Shelanski, {Michael L.} and Slifer, {Michael A.} and Smith, {Charles D.} and Sonnen, {Joshua A.} and Salvatore Spina and Stern, {Robert A.} and Tanzi, {Rudolph E.} and Trojanowski, {John Q.} and Troncoso, {Juan C.} and {Van Deerlin}, {Vivianna M.} and Vinters, {Harry V.} and Vonsattel, {Jean Paul} and Sandra Weintraub and Welsh-Bohmer, {Kathleen A.} and Jennifer Williamson and Woltjer, {Randall L.} and Cantwell, {Laura B.} and Dombroski, {Beth A.} and Duane Beekly and Lunetta, {Kathryn L.} and Martin, {Eden R.} and Kamboh, {M. Ilyas} and Saykin, {Andrew J.} and Reiman, {Eric M.} and Bennett, {David A.} and Morris, {John C.} and Montine, {Thomas J.} and Goate, {Alison M.} and Deborah Blacker and Tsuang, {Debby W.} and Hakon Hakonarson and Kukull, {Walter A.} and Foroud, {Tatiana M.} and Haines, {Jonathan L.} and Richard Mayeux and Pericak-Vance, {Margaret A.} and Farrer, {Lindsay A.} and Schellenberg, {Gerard D.}",

note = "Funding Information: The National Institutes of Health, National Institute on Aging (NIH-NIA) supported this work through the following grants: ADGC, U01 AG032984, RC2 AG036528; NACC, U01 AG016976; NCRAD, U24 AG021886; NIA LOAD, U24 AG026395, U24 AG026390; Boston University, P30 AG013846, R01 HG02213, K24 AG027841, U01 AG10483, R01 CA129769, R01 MH080295, R01 AG009029, R01 AG017173, R01 AG025259; Columbia University, P50 AG008702, R37 AG015473; Duke University, P30 AG028377; Emory University, AG025688; Indiana University, P30 AG10133; Johns Hopkins University, P50 AG005146, R01 AG020688; Massachusetts General Hospital, P50 AG005134; Mayo Clinic, P50 AG016574; Mount Sinai School of Medicine, P50 AG005138, P01 AG002219; New York University, P30 AG08051, MO1RR00096, and UL1 RR029893; Northwestern University, P30 AG013854; Oregon Health & Science University, P30 AG008017, R01 AG026916; Rush University, P30 AG010161, R01 AG019085, R01 AG15819, R01 AG17917, R01 AG30146; University of Alabama at Birmingham, P50 AG016582, UL1RR02777; University of Arizona/TGEN, P30 AG019610, R01 AG031581, R01 NS059873; University of California, Davis, P30 AG010129; University of California, Irvine, P50 AG016573, P50, P50 AG016575, P50 AG016576, P50 AG016577; University of California, Los Angeles, P50 AG016570; University of California, San Diego, P50 AG005131; University of California, San Francisco, P50 AG023501, P01 AG019724; University of Kentucky, P30 AG028383; University of Michigan, P50 AG008671; University of Pennsylvania, P30 AG010124; University of Pittsburgh, P50 AG005133, AG030653; University of Southern California, P50 AG005142; University of Texas Southwestern, P30 AG012300; University of Miami, R01 AG027944, AG010491, AG027944, AG021547, AG019757; University of Washington, P50 AG005136, UO1 AG06781, UO1 HG004610; Vanderbilt University, R01 AG019085; and Washington University, P50 AG005681, P01 AG03991. ADNI Funding for ADNI is through the Northern California Institute for Research and Education by grants from Abbott, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare, GlaxoSmithKline, Innogenetics, Johnson and Johnson, Eli Lilly and Co., Medpace, Inc., Merck and Co., Inc., Novartis AG, Pfizer Inc., F. Hoffman-La Roche, Schering-Plough, Synarc, Inc., Alzheimer{\textquoteright}s Association, Alzheimer{\textquoteright}s Drug Discovery Foundation, the Dana Foundation, and by the National Institute of Biomedical Imaging and Bioengineering and NIA grants U01 AG024904, RC2 AG036535, K01 AG030514. We thank C. Phelps, M. Morrison-Bogorad and M. Miller from NIA who are ex-officio ADGC members. Support was also from the Alzheimer{\textquoteright}s Association (LAF, IIRG-08-89720; MP-V, IIRG-05-14147) and the Veterans Affairs Administration. P.S.-H. is supported by Wellcome Trust, Howard Hughes Medical Institute, and the Canadian Institute of Health Research.",

year = "2011",

month = may,

doi = "10.1038/ng.801",

language = "English",

volume = "43",

pages = "436--443",

number = "5",

}

Naj, AC, Jun, G, Beecham, GW, Wang, LS, Vardarajan, BN, Buros, J, Gallins, PJ, Buxbaum, JD, Jarvik, GP, Crane, PK, Larson, EB, Bird, TD, Boeve, BF, Graff-Radford, NR, De Jager, PL, Evans, D, Schneider, JA, Carrasquillo, MM, Ertekin-Taner, N, Younkin, SG, Cruchaga, C, Kauwe, JSK, Nowotny, P, Kramer, P, Hardy, J, Huentelman, MJ, Myers, AJ, Barmada, MM, Demirci, FY, Baldwin, CT, Green, RC, Rogaeva, E, George-Hyslop, PS, Arnold, SE, Barber, R, Beach, T, Bigio, EH, Bowen, JD, Boxer, A, Burke, JR, Cairns, NJ, Carlson, CS, Carney, RM, Carroll, SL, Chui, HC, Clark, DG, Corneveaux, J, Cotman, CW, Cummings, JL, Decarli, C, Dekosky, ST, Diaz-Arrastia, R, Dick, M, Dickson, DW, Ellis, WG, Faber, KM, Fallon, KB, Farlow, MR, Ferris, S, Frosch, MP, Galasko, DR, Ganguli, M, Gearing, M, Geschwind, DH, Ghetti, B, Gilbert, JR, Gilman, S, Giordani, B, Glass, JD, Growdon, JH, Hamilton, RL, Harrell, LE, Head, E, Honig, LS, Hulette, CM, Hyman, BT, Jicha, GA, Jin, LW, Johnson, N, Karlawish, J, Karydas, A, Kaye, JA, Kim, R, Koo, EH, Kowall, NW, Lah, JJ, Levey, AI, Lieberman, AP, Lopez, OL, 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, Parisi, JE, Perl, DP, Peskind, E, Petersen, RC, Poon, WW, Quinn, JF, Rajbhandary, RA, Raskind, M, Reisberg, B, Ringman, JM, Roberson, ED, Rosenberg, RN, Sano, M, Schneider, LS, Seeley, W, Shelanski, ML, Slifer, MA, Smith, CD, Sonnen, JA, Spina, S, Stern, RA, Tanzi, RE, Trojanowski, JQ, Troncoso, JC, Van Deerlin, VM, Vinters, HV, Vonsattel, JP, Weintraub, S, Welsh-Bohmer, KA, Williamson, J, Woltjer, RL, Cantwell, LB, Dombroski, BA, Beekly, D, Lunetta, KL, Martin, ER, Kamboh, MI, Saykin, AJ, Reiman, EM, Bennett, DA, Morris, JC, Montine, TJ, Goate, AM, Blacker, D, Tsuang, DW, Hakonarson, H, Kukull, WA, Foroud, TM, Haines, JL, Mayeux, R, Pericak-Vance, MA, Farrer, LA & Schellenberg, GD 2011, 'Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease', Nature Genetics, vol. 43, no. 5, pp. 436-443. https://doi.org/10.1038/ng.801

TY - JOUR

T1 - Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease

AU - Naj, Adam C.

AU - Jun, Gyungah

AU - Beecham, Gary W.

AU - Wang, Li San

AU - Vardarajan, Badri Narayan

AU - Buros, Jacqueline

AU - Gallins, Paul J.

AU - Buxbaum, Joseph D.

AU - Jarvik, Gail P.

AU - Crane, Paul K.

AU - Larson, Eric B.

AU - Bird, Thomas D.

AU - Boeve, Bradley F.

AU - Graff-Radford, Neill R.

AU - De Jager, Philip L.

AU - Evans, Denis

AU - Schneider, Julie A.

AU - Carrasquillo, Minerva M.

AU - Ertekin-Taner, Nilufer

AU - Younkin, Steven G.

AU - Cruchaga, Carlos

AU - Kauwe, John S.K.

AU - Nowotny, Petra

AU - Kramer, Patricia

AU - Hardy, John

AU - Huentelman, Matthew J.

AU - Myers, Amanda J.

AU - Barmada, Michael M.

AU - Demirci, F. Yesim

AU - Baldwin, Clinton T.

AU - Green, Robert C.

AU - Rogaeva, Ekaterina

AU - George-Hyslop, Peter St

AU - Arnold, Steven E.

AU - Barber, Robert

AU - Beach, Thomas

AU - Bigio, Eileen H.

AU - Bowen, James D.

AU - Boxer, Adam

AU - Burke, James R.

AU - Cairns, Nigel J.

AU - Carlson, Chris S.

AU - Carney, Regina M.

AU - Carroll, Steven L.

AU - Chui, Helena C.

AU - Clark, David G.

AU - Corneveaux, Jason

AU - Cotman, Carl W.

AU - Cummings, Jeffrey L.

AU - Decarli, Charles

AU - Dekosky, Steven T.

AU - Diaz-Arrastia, Ramon

AU - Dick, Malcolm

AU - Dickson, Dennis W.

AU - Ellis, William G.

AU - Faber, Kelley M.

AU - Fallon, Kenneth B.

AU - Farlow, Martin R.

AU - Ferris, Steven

AU - Frosch, Matthew P.

AU - Galasko, Douglas R.

AU - Ganguli, Mary

AU - Gearing, Marla

AU - Geschwind, Daniel H.

AU - Ghetti, Bernardino

AU - Gilbert, John R.

AU - Gilman, Sid

AU - Giordani, Bruno

AU - Glass, Jonathan D.

AU - Growdon, John H.

AU - Hamilton, Ronald L.

AU - Harrell, Lindy E.

AU - Head, Elizabeth

AU - Honig, Lawrence S.

AU - Hulette, Christine M.

AU - Hyman, Bradley T.

AU - Jicha, Gregory A.

AU - Jin, Lee Way

AU - Johnson, Nancy

AU - Karlawish, Jason

AU - Karydas, Anna

AU - Kaye, Jeffrey A.

AU - Kim, Ronald

AU - Koo, Edward H.

AU - Kowall, Neil W.

AU - Lah, James J.

AU - Levey, Allan I.

AU - Lieberman, Andrew P.

AU - Lopez, Oscar L.

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 - Parisi, Joseph E.

AU - Perl, Daniel P.

AU - Peskind, Elaine

AU - Petersen, Ronald C.

AU - Poon, Wayne W.

AU - Quinn, Joseph F.

AU - Rajbhandary, Ruchita A.

AU - Raskind, Murray

AU - Reisberg, Barry

AU - Ringman, John M.

AU - Roberson, Erik D.

AU - Rosenberg, Roger N.

AU - Sano, Mary

AU - Schneider, Lon S.

AU - Seeley, William

AU - Shelanski, Michael L.

AU - Slifer, Michael A.

AU - Smith, Charles D.

AU - Sonnen, Joshua A.

AU - Spina, Salvatore

AU - Stern, Robert A.

AU - Tanzi, Rudolph E.

AU - Trojanowski, John Q.

AU - Troncoso, Juan C.

AU - Van Deerlin, Vivianna M.

AU - Vinters, Harry V.

AU - Vonsattel, Jean Paul

AU - Weintraub, Sandra

AU - Welsh-Bohmer, Kathleen A.

AU - Williamson, Jennifer

AU - Woltjer, Randall L.

AU - Cantwell, Laura B.

AU - Dombroski, Beth A.

AU - Beekly, Duane

AU - Lunetta, Kathryn L.

AU - Martin, Eden R.

AU - Kamboh, M. Ilyas

AU - Saykin, Andrew J.

AU - Reiman, Eric M.

AU - Bennett, David A.

AU - Morris, John C.

AU - Montine, Thomas J.

AU - Goate, Alison M.

AU - Blacker, Deborah

AU - Tsuang, Debby W.

AU - Hakonarson, Hakon

AU - Kukull, Walter A.

AU - Foroud, Tatiana M.

AU - Haines, Jonathan L.

AU - Mayeux, Richard

AU - Pericak-Vance, Margaret A.

AU - Farrer, Lindsay A.

AU - Schellenberg, Gerard D.

N1 - Funding Information: The National Institutes of Health, National Institute on Aging (NIH-NIA) supported this work through the following grants: ADGC, U01 AG032984, RC2 AG036528; NACC, U01 AG016976; NCRAD, U24 AG021886; NIA LOAD, U24 AG026395, U24 AG026390; Boston University, P30 AG013846, R01 HG02213, K24 AG027841, U01 AG10483, R01 CA129769, R01 MH080295, R01 AG009029, R01 AG017173, R01 AG025259; Columbia University, P50 AG008702, R37 AG015473; Duke University, P30 AG028377; Emory University, AG025688; Indiana University, P30 AG10133; Johns Hopkins University, P50 AG005146, R01 AG020688; Massachusetts General Hospital, P50 AG005134; Mayo Clinic, P50 AG016574; Mount Sinai School of Medicine, P50 AG005138, P01 AG002219; New York University, P30 AG08051, MO1RR00096, and UL1 RR029893; Northwestern University, P30 AG013854; Oregon Health & Science University, P30 AG008017, R01 AG026916; Rush University, P30 AG010161, R01 AG019085, R01 AG15819, R01 AG17917, R01 AG30146; University of Alabama at Birmingham, P50 AG016582, UL1RR02777; University of Arizona/TGEN, P30 AG019610, R01 AG031581, R01 NS059873; University of California, Davis, P30 AG010129; University of California, Irvine, P50 AG016573, P50, P50 AG016575, P50 AG016576, P50 AG016577; University of California, Los Angeles, P50 AG016570; University of California, San Diego, P50 AG005131; University of California, San Francisco, P50 AG023501, P01 AG019724; University of Kentucky, P30 AG028383; University of Michigan, P50 AG008671; University of Pennsylvania, P30 AG010124; University of Pittsburgh, P50 AG005133, AG030653; University of Southern California, P50 AG005142; University of Texas Southwestern, P30 AG012300; University of Miami, R01 AG027944, AG010491, AG027944, AG021547, AG019757; University of Washington, P50 AG005136, UO1 AG06781, UO1 HG004610; Vanderbilt University, R01 AG019085; and Washington University, P50 AG005681, P01 AG03991. ADNI Funding for ADNI is through the Northern California Institute for Research and Education by grants from Abbott, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare, GlaxoSmithKline, Innogenetics, Johnson and Johnson, Eli Lilly and Co., Medpace, Inc., Merck and Co., Inc., Novartis AG, Pfizer Inc., F. Hoffman-La Roche, Schering-Plough, Synarc, Inc., Alzheimer’s Association, Alzheimer’s Drug Discovery Foundation, the Dana Foundation, and by the National Institute of Biomedical Imaging and Bioengineering and NIA grants U01 AG024904, RC2 AG036535, K01 AG030514. We thank C. Phelps, M. Morrison-Bogorad and M. Miller from NIA who are ex-officio ADGC members. Support was also from the Alzheimer’s Association (LAF, IIRG-08-89720; MP-V, IIRG-05-14147) and the Veterans Affairs Administration. P.S.-H. is supported by Wellcome Trust, Howard Hughes Medical Institute, and the Canadian Institute of Health Research.

PY - 2011/5

Y1 - 2011/5

N2 - The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P M) = 1.7 × 10 -9, joint analysis P (P J) = 1.7 × 10 -9; stages 1, 2 and 3, P M = 8.2 × 10 -12), CD2AP (rs9349407; stages 1, 2 and 3, P M = 8.6 × 10 -9), EPHA1 (rs11767557; stages 1, 2 and 3, P M = 6.0 × 10 -10) and CD33 (rs3865444; stages 1, 2 and 3, P M = 1.6 × 10 -9). We also replicated previous associations at CR1 (rs6701713; P M = 4.6 × 10 -10, P J = 5.2 × 10 -11), CLU (rs1532278; P M = 8.3 × 10 -8, P J = 1.9 × 10 -8), BIN1 (rs7561528; P M = 4.0 × 10 -14, P J = 5.2 × 10 -14) and PICALM (rs561655; P M = 7.0 × 10 -11, P J = 1.0 × 10 -10), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.

AB - The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P M) = 1.7 × 10 -9, joint analysis P (P J) = 1.7 × 10 -9; stages 1, 2 and 3, P M = 8.2 × 10 -12), CD2AP (rs9349407; stages 1, 2 and 3, P M = 8.6 × 10 -9), EPHA1 (rs11767557; stages 1, 2 and 3, P M = 6.0 × 10 -10) and CD33 (rs3865444; stages 1, 2 and 3, P M = 1.6 × 10 -9). We also replicated previous associations at CR1 (rs6701713; P M = 4.6 × 10 -10, P J = 5.2 × 10 -11), CLU (rs1532278; P M = 8.3 × 10 -8, P J = 1.9 × 10 -8), BIN1 (rs7561528; P M = 4.0 × 10 -14, P J = 5.2 × 10 -14) and PICALM (rs561655; P M = 7.0 × 10 -11, P J = 1.0 × 10 -10), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.

UR - http://www.scopus.com/inward/record.url?scp=79955464911&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79955464911&partnerID=8YFLogxK

U2 - 10.1038/ng.801

DO - 10.1038/ng.801

M3 - Article

C2 - 21460841

AN - SCOPUS:79955464911

SN - 1061-4036

VL - 43

SP - 436

EP - 443

JO - Nature Genetics

JF - Nature Genetics

IS - 5

ER -

Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease

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