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


CONCLUSIONS
Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci.
Neurogenetics and Integrated Genomics, Andover Innovative Medicines Institute, Eisai Inc, Andover, MA, USA; Department of Medicine (Biomedical Genetics), Boston University Schools of Medicine, Boston, MA, USA.
Gyungah R
GR
Jun
Department of Medicine (Biomedical Genetics), Boston University Schools of Medicine, Boston, MA, USA.
Jaeyoon
J
Chung
Department of Neurology, Boston University Schools of Medicine, Boston, MA, USA.
Jesse
J
Mez
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, USA.
Robert
R
Barber
The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.
Gary W
GW
Beecham
Department of Neurological Sciences and Rush Alzheimer's Disease Center, Chicago, IL, USA.
David A
DA
Bennett
Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA; Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA; Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA.
Joseph D
JD
Buxbaum
Department of Biology, North Carolina A&T State University, Greensboro, NC, USA.
Goldie S
GS
Byrd
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Minerva M
MM
Carrasquillo
Department of Medicine, University of Washington, Seattle, WA, USA.
Paul K
PK
Crane
Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, St Louis, MO, USA; Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.
Carlos
C
Cruchaga
Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology & Psychiatry, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
Philip
P
De Jager
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Nilufer
N
Ertekin-Taner
Rush Institute for Healthy Aging, Department of Internal Medicine, Rush University Medical Center, Chicago, IL, USA.
Denis
D
Evans
Department of Mental Health, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
M Danielle
MD
Fallin
Department of Medical & Molecular Genetics, Indiana University, Indianapolis, IN, USA.
Tatiana M
TM
Foroud
Department of Neurology, University of Louisville, Louisville, KY, USA.
Robert P
RP
Friedland
Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA.
Alison M
AM
Goate
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Neill R
NR
Graff-Radford
Department of Psychiatry, Indiana University, Indianapolis, IN, USA; Regenstrief Institute, Inc, Indianapolis, IN, USA.
Hugh
H
Hendrie
Regenstrief Institute, Inc, Indianapolis, IN, USA; Department of Medicine, Indiana University, Indianapolis, IN, USA.
Kathleen S
KS
Hall
The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.
Kara L
KL
Hamilton-Nelson
Department of Neurology and Neurosurgery, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Rivka
R
Inzelberg
University of Pittsburgh Alzheimer's Disease Research Center and Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA.
M Ilyas
MI
Kamboh
Department of Biology, Brigham Young University, Provo, UT, USA.
John S K
JSK
Kauwe
Department of Epidemiology, University of Washington, Seattle, WA, USA; National Alzheimer's Coordinating Center, University of Washington, Seattle, WA, USA.
Walter A
WA
Kukull
The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.
Brian W
BW
Kunkle
Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata, Japan.
Ryozo
R
Kuwano
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA; Group Health, Group Health Research Institute, Seattle, WA, USA.
Eric B
EB
Larson
Department of Medicine (Biomedical Genetics), Boston University Schools of Medicine, Boston, MA, USA; Department of Neurological Sciences and Rush Alzheimer's Disease Center, Chicago, IL, USA; National Center for PTSD, Behavioral Science Division, Boston VA Healthcare System, Boston, MA, USA.
Mark W
MW
Logue
The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA; The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
Jennifer J
JJ
Manly
The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.
Eden R
ER
Martin
Department of Pathology, Stanford University, Stanford, CA, USA.
Thomas J
TJ
Montine
Department of Medicine, University of Washington, Seattle, WA, USA.
Shubhabrata
S
Mukherjee
Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Adam
A
Naj
Arizona Alzheimer's Consortium, Phoenix, AZ, USA; Department of Psychiatry, University of Arizona, Phoenix, AZ, USA; Banner Alzheimer's Institute, Phoenix, AZ, USA; Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA.
Eric M
EM
Reiman
The Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA; The Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, USA; The Department of Epidemiology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
Christiane
C
Reitz
Department of Medicine (Biomedical Genetics), Boston University Schools of Medicine, Boston, MA, USA.
Richard
R
Sherva
Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Canada; Cambridge Institute for Medical Research and Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
Peter H
PH
St George-Hyslop
Department of Medicine, University of Washington, Seattle, WA, USA.
Timothy
T
Thornton
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Steven G
SG
Younkin
The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA; The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA; The Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
Badri N
BN
Vardarajan
Arizona Alzheimer's Consortium, Phoenix, AZ, USA.
Li-San
LS
Wang
PharmaTherapeutics Clinical Research, Pfizer Worldwide Research and Development, Cambridge, MA, USA.
Jens R
JR
Wendlund
PharmaTherapeutics Clinical Research, Pfizer Worldwide Research and Development, Cambridge, MA, USA.
Ashley R
AR
Winslow
Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA.
Jonathan
J
Haines
The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA; The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA; The Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA; The Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, USA; The Department of Epidemiology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
Richard
R
Mayeux
The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.
Margaret A
MA
Pericak-Vance
Arizona Alzheimer's Consortium, Phoenix, AZ, USA.
Gerard
G
Schellenberg
Department of Biostatistics, Boston University Schools of Public Health, Boston, MA, USA.
Kathryn L
KL
Lunetta
Department of Medicine (Biomedical Genetics), Boston University Schools of Medicine, Boston, MA, USA; Department of Neurology, Boston University Schools of Medicine, Boston, MA, USA; Department of Biostatistics, Boston University Schools of Public Health, Boston, MA, USA; Department of Ophthalmology, Boston University Schools of Medicine, Boston, MA, USA; Department of Epidemiology, Boston University Schools of Public Health, Boston, MA, USA. Electronic address: farrer@bu.edu.
Lindsay A
LA
Farrer
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000544:Alzheimer Disease / Q000235:genetics*; D053327:Apolipoprotein E4 / Q000235:genetics; D020690:GTPase-Activating Proteins / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D066257:Heparin-binding EGF-like Growth Factor / Q000235:genetics; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics; D018832:Molecular Chaperones / Q000235:genetics; D051839:NFI Transcription Factors / Q000235:genetics; D063994:Peroxisomal Bifunctional Enzyme / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D018079:Receptors, GABA / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D053327:Apolipoprotein E4; D020690:GTPase-Activating Proteins; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D051839:NFI Transcription Factors; C497647:NFIC protein, human; D018079:Receptors, GABA; C499229:TSPO protein, human; C100665:USP6NL protein, human; C112806:prefoldin; C063709:trophoblastic glycoprotein 5T4, human; C576253:EHHADH protein, human; D063994:Peroxisomal Bifunctional Enzyme
APOE interaction; Alzheimer's disease; Genome-wide association; Transethnic