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

Neurology

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

137 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 - 1 Jul 2017

Funding

Funders	Funder number
Johnson and Johnson
Northern California Institute for Research and Education
Canadian Institute of Health
Alzheimer's Association
GE Healthcare
Biomedical Laboratory Research Program
North Bristol NHS Trust Research and Innovation Department and DeNDRoN
Merck
Banner Alzheimer’s Foundation
Alzheimer's Research Trust
Bayer Schering
Netherlands Brain Bank
Internationale Stichting Alzheimer Onderzoek
Schering-Plough
Hersenstichting Nederland Breinbrekend Werk
Newcastle Brain Tissue Resource
Synarc
Southwest Dementia Brain Bank
Institut de Neuropatologia
National Institute of Biomedical Imaging and Bioengineering
Higher Education Funding Council for England
Dana Foundation
BRACE
National Institutes of Health
Wellcome Trust
Eli Lilly and Co.
Abbott Laboratories
Medpace
F. Hoffmann-La Roche
Office of Research and Development
Novartis
Eisai Global Clinical Development
Stichting MS
Astrobiology Research Trust
Universitat de Barcelona
Eaton Corporation
Bristol-Myers Squibb
GlaxoSmithKline
Newcastle University
US Department of Veterans Affairs Administration
State of Arizona
MRC London Brain Bank for Neurodegenerative Diseases
Pfizer
NIH-NIA
International Parkinson Fonds
AstraZeneca
Genentech
Alzheimer's Drug Discovery Foundation
Innogenetics
Howard Hughes Medical Institute
Vanderbilt University
National Institute of Mental Health	P50MH060451, R01MH080295
National Institute of General Medical Sciences	P01GM099568
University 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	R01 AG33193, P30 AG013846, R01 AG048927, U01 AG10483, R01 MH080295, R01 AG017173, R01 CA129769
University of Pennsylvania	P30 AG010124
National Institute of Neurological Disorders and Stroke	R01NS080820, 39764, R01NS059873, P50NS039764
University of Washington	P50 AG005136, P50 AG005681, P01 AG03991
Indiana University	P30 AG10133
Banner Sun Health Research Institute	P30 AG019610
Mayo Clinic	P50 AG016574
National Center for Research Resources	M01RR000096, UL1RR029893
University of Arizona	R01 AG031581
National Center for Advancing Translational Sciences	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	P50 AG023501, P01 AG019724, P50 AG005131
National Association for Colitis and Crohn's Disease	U01 AG016976
Johns Hopkins University	R01 AG020688, P50 AG005146
Japan Society for the Promotion of Science	16K14649
Duke University	AG05128, P30 AG028377
University of Alabama	UL1RR02777, P50 AG016582
Massachusetts General Hospital	P50 AG005134
University of Miami	AG027944, AG021547, R01 AG027944, AG010491, AG019757
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
Emory University	AG025688
Kronos Science	AG034504
Columbia University	P50 AG008702, R37 AG015473
Oregon Health and Science University	P30 AG008017, R01 AG026916
Medical Research Council	G1001253, MR/L501542/1, MR/K01417X/1, MR/J004758/1, G0901254
New York University	UL1 RR029893, P30 AG08051, MO1RR00096
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
University of Texas Southwestern Medical Center	P30 AG012300
Northwestern University	P30 AG013854
NCRAD	U24 AG021886, U24 AG026395, R01 AG025259, U24 AG026390

Keywords

APOE interaction
Alzheimer's disease
Genome-wide association
Transethnic

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10.1016/j.jalz.2016.12.012

Cite this

@article{7de825616af54ba5b762a2476a460a12,

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 Barnes, {Lisa L.} and Beach, {Thomas G.} and Montine, {Thomas J.} and Adam Naj",

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

year = "2017",

month = jul,

day = "1",

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

language = "אנגלית",

volume = "13",

pages = "727--738",

journal = "Alzheimer's and Dementia",

issn = "1552-5260",

publisher = "John Wiley and Sons 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 - Barnes, Lisa L.

AU - Beach, Thomas G.

AU - Montine, Thomas J.

AU - Naj, Adam

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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U2 - 10.1016/j.jalz.2016.12.012

DO - 10.1016/j.jalz.2016.12.012

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C2 - 28183528

AN - SCOPUS:85014178309

SN - 1552-5260

VL - 13

SP - 727

EP - 738

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

IS - 7

ER -

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

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