Transethnic genome-wide scan identifies novel Alzheimer's disease loci

Alzheimer's Disease Genetics Consortium

doi:10.1016/j.jalz.2016.12.012

Transethnic genome-wide scan identifies novel Alzheimer's disease loci

Alzheimer's Disease Genetics Consortium

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

51 Scopus citations

Abstract

Introduction Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. Methods We conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset. Results Genome-wide significant (GWS) associations in single-nucleotide polymorphism (SNP)–based tests (P < 5 × 10⁻⁸) were identified for SNPs in PFDN1/HBEGF, USP6NL/ECHDC3, and BZRAP1-AS1 and for the interaction of the (apolipoprotein E) APOE ε4 allele with NFIC SNP. We also obtained GWS evidence (P < 2.7 × 10⁻⁶) for gene-based association in the total sample with a novel locus, TPBG (P = 1.8 × 10⁻⁶). Discussion Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci.

Original language	English (US)
Pages (from-to)	727-738
Number of pages	12
Journal	Alzheimer's and Dementia
Volume	13
Issue number	7
DOIs	https://doi.org/10.1016/j.jalz.2016.12.012
State	Published - Jul 2017

Keywords

APOE interaction
Alzheimer's disease
Genome-wide association
Transethnic

ASJC Scopus subject areas

Epidemiology
Health Policy
Developmental Neuroscience
Clinical Neurology
Geriatrics and Gerontology
Psychiatry and Mental health
Cellular and Molecular Neuroscience

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@article{9778aeec9df64c69b0cdb3d64ce0b214,

title = "Transethnic genome-wide scan identifies novel Alzheimer's disease loci",

abstract = "Introduction Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. Methods We conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset. Results Genome-wide significant (GWS) associations in single-nucleotide polymorphism (SNP)–based tests (P < 5 × 10−8) were identified for SNPs in PFDN1/HBEGF, USP6NL/ECHDC3, and BZRAP1-AS1 and for the interaction of the (apolipoprotein E) APOE ε4 allele with NFIC SNP. We also obtained GWS evidence (P < 2.7 × 10−6) for gene-based association in the total sample with a novel locus, TPBG (P = 1.8 × 10−6). Discussion Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci.",

keywords = "APOE interaction, Alzheimer's disease, Genome-wide association, Transethnic",

author = "{Alzheimer's Disease Genetics Consortium} and Jun, {Gyungah R.} and Jaeyoon Chung and Logue, {Mark W.} and Richard Sherva and Farrer, {Lindsay A.} and Jesse Mez and Robert Barber and Beecham, {Gary W.} and Hamilton-Nelson, {Kara L.} and Kunkle, {Brian W.} and Martin, {Eden R.} and Pericak-Vance, {Margaret A.} and Bennett, {David A.} and Buxbaum, {Joseph D.} and Goate, {Alison M.} and Alison Goate and M. Carlos and Byrd, {Goldie S.} and Carrasquillo, {Minerva M.} and Nilufer Ertekin-Taner and Graff-Radford, {Neill R.} and Younkin, {Steven G.} and Crane, {Paul K.} and Shubhabrata Mukherjee and Timothy Thornton and Carlos Cruchaga and {De Jager}, Philip and Larson, {Eric B.} and Denis Evans and Fallin, {M. Danielle} and Foroud, {Tatiana M.} and Friedland, {Robert P.} and Hugh Hendrie and Hall, {Kathleen S.} and Rivka Inzelberg and Kamboh, {M. Ilyas} and Kauwe, {John S.K.} and Kukull, {Walter A.} and Adams, {Perrie M.} and Ryozo Kuwano and Albin, {Roger L.} and Apostolova, {Liana G.} and Manly, {Jennifer J.} and Vardarajan, {Badri N.} and Richard Mayeux and Barmada, {Michjael M.} and Kaye, {Jeffrey A.} and Aimee Pierce and Quinn, {Joseph F.} and Woltjer, {Randall L.}",

note = "Funding Information: We thank Drs D. Stephen Snyder and Marilyn Miller from National Institute on Aging (NIA) who are ex-officio Alzheimer's Disease Genetics Consortium (ADGC) members. Funding support: 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; MIRAGE: R01 AG025259; Banner Sun Health Research Institute P30 AG019610; Boston University, P30 AG013846, U01 AG10483, R01 CA129769, R01 MH080295, R01 AG017173, R01 AG33193, R01 AG048927; Columbia University, P50 AG008702, R37 AG015473; Duke University, P30 AG028377, AG05128; Emory University, AG025688; Group Health Research Institute, UO1 AG06781, UO1 HG004610; U01 HG006375; 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; TGen, R01 NS059873; University of Alabama at Birmingham, P50 AG016582, UL1RR02777; University of Arizona, R01 AG031581; 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; Vanderbilt University, R01 AG019085; and Washington University, P50 AG005681, P01 AG03991. The Kathleen Price Bryan Brain Bank at Duke University Medical Center is funded by NINDS grant #NS39764, NIMH MH60451, and by GlaxoSmithKline. Genotyping of the TGEN2 cohort was supported by Kronos Science. The TGen series was also funded by NIA grant AG034504 to AJM, The Banner Alzheimer's Foundation, The Johnnie B. Byrd Sr. Alzheimer's Institute, the Medical Research Council, and the State of Arizona and also includes samples from the following sites: Newcastle Brain Tissue Resource (funding via the Medical Research Council, local NHS trusts, and Newcastle University), MRC London Brain Bank for Neurodegenerative Diseases (funding via the Medical Research Council), Southwest Dementia Brain Bank (funding via numerous sources including the Higher Education Funding Council for England, Alzheimer's Research Trust [ART], BRACE, and North Bristol NHS Trust Research and Innovation Department and DeNDRoN), The Netherlands Brain Bank (funding via numerous sources including Stichting MS Research, Brain Net Europe, Hersenstichting Nederland Breinbrekend Werk, International Parkinson Fonds, Internationale Stiching Alzheimer Onderzoek), Institut de Neuropatologia, Servei Anatomia Patologica, Universitat de Barcelona. Marcelle Morrison-Bogorad, PhD, Tony Phelps, PhD, and Walter Kukull PhD are thanked for helping to coordinate this collection. Alzheimer's Disease Neuroimaging Initiative funding 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, Merck & Co., Inc., Novartis AG, Pfizer, F. Homan-La Roche, Schering-Plough, Synarc, 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. Support was also from the Alzheimer's Association (LAF, IIRG-08-89720; MP-V, IIRG-05-14147) and the US Department of Veterans Affairs Administration, Office of Research and Development, Biomedical Laboratory Research Program. P.S.G.-H. is supported by the Wellcome Trust, Howard Hughes Medical Institute, and Canadian Institute of Health. ADGC members are as follows: Perrie M. Adams, PhD; Marilyn S. Albert, PhD; Roger L. Albin, MD; Liana G. Apostolova, MD; Steven E. Arnold, MD; Sanjay Asthana, MD; Craig S. Atwood, PhD; Michjael M. Barmada, PhD; Lisa L. Barnes, PhD; Thomas G. Beach, MD, PhD; James T. Becker, PhD; Eileen H. Bigio, MD; Thomas D. Bird, MD; Deborah Blacker, MD; Bradley F. Boeve, MD; James D. Bowen, MD; Adam Boxer, MD, PhD, James R. Burke, MD, PhD; Nigel J. Cairns, PhD, FRCPath; Chuanhai Cao, PhD; Chris S. Carlson, PhD; Cynthia M. Carlsson, MD; Regina M. Carney, MD; Minerva M. Carrasquillo, PhD; Steven L. Carroll, MD, PhD; Helena C. Chui, MD; David G. Clark, MD; Jason Corneveaux, BS; David H. Cribbs, PhD; Elizabeth A. Crocco, MD; Carlos Cruchaga, PhD; Philip L. De Jager, MD, PhD; Charles DeCarli, MD; Steven T. DeKosky, MD; F. Yesim Demirci, MD; Malcolm Dick, PhD; Dennis W. Dickson, MD; Rachelle S. Doody, MD, PhD; Ranjan Duara, MD; Nilufer Ertekin-Taner, MD, PhD; Kelley M. Faber, MS; Thomas J. Fairchild, PhD; Kenneth B. Fallon, MD; Martin R. Farlow, MD; Steven Ferris, PhD; Matthew P. Frosch, MD, PhD; Douglas R. Galasko, MD; Marla Gearing, PhD; Daniel H. Geschwind, MD, PhD; Bernardino Ghetti, MD; John R. Gilbert PhD; Jonathan D. Glass, MD; Neill R. Graff-Radford, MD; Robert C. Green, MD, MPH; John H. Growdon, MD; Hakon Hakonarson, MD, PhD; Ronald L. Hamilton, MD; John Hardy, PhD; Lindy E. Harrell, MD, PhD; Elizabeth Head, PhD; Lawrence S. Honig, MD, PhD; Ryan M. Huebinger, PhD, Matthew J. Huentelman, PhD; Christine M. Hulette, MD; Bradley T. Hyman, MD, PhD; Gail P. Jarvik, MD, PhD; Gregory A. Jicha, MD, PhD; Lee-Way Jin, MD, PhD; Anna Karydas, BA; John S.K. Kauwe, PhD; Jeffrey A. Kaye, MD; Ronald Kim, MD; Edward H. Koo, MD; Neil W. Kowall, MD; Joel H. Kramer, PsyD; Frank M. LaFerla, PhD; James J. Lah, MD, PhD; James B. Leverenz, MD; Allan I. Levey, MD, PhD; Ge Li, MD, PhD; Andrew P. Lieberman, MD, PhD; Chiao-Feng Lin, PhD; Oscar L. Lopez, MD; Constantine G. Lyketsos, MD, MHS; Wendy J. Mack, PhD; Daniel C. Marson, JD, PhD; Frank Martiniuk, PhD; Deborah C. Mash, PhD; Eliezer Masliah, MD; Wayne C. McCormick, MD, MPH; Susan M. McCurry, PhD; Andrew N. McDavid, BA; Ann C. McKee, MD; Marsel Mesulam, MD; Bruce L. Miller, MD; Carol A. Miller, MD; Joshua W. Miller, PhD; John C. Morris, MD; Shubhabrata Mukherjee, PhD; Jill R. Murrell, PhD, Amanda J. Myers, PhD; Sid O'Bryant, PhD; John M. Olichney, MD; Vernon S. Pankratz, PhD; Joseph E. Parisi, MD; Amanda Partch, MS; Henry L. Paulson, MD, PhD; William Perry, MPH; Elaine Peskind, MD; Ronald C. Petersen, MD, PhD; Aimee Pierce, MD; Wayne W. Poon, PhD; Huntington Potter, PhD; Joseph F. Quinn, MD; Ashok Raj, MD; Murray Raskind, MD; Barry Reisberg, MD; Joan S. Reisch, PhD; Christiane Reitz, MD, PhD; John M. Ringman; MD; Erik D. Roberson, MD, PhD; Ekaterina Rogaeva, PhD; Howard J. Rosen, MD; Roger N. Rosenberg, MD; Donald R. Royall, MD; Mark A. Sager, MD; Mary Sano, PhD; Andrew J. Saykin, PsyD; Julie A. Schneider, MD; Lon S. Schneider, MD; William W. Seeley, MD; Amanda G. Smith, MD; Joshua A. Sonnen, MD; Salvatore Spina, MD; Robert A. Stern, PhD; Rudolph E. Tanzi, PhD; Tricia A. Thornton-Wells, PhD; John Q. Trojanowski, MD, PhD; Juan C. Troncoso, MD; Debby W. Tsuang, MD; Vivianna M. Van Deerlin, MD, PhD; Linda J. Van Eldik, PhD; Badri N. Vardarajan, PhD; Harry V. Vinters, MD; Jean Paul Vonsattel, MD; Sandra Weintraub, PhD; Kathleen A. Welsh-Bohmer, PhD; Jennifer Williamson, MS; Sarah Wishnek, MPH; Randall L. Woltjer, MD, PhD; Clinton B. Wright, MD, MS; Chuang-Kuo Wu, MD, PhD; Chang-En Yu, PhD; Lei Yu, PhD; and Xiaoling Zhang, PhD. Conflicts of interest: The authors of this article have no conflicts of interest to report. Web resources: NIA Genetics of Alzheimer's Disease Data Storage Site: https://www.niagads.org/ . ",

year = "2017",

month = jul,

doi = "10.1016/j.jalz.2016.12.012",

language = "English (US)",

volume = "13",

pages = "727--738",

journal = "Alzheimer's and Dementia",

issn = "1552-5260",

publisher = "Elsevier Inc.",

number = "7",

}

TY - JOUR

T1 - Transethnic genome-wide scan identifies novel Alzheimer's disease loci

AU - Alzheimer's Disease Genetics Consortium

AU - Jun, Gyungah R.

AU - Chung, Jaeyoon

AU - Logue, Mark W.

AU - Sherva, Richard

AU - Farrer, Lindsay A.

AU - Mez, Jesse

AU - Barber, Robert

AU - Beecham, Gary W.

AU - Hamilton-Nelson, Kara L.

AU - Kunkle, Brian W.

AU - Martin, Eden R.

AU - Pericak-Vance, Margaret A.

AU - Bennett, David A.

AU - Buxbaum, Joseph D.

AU - Goate, Alison M.

AU - Goate, Alison

AU - Carlos, M.

AU - Byrd, Goldie S.

AU - Carrasquillo, Minerva M.

AU - Ertekin-Taner, Nilufer

AU - Graff-Radford, Neill R.

AU - Younkin, Steven G.

AU - Crane, Paul K.

AU - Mukherjee, Shubhabrata

AU - Thornton, Timothy

AU - Cruchaga, Carlos

AU - De Jager, Philip

AU - Larson, Eric B.

AU - Evans, Denis

AU - Fallin, M. Danielle

AU - Foroud, Tatiana M.

AU - Friedland, Robert P.

AU - Hendrie, Hugh

AU - Hall, Kathleen S.

AU - Inzelberg, Rivka

AU - Kamboh, M. Ilyas

AU - Kauwe, John S.K.

AU - Kukull, Walter A.

AU - Adams, Perrie M.

AU - Kuwano, Ryozo

AU - Albin, Roger L.

AU - Apostolova, Liana G.

AU - Manly, Jennifer J.

AU - Vardarajan, Badri N.

AU - Mayeux, Richard

AU - Barmada, Michjael M.

AU - Kaye, Jeffrey A.

AU - Pierce, Aimee

AU - Quinn, Joseph F.

AU - Woltjer, Randall L.

N1 - Funding Information: We thank Drs D. Stephen Snyder and Marilyn Miller from National Institute on Aging (NIA) who are ex-officio Alzheimer's Disease Genetics Consortium (ADGC) members. Funding support: 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; MIRAGE: R01 AG025259; Banner Sun Health Research Institute P30 AG019610; Boston University, P30 AG013846, U01 AG10483, R01 CA129769, R01 MH080295, R01 AG017173, R01 AG33193, R01 AG048927; Columbia University, P50 AG008702, R37 AG015473; Duke University, P30 AG028377, AG05128; Emory University, AG025688; Group Health Research Institute, UO1 AG06781, UO1 HG004610; U01 HG006375; 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; TGen, R01 NS059873; University of Alabama at Birmingham, P50 AG016582, UL1RR02777; University of Arizona, R01 AG031581; 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; Vanderbilt University, R01 AG019085; and Washington University, P50 AG005681, P01 AG03991. The Kathleen Price Bryan Brain Bank at Duke University Medical Center is funded by NINDS grant #NS39764, NIMH MH60451, and by GlaxoSmithKline. Genotyping of the TGEN2 cohort was supported by Kronos Science. The TGen series was also funded by NIA grant AG034504 to AJM, The Banner Alzheimer's Foundation, The Johnnie B. Byrd Sr. Alzheimer's Institute, the Medical Research Council, and the State of Arizona and also includes samples from the following sites: Newcastle Brain Tissue Resource (funding via the Medical Research Council, local NHS trusts, and Newcastle University), MRC London Brain Bank for Neurodegenerative Diseases (funding via the Medical Research Council), Southwest Dementia Brain Bank (funding via numerous sources including the Higher Education Funding Council for England, Alzheimer's Research Trust [ART], BRACE, and North Bristol NHS Trust Research and Innovation Department and DeNDRoN), The Netherlands Brain Bank (funding via numerous sources including Stichting MS Research, Brain Net Europe, Hersenstichting Nederland Breinbrekend Werk, International Parkinson Fonds, Internationale Stiching Alzheimer Onderzoek), Institut de Neuropatologia, Servei Anatomia Patologica, Universitat de Barcelona. Marcelle Morrison-Bogorad, PhD, Tony Phelps, PhD, and Walter Kukull PhD are thanked for helping to coordinate this collection. Alzheimer's Disease Neuroimaging Initiative funding 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, Merck & Co., Inc., Novartis AG, Pfizer, F. Homan-La Roche, Schering-Plough, Synarc, 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. Support was also from the Alzheimer's Association (LAF, IIRG-08-89720; MP-V, IIRG-05-14147) and the US Department of Veterans Affairs Administration, Office of Research and Development, Biomedical Laboratory Research Program. P.S.G.-H. is supported by the Wellcome Trust, Howard Hughes Medical Institute, and Canadian Institute of Health. ADGC members are as follows: Perrie M. Adams, PhD; Marilyn S. Albert, PhD; Roger L. Albin, MD; Liana G. Apostolova, MD; Steven E. Arnold, MD; Sanjay Asthana, MD; Craig S. Atwood, PhD; Michjael M. Barmada, PhD; Lisa L. Barnes, PhD; Thomas G. Beach, MD, PhD; James T. Becker, PhD; Eileen H. Bigio, MD; Thomas D. Bird, MD; Deborah Blacker, MD; Bradley F. Boeve, MD; James D. Bowen, MD; Adam Boxer, MD, PhD, James R. Burke, MD, PhD; Nigel J. Cairns, PhD, FRCPath; Chuanhai Cao, PhD; Chris S. Carlson, PhD; Cynthia M. Carlsson, MD; Regina M. Carney, MD; Minerva M. Carrasquillo, PhD; Steven L. Carroll, MD, PhD; Helena C. Chui, MD; David G. Clark, MD; Jason Corneveaux, BS; David H. Cribbs, PhD; Elizabeth A. Crocco, MD; Carlos Cruchaga, PhD; Philip L. De Jager, MD, PhD; Charles DeCarli, MD; Steven T. DeKosky, MD; F. Yesim Demirci, MD; Malcolm Dick, PhD; Dennis W. Dickson, MD; Rachelle S. Doody, MD, PhD; Ranjan Duara, MD; Nilufer Ertekin-Taner, MD, PhD; Kelley M. Faber, MS; Thomas J. Fairchild, PhD; Kenneth B. Fallon, MD; Martin R. Farlow, MD; Steven Ferris, PhD; Matthew P. Frosch, MD, PhD; Douglas R. Galasko, MD; Marla Gearing, PhD; Daniel H. Geschwind, MD, PhD; Bernardino Ghetti, MD; John R. Gilbert PhD; Jonathan D. Glass, MD; Neill R. Graff-Radford, MD; Robert C. Green, MD, MPH; John H. Growdon, MD; Hakon Hakonarson, MD, PhD; Ronald L. Hamilton, MD; John Hardy, PhD; Lindy E. Harrell, MD, PhD; Elizabeth Head, PhD; Lawrence S. Honig, MD, PhD; Ryan M. Huebinger, PhD, Matthew J. Huentelman, PhD; Christine M. Hulette, MD; Bradley T. Hyman, MD, PhD; Gail P. Jarvik, MD, PhD; Gregory A. Jicha, MD, PhD; Lee-Way Jin, MD, PhD; Anna Karydas, BA; John S.K. Kauwe, PhD; Jeffrey A. Kaye, MD; Ronald Kim, MD; Edward H. Koo, MD; Neil W. Kowall, MD; Joel H. Kramer, PsyD; Frank M. LaFerla, PhD; James J. Lah, MD, PhD; James B. Leverenz, MD; Allan I. Levey, MD, PhD; Ge Li, MD, PhD; Andrew P. Lieberman, MD, PhD; Chiao-Feng Lin, PhD; Oscar L. Lopez, MD; Constantine G. Lyketsos, MD, MHS; Wendy J. Mack, PhD; Daniel C. Marson, JD, PhD; Frank Martiniuk, PhD; Deborah C. Mash, PhD; Eliezer Masliah, MD; Wayne C. McCormick, MD, MPH; Susan M. McCurry, PhD; Andrew N. McDavid, BA; Ann C. McKee, MD; Marsel Mesulam, MD; Bruce L. Miller, MD; Carol A. Miller, MD; Joshua W. Miller, PhD; John C. Morris, MD; Shubhabrata Mukherjee, PhD; Jill R. Murrell, PhD, Amanda J. Myers, PhD; Sid O'Bryant, PhD; John M. Olichney, MD; Vernon S. Pankratz, PhD; Joseph E. Parisi, MD; Amanda Partch, MS; Henry L. Paulson, MD, PhD; William Perry, MPH; Elaine Peskind, MD; Ronald C. Petersen, MD, PhD; Aimee Pierce, MD; Wayne W. Poon, PhD; Huntington Potter, PhD; Joseph F. Quinn, MD; Ashok Raj, MD; Murray Raskind, MD; Barry Reisberg, MD; Joan S. Reisch, PhD; Christiane Reitz, MD, PhD; John M. Ringman; MD; Erik D. Roberson, MD, PhD; Ekaterina Rogaeva, PhD; Howard J. Rosen, MD; Roger N. Rosenberg, MD; Donald R. Royall, MD; Mark A. Sager, MD; Mary Sano, PhD; Andrew J. Saykin, PsyD; Julie A. Schneider, MD; Lon S. Schneider, MD; William W. Seeley, MD; Amanda G. Smith, MD; Joshua A. Sonnen, MD; Salvatore Spina, MD; Robert A. Stern, PhD; Rudolph E. Tanzi, PhD; Tricia A. Thornton-Wells, PhD; John Q. Trojanowski, MD, PhD; Juan C. Troncoso, MD; Debby W. Tsuang, MD; Vivianna M. Van Deerlin, MD, PhD; Linda J. Van Eldik, PhD; Badri N. Vardarajan, PhD; Harry V. Vinters, MD; Jean Paul Vonsattel, MD; Sandra Weintraub, PhD; Kathleen A. Welsh-Bohmer, PhD; Jennifer Williamson, MS; Sarah Wishnek, MPH; Randall L. Woltjer, MD, PhD; Clinton B. Wright, MD, MS; Chuang-Kuo Wu, MD, PhD; Chang-En Yu, PhD; Lei Yu, PhD; and Xiaoling Zhang, PhD. Conflicts of interest: The authors of this article have no conflicts of interest to report. Web resources: NIA Genetics of Alzheimer's Disease Data Storage Site: https://www.niagads.org/ .

PY - 2017/7

Y1 - 2017/7

N2 - Introduction Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. Methods We conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset. Results Genome-wide significant (GWS) associations in single-nucleotide polymorphism (SNP)–based tests (P < 5 × 10−8) were identified for SNPs in PFDN1/HBEGF, USP6NL/ECHDC3, and BZRAP1-AS1 and for the interaction of the (apolipoprotein E) APOE ε4 allele with NFIC SNP. We also obtained GWS evidence (P < 2.7 × 10−6) for gene-based association in the total sample with a novel locus, TPBG (P = 1.8 × 10−6). Discussion Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci.

AB - Introduction Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. Methods We conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset. Results Genome-wide significant (GWS) associations in single-nucleotide polymorphism (SNP)–based tests (P < 5 × 10−8) were identified for SNPs in PFDN1/HBEGF, USP6NL/ECHDC3, and BZRAP1-AS1 and for the interaction of the (apolipoprotein E) APOE ε4 allele with NFIC SNP. We also obtained GWS evidence (P < 2.7 × 10−6) for gene-based association in the total sample with a novel locus, TPBG (P = 1.8 × 10−6). Discussion Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci.

KW - APOE interaction

KW - Alzheimer's disease

KW - Genome-wide association

KW - Transethnic

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UR - http://www.scopus.com/inward/citedby.url?scp=85014178309&partnerID=8YFLogxK

U2 - 10.1016/j.jalz.2016.12.012

DO - 10.1016/j.jalz.2016.12.012

M3 - Article

C2 - 28183528

AN - SCOPUS:85014178309

VL - 13

SP - 727

EP - 738

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

SN - 1552-5260

IS - 7

ER -