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

Gyungah R Jun; Jaeyoon Chung; Jesse Mez; Robert Barber; Gary W Beecham; David A Bennett; Joseph D Buxbaum; Goldie S Byrd; Minerva M Carrasquillo; Paul K Crane; Carlos Cruchaga; Philip De Jager; Nilufer Ertekin-Taner; Denis Evans; M Danielle Fallin; Tatiana M Foroud; Robert P Friedland; Alison M Goate; Neill R Graff-Radford; Hugh Hendrie; Kathleen S Hall; Kara L Hamilton-Nelson; Rivka Inzelberg; M Ilyas Kamboh; John S K Kauwe; Walter A Kukull; Brian W Kunkle; Ryozo Kuwano; Eric B Larson; Mark W Logue; Jennifer J Manly; Eden R Martin; Thomas J Montine; Shubhabrata Mukherjee; Adam Naj; Eric M Reiman; Christiane Reitz; Richard Sherva; Peter H St George-Hyslop; Timothy Thornton; Steven G Younkin; Badri N Vardarajan; Li-San Wang; Jens R Wendlund; Ashley R Winslow; Alzheimer's Disease Genetics Consortium; Jonathan Haines; Richard Mayeux; Margaret A Pericak-Vance; Gerard Schellenberg; Kathryn L Lunetta; Lindsay A Farrer

doi:10.1016/j.jalz.2016.12.012

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

Alzheimers Dement. 2017 Jul;13(7):727-738. doi: 10.1016/j.jalz.2016.12.012. Epub 2017 Feb 7.

Authors

Gyungah R Jun¹, Jaeyoon Chung², Jesse Mez³, Robert Barber⁴, Gary W Beecham⁵, David A Bennett⁶, Joseph D Buxbaum⁷, Goldie S Byrd⁸, Minerva M Carrasquillo⁹, Paul K Crane¹⁰, Carlos Cruchaga¹¹, Philip De Jager¹², Nilufer Ertekin-Taner⁹, Denis Evans¹³, M Danielle Fallin¹⁴, Tatiana M Foroud¹⁵, Robert P Friedland¹⁶, Alison M Goate¹⁷, Neill R Graff-Radford⁹, Hugh Hendrie¹⁸, Kathleen S Hall¹⁹, Kara L Hamilton-Nelson⁵, Rivka Inzelberg²⁰, M Ilyas Kamboh²¹, John S K Kauwe²², Walter A Kukull²³, Brian W Kunkle⁵, Ryozo Kuwano²⁴, Eric B Larson²⁵, Mark W Logue²⁶, Jennifer J Manly²⁷, Eden R Martin⁵, Thomas J Montine²⁸, Shubhabrata Mukherjee¹⁰, Adam Naj²⁹, Eric M Reiman³⁰, Christiane Reitz³¹, Richard Sherva², Peter H St George-Hyslop³², Timothy Thornton¹⁰, Steven G Younkin⁹, Badri N Vardarajan³³, Li-San Wang³⁴, Jens R Wendlund³⁵, Ashley R Winslow³⁵; Alzheimer's Disease Genetics Consortium; Jonathan Haines³⁶, Richard Mayeux³⁷, Margaret A Pericak-Vance⁵, Gerard Schellenberg³⁴, Kathryn L Lunetta³⁸, Lindsay A Farrer³⁹

Collaborators

Alzheimer's Disease Genetics Consortium:
Perrie M Adams, Marilyn S Albert, Roger L Albin, Liana G Apostolova, Steven E Arnold, Sanjay Asthana, Craig S Atwood, Michjael M Barmada, Lisa L Barnes, Thomas G Beach, James T Becker, Eileen H Bigio, Thomas D Bird, Deborah Blacker, Bradley F Boeve, James D Bowen, Adam Boxer, James R Burke, Nigel J Cairns, Chuanhai Cao, Chris S Carlson, Cynthia M Carlsson, Regina M Carney, Minerva M Carrasquillo, Steven L Carroll, Helena C Chui, David G Clark, Jason Corneveaux, David H Cribbs, Elizabeth A Crocco, Carlos Cruchaga, Philip L De Jager, Charles DeCarli, Steven T DeKosky, F Yesim Demirci, Malcolm Dick, Dennis W Dickson, Rachelle S Doody, Ranjan Duara, Nilufer Ertekin-Taner, Kelley M Faber, Thomas J Fairchild, Kenneth B Fallon, Martin R Farlow, Steven Ferris, Matthew P Frosch, Douglas R Galasko, Marla Gearing, Daniel H Geschwind, Bernardino Ghetti, John R Gilbert, Jonathan D Glass, Neill R Graff-Radford, Robert C Green, John H Growdon, Hakon Hakonarson, Ronald L Hamilton, John Hardy, Lindy E Harrell, Elizabeth Head, Lawrence S Honig, Ryan M Huebinger, Matthew J Huentelman, Christine M Hulette, Bradley T Hyman, Gail P Jarvik, Gregory A Jicha, Lee-Way Jin, Anna Karydas, John S K Kauwe, Jeffrey A Kaye, Ronald Kim, Edward H Koo, Neil W Kowall, Joel H Kramer, Frank M LaFerla, James J Lah, James B Leverenz, Allan I Levey, Ge Li, Andrew P Lieberman, Chiao-Feng Lin, Oscar L Lopez, Constantine G Lyketsos, 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, John C Morris, Shubhabrata Mukherjee, Jill R Murrell, Amanda J Myers, Sid O'Bryant, John M Olichney, Vernon S Pankratz, Joseph E Parisi, Amanda Partch, Henry L Paulson, William Perry, Elaine Peskind, Ronald C Petersen, Aimee Pierce, Wayne W Poon, Huntington Potter, Joseph F Quinn, Ashok Raj, Murray Raskind, Barry Reisberg, Joan S Reisch, Christiane Reitz, John M Ringman, Erik D Roberson, Ekaterina Rogaeva, Howard J Rosen, Roger N Rosenberg, Donald R Royall, Mark A Sager, Mary Sano, Andrew J Saykin, Julie A Schneider, Lon S Schneider, William W Seeley, Amanda G Smith, Joshua A Sonnen, Salvatore Spina, Robert A Stern, Rudolph E Tanzi, Tricia A Thornton-Wells, John Q Trojanowski, Juan C Troncoso, Debby W Tsuang, Vivianna M Van Deerlin, Linda J Van Eldik, Badri N Vardarajan, Harry V Vinters, Jean Paul Vonsattel, Sandra Weintraub, Kathleen A Welsh-Bohmer, Jennifer Williamson, Sarah Wishnek, Randall L Woltjer, Clinton B Wright, Chuang-Kuo Wu, Chang-En Yu, Lei Yu, Xiaoling Zhang

Affiliations

¹ 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.
² Department of Medicine (Biomedical Genetics), Boston University Schools of Medicine, Boston, MA, USA.
³ Department of Neurology, Boston University Schools of Medicine, Boston, MA, USA.
⁴ Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, USA.
⁵ The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.
⁶ Department of Neurological Sciences and Rush Alzheimer's Disease Center, Chicago, IL, USA.
⁷ 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.
⁸ Department of Biology, North Carolina A&T State University, Greensboro, NC, USA.
⁹ Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
¹⁰ Department of Medicine, University of Washington, Seattle, WA, USA.
¹¹ 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.
¹² 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.
¹³ Rush Institute for Healthy Aging, Department of Internal Medicine, Rush University Medical Center, Chicago, IL, USA.
¹⁴ Department of Mental Health, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁵ Department of Medical & Molecular Genetics, Indiana University, Indianapolis, IN, USA.
¹⁶ Department of Neurology, University of Louisville, Louisville, KY, USA.
¹⁷ Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA.
¹⁸ Department of Psychiatry, Indiana University, Indianapolis, IN, USA; Regenstrief Institute, Inc, Indianapolis, IN, USA.
¹⁹ Regenstrief Institute, Inc, Indianapolis, IN, USA; Department of Medicine, Indiana University, Indianapolis, IN, USA.
²⁰ Department of Neurology and Neurosurgery, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
²¹ University of Pittsburgh Alzheimer's Disease Research Center and Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA.
²² Department of Biology, Brigham Young University, Provo, UT, USA.
²³ Department of Epidemiology, University of Washington, Seattle, WA, USA; National Alzheimer's Coordinating Center, University of Washington, Seattle, WA, USA.
²⁴ Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata, Japan.
²⁵ Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA; Group Health, Group Health Research Institute, Seattle, WA, USA.
²⁶ 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.
²⁷ 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.
²⁸ Department of Pathology, Stanford University, Stanford, CA, USA.
²⁹ Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
³⁰ 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.
³¹ 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.
³² 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.
³³ 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.
³⁴ Arizona Alzheimer's Consortium, Phoenix, AZ, USA.
³⁵ PharmaTherapeutics Clinical Research, Pfizer Worldwide Research and Development, Cambridge, MA, USA.
³⁶ Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA.
³⁷ 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.
³⁸ Department of Biostatistics, Boston University Schools of Public Health, Boston, MA, USA.
³⁹ 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.

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.

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Alzheimer Disease / genetics*
Apolipoprotein E4 / genetics
GTPase-Activating Proteins / genetics
Genetic Predisposition to Disease
Genome-Wide Association Study*
Heparin-binding EGF-like Growth Factor / genetics
Humans
Membrane Glycoproteins / genetics
Molecular Chaperones / genetics
NFI Transcription Factors / genetics
Peroxisomal Bifunctional Enzyme / genetics
Polymorphism, Single Nucleotide*
Receptors, GABA / genetics

Substances

Adaptor Proteins, Signal Transducing
Apolipoprotein E4
GTPase-Activating Proteins
HBEGF protein, human
Heparin-binding EGF-like Growth Factor
Membrane Glycoproteins
Molecular Chaperones
NFI Transcription Factors
NFIC protein, human
Receptors, GABA
TSPO protein, human
USP6NL protein, human
prefoldin
trophoblastic glycoprotein 5T4, human
EHHADH protein, human
Peroxisomal Bifunctional Enzyme

Abstract

MeSH terms

Substances

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