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

doi:10.1016/j.jalz.2016.12.012

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

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

144 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
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 1 2017

Bibliographical note

Publisher Copyright:
© 2017 The Authors

Funding

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/ .

Funders	Funder number
Johnson and Johnson Pharmaceutical Research and Development
Northern California Institute for Research and Education
Canadian Health Research Institute
Alzheimer's Association
GE Healthcare
Biomedical Laboratory Research Program
North Bristol NHS Trust Research and Innovation Department and DeNDRoN
Merck
Banner Alzheimer’s Foundation
Coins for Alzheimer's Research Trust
Bayer Schering
Netherlands Brain Bank
Internationale Stichting Alzheimer Onderzoek
Schering Plough Co
Hersenstichting Nederland Breinbrekend Werk
Newcastle Brain Tissue Resource
Synarc, Inc.
Southwest Dementia Brain Bank
Institut de Neuropatologia
National Institute of Biomedical Imaging and Bioengineering
Higher Education Funding Council for England
Charles A Dana Foundation
BRACE
National Institutes of Health (NIH)
Wellcome Trust
Eli Lilly and Company
Abbott Laboratories
Medpace, Inc.
F. Hoffmann-La Roche AG
Biomedical Laboratory Research and Development, VA Office of Research and Development
Novartis
Eisai Global Clinical Development
Stichting Vanderes
Astrobiology Research Trust
Universitat de Barcelona
Eaton Corporation
Bristol-Myers Squibb
GlaxoSmithKline
Newcastle University
US Department of Veterans Affairs Administration
Arizona State University
MRC London Brain Bank for Neurodegenerative Diseases
Pfizer
NIA/NIH
International Parkinson Fonds
AstraZeneca
Genentech Incorporated
Alzheimer's Drug Discovery Foundation
Innogenetics
Howard Hughes Medical Institute
Vanderbilt Digestive Diseases Research Center, Vanderbilt University Medical Center
National Institute of Mental Health	P50MH060451, R01MH080295
National Institute of General Medical Sciences DP2GM119177 Sophie Dumont National Institute of General Medical Sciences	P01GM099568
University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh	AG030653, P50 AG005133
National Institute on Aging	R01AG033193, P50AG005146, RC2AG036535, R01AG048927, P50AG005142, RF1AG054023, U24AG021886, U01AG024904, R01AG019085, R01AG025259, P30AG053760, U01AG016976, P01AG010491, P50AG005133, RC2AG036528, P01AG000538, P50AG005134, R01AG054060, P50AG005131, K01AG030514, RF1AG051504, P30AG013854, K23AG046377, P30AG028383, R01AG027944, U24AG056270, R01AG034504, P50AG016582, U01AG010483, P50AG005136, P50AG025688, R01AG041232, P50AG023501, P50AG005138, R01AG041797, R01AG021547, P50AG008671, P50AG005681, P30AG028377, R37AG015473, R01AG026916, R01AG030146, P01AG019724, U01AG006781, P50AG016573, P50AG016574, P30AG013846, P30AG010133, R01AG030653, P50AG016570, R01AG017917, P50AG005128, P01AG002219, R01AG015819, U01AG032984, R01AG026390, R01AG019757, R01AG020688, R01AG017173, R01AG031581, P30AG008017, U24AG026395, P30AG010124, P30AG012300, P30AG010161, P01AG003991, P30AG010129, P30AG019610, P30AG008051, P50AG008702
Boston University School of Public Health/Boston University Medical Campus	R01 AG33193, P30 AG013846, R01 AG048927, U01 AG10483, R01 MH080295, R01 AG017173, R01 CA129769
The Pennsylvania State University	P30 AG010124
Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council	R01NS080820, 39764, R01NS059873, P50NS039764
The George Washington University	P50 AG005136, P50 AG005681, P01 AG03991
University of Southern Indiana	P30 AG10133
Banner Sun Health Research Institute	P30 AG019610
Mayo Clinic Rochester	P50 AG016574
National Center for Research Resources	M01RR000096, UL1RR029893
University of Northern Arizona	R01 AG031581
National Center for Advancing Translational Sciences (NCATS)	UL1TR001445
University of California Davis	P30 AG010129
University of Kentucky	P30 AG028383
National Human Genome Research Institute	U01HG006375, U01HG004610
University of California Irvine	P50 AG016577, P50 AG016576, P50 AG016575, P50 AG016573
University of California San Diego Health	P50 AG023501, P01 AG019724, P50 AG005131
National Association for Colitis and Crohn's Disease	U01 AG016976
The Johns Hopkins University	R01 AG020688, P50 AG005146
Japan Society for the Promotion of Science	16K14649
Duke-Kunshan University	AG05128, P30 AG028377
University of Alabama	UL1RR02777, P50 AG016582
Massachusetts General Hospital	P50 AG005134
Miami Clinical and Translational Science Institute, University of Miami	AG027944, AG021547, R01 AG027944, AG010491, AG019757
Michigan Diabetes Research Center, University of Michigan	P50 AG008671
ADGC	RC2 AG036528, U01 AG032984
University of California, Los Angeles	P50 AG016570
Lance Armstrong Foundation	IIRG-05-14147, IIRG-08-89720
Icahn School of Medicine at Mount Sinai	P01 AG002219, P50 AG005138
University Research Committee, Emory University	AG025688
Kronos Science	AG034504
Columbia University	P50 AG008702, R37 AG015473
Oregon Health and Science University	P30 AG008017, R01 AG026916
UK Medical Research Council, Engineering and Physical Sciences Research Council	G1001253, MR/L501542/1, MR/K01417X/1, MR/J004758/1, G0901254
York University, New York, New York, USA bbbUniversity of Rochester, Rochester, New York	UL1 RR029893, P30 AG08051, MO1RR00096
National Childhood Cancer Registry – National Cancer Institute	R01CA129769
Group Health Research Institute	UO1 AG06781, UO1 HG004610, U01 HG006375
University of Southern California	P50 AG005142
Rush University	R01 AG30146, R01 AG15819, R01 NS059873, R01 AG17917, P30 AG010161, R01 AG019085
The University of Texas Southwestern Medical Center	P30 AG012300
Northwestern Polytechnical University	P30 AG013854
NCRAD	U24 AG021886, U24 AG026395, R01 AG025259, U24 AG026390

Keywords

APOE interaction
Alzheimer's disease
Genome-wide association
Transethnic

ASJC Scopus subject areas

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jalz.2016.12.012

Cite this

@article{6e225f8f88ed487b9bd75daf750e6112,

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 = "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 Barnes, \{Lisa L.\} and Beach, \{Thomas G.\} and Jicha, \{Gregory A.\} and \{Van Eldik\}, \{Linda J.\}",

note = "Publisher Copyright: {\textcopyright} 2017 The Authors",

year = "2017",

month = jul,

day = "1",

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

language = "English",

volume = "13",

pages = "727--738",

number = "7",

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TY - JOUR

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

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 - Barnes, Lisa L.

AU - Beach, Thomas G.

AU - Jicha, Gregory A.

AU - Van Eldik, Linda J.

PY - 2017/7/1

Y1 - 2017/7/1

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

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