Meta-Analysis

. 2014 Nov;71(11):1394-404.

doi: 10.1001/jamaneurol.2014.1491.

Effects of multiple genetic loci on age at onset in late-onset Alzheimer disease: a genome-wide association study

Adam C Naj¹, Gyungah Jun², Christiane Reitz³, Brian W Kunkle⁴, William Perry⁴, Yo Son Park⁵, Gary W Beecham⁶, Ruchita A Rajbhandary⁴, Kara L Hamilton-Nelson⁴, Li-San Wang⁷, John S K Kauwe⁸, Matthew J Huentelman⁹, Amanda J Myers¹⁰, Thomas D Bird¹¹, Bradley F Boeve¹², Clinton T Baldwin¹³, Gail P Jarvik¹⁴, Paul K Crane¹⁵, Ekaterina Rogaeva¹⁶, M Michael Barmada¹⁷, F Yesim Demirci¹⁷, Carlos Cruchaga¹⁸, Patricia L Kramer¹⁹, Nilufer Ertekin-Taner²⁰, John Hardy²¹, Neill R Graff-Radford²⁰, Robert C Green²², Eric B Larson²³, Peter H St George-Hyslop²⁴, Joseph D Buxbaum²⁵, Denis A Evans²⁶, Julie A Schneider²⁷, Kathryn L Lunetta²⁸, M Ilyas Kamboh²⁹, Andrew J Saykin³⁰, Eric M Reiman³¹, Philip L De Jager³², David A Bennett³³, John C Morris³⁴, Thomas J Montine³⁵, Alison M Goate¹⁸, Deborah Blacker³⁶, Debby W Tsuang³⁷, Hakon Hakonarson³⁸, Walter A Kukull³⁹, Tatiana M Foroud⁴⁰, Eden R Martin⁶, Jonathan L Haines⁴¹, Richard P Mayeux⁴², Lindsay A Farrer⁴³, Gerard D Schellenberg⁷, Margaret A Pericak-Vance⁶; Alzheimer Disease Genetics Consortium; Marilyn S Albert⁴⁴, Roger L Albin⁴⁵, Liana G Apostolova⁴⁶, Steven E Arnold⁴⁷, Robert Barber⁴⁸, Lisa L Barnes⁴⁹, Thomas G Beach⁵⁰, James T Becker⁵¹, Duane Beekly⁵², Eileen H Bigio⁵³, James D Bowen⁵⁴, Adam Boxer⁵⁵, James R Burke⁵⁶, Nigel J Cairns⁵⁷, Laura B Cantwell⁷, Chuanhai Cao⁵⁸, Chris S Carlson⁵⁹, Regina M Carney¹⁰, Minerva M Carrasquillo⁶⁰, Steven L Carroll⁶¹, Helena C Chui⁶², David G Clark⁶³, Jason Corneveaux⁹, David H Cribbs⁶⁴, Elizabeth A Crocco¹⁰, Charles DeCarli⁶⁵, Steven T DeKosky⁶⁶, Malcolm Dick⁶⁷, Dennis W Dickson⁶⁰, Ranjan Duara⁶⁸, Kelley M Faber⁴⁰, Kenneth B Fallon⁶¹, Martin R Farlow⁶⁹, Steven Ferris⁷⁰, Matthew P Frosch⁷¹, Douglas R Galasko⁷², Mary Ganguli⁷³, Marla Gearing⁷⁴, Daniel H Geschwind⁷⁵, Bernardino Ghetti⁷⁶, John R Gilbert⁶, Jonathan D Glass⁷⁷, John H Growdon⁷⁸, Ronald L Hamilton⁷⁹, Lindy E Harrell⁶³, Elizabeth Head⁸⁰, Lawrence S Honig⁸¹, Christine M Hulette⁸², Bradley T Hyman⁷⁸, Gregory A Jicha⁸³, Lee-Way Jin⁸⁴, Anna Karydas⁵⁵, Jeffrey A Kaye⁸⁵, Ronald Kim⁸⁶, Edward H Koo⁷², Neil W Kowall⁸⁷, Joel H Kramer⁸⁸, Frank M LaFerla⁸⁹, James J Lah⁷⁷, James B Leverenz³⁵, Allan I Levey⁷⁷, Ge Li⁹⁰, Andrew P Lieberman⁹¹, Chiao-Feng Lin⁷, Oscar L Lopez⁹², Constantine G Lyketsos⁹³, Wendy J Mack⁹⁴, Frank Martiniuk⁹⁵, Deborah C Mash⁹⁶, Eliezer Masliah⁹⁷, Wayne C McCormick¹⁵, Susan M McCurry⁹⁸, Andrew N McDavid⁵⁹, Ann C McKee⁸⁷, Marsel Mesulam⁹⁹, Bruce L Miller⁵⁵, Carol A Miller¹⁰⁰, Joshua W Miller⁸⁴, Jill R Murrell¹⁰¹, John M Olichney⁶⁵, Vernon S Pankratz¹⁰², Joseph E Parisi¹⁰³, Henry L Paulson¹⁰⁴, Elaine Peskind⁹⁰, Ronald C Petersen¹², Aimee Pierce⁶⁴, Wayne W Poon⁶⁷, Huntington Potter⁵⁸, Joseph F Quinn¹⁰⁵, Ashok Raj⁵⁸, Murray Raskind⁹⁰, Barry Reisberg¹⁰⁶, John M Ringman⁴⁶, Erik D Roberson⁶³, Howard J Rosen⁵⁵, Roger N Rosenberg¹⁰⁷, Mary Sano¹⁰⁸, Lon S Schneider¹⁰⁹, William W Seeley⁵⁵, Amanda G Smith⁵⁸, Joshua A Sonnen³⁵, Salvatore Spina⁷⁶, Robert A Stern¹¹⁰, Rudolph E Tanzi⁷⁸, Tricia A Thornton-Wells¹¹¹, John Q Trojanowski⁷, Juan C Troncoso¹¹², Otto Valladares⁷, Vivianna M Van Deerlin⁷, Linda J Van Eldik¹¹³, Badri N Vardarajan¹¹⁴, Harry V Vinters¹¹⁵, Jean Paul Vonsattel¹¹⁶, Sandra Weintraub¹¹⁷, Kathleen A Welsh-Bohmer¹¹⁸, Jennifer Williamson⁸¹, Sarah Wishnek⁴, Randall L Woltjer¹¹⁹, Clinton B Wright¹²⁰, Steven G Younkin⁶⁰, Chang-En Yu¹⁵, Lei Yu¹²¹

Affiliations

¹ Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia.
² Genetics Program, Department of Medicine, Boston University, Boston, Massachusetts4Department of Biostatistics, Boston University, Boston, Massachusetts5Department of Ophthalmology, Boston University, Boston, Massachusetts.
³ Taub Institute on Alzheimer's Disease and the Aging Brain, Department of Neurology, Columbia University, New York, New York7Gertrude H. Sergievsky Center, Columbia University, New York, New York8Department of Neurology, Columbia University, New York, New.
⁴ John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida.
⁵ The Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, Florida.
⁶ John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida9The Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, Florida.
⁷ Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia.
⁸ Department of Biology, Brigham Young University, Provo, Utah.
⁹ Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona.
¹⁰ Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, Florida.
¹¹ Department of Neurology, University of Washington, Seattle15Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington.
¹² Department of Neurology, Mayo Clinic, Rochester, Minnesota.
¹³ Genetics Program, Department of Medicine, Boston University, Boston, Massachusetts.
¹⁴ Department of Genome Sciences, University of Washington, Seattle18Division of Medical Genetics, Department of Medicine, University of Washington, Seattle.
¹⁵ Department of Medicine, University of Washington, Seattle.
¹⁶ Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada.
¹⁷ Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania.
¹⁸ Department of Psychiatry and Hope Center Program on Protein Aggregation and Neurodegeneration, School of Medicine, Washington University in St Louis, St Louis, Missouri.
¹⁹ Department of Neurology, Oregon Health & Science University, Portland24Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland.
²⁰ Department of Neuroscience, Mayo Clinic, Jacksonville, Florida26Department of Neurology, Mayo Clinic, Jacksonville, Florida.
²¹ Institute of Neurology, University College London, London, England.
²² Division of Genetics, Department of Medicine, and Partners Center for Personalized Genetic Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
²³ Department of Medicine, University of Washington, Seattle29Group Health Research Institute, Group Health Cooperative, Seattle, Washington.
²⁴ Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada30Cambridge Institute for Medical Research, Department of Clinical Neurosciences, University of Cambridge, Cambridge, England.
²⁵ Department of Neuroscience, Mount Sinai School of Medicine, New York, New York32Department of Psychiatry, Mount Sinai School of Medicine, New York, New York33Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York.
²⁶ Rush Institute for Healthy Aging, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois.
²⁷ Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois36Neuropathology, Department of Pathology, Rush University Medical Center, Chicago, Illinois.
²⁸ Department of Biostatistics, Boston University, Boston, Massachusetts.
²⁹ Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania37Alheimer Disease Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania.
³⁰ Department of Medical and Molecular Genetics, Indiana University, Indianapolis39Department of Radiology and Imaging Sciences, Indiana University, Indianapolis.
³¹ Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona40Arizona Alzheimer's Consortium, Phoenix41Department of Psychiatry, University of Arizona, Phoenix42Banner Alzheimer's Institute, Phoenix, Arizona.
³² Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology and Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts44Program in Medical and Population Genetics, Broad Ins.
³³ Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois45Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois.
³⁴ Department of Pathology and Immunology, Washington University in St Louis, St Louis, Missouri47Department of Neurology, Washington University in St Louis, St Louis, Missouri.
³⁵ Department of Pathology, University of Washington, Seattle.
³⁶ Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts50Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston.
³⁷ Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington51Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle.
³⁸ Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
³⁹ Department of Epidemiology, University of Washington, Seattle.
⁴⁰ Department of Medical and Molecular Genetics, Indiana University, Indianapolis.
⁴¹ Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee55Vanderbilit Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee.
⁴² Taub Institute on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York57Gertrude H. Sergievsky Center, Columbia University, New York, New York58Department of Neurology, Columbia University, New York, New York.
⁴³ Genetics Program, Department of Medicine, Boston University, Boston, Massachusetts4Department of Biostatistics, Boston University, Boston, Massachusetts5Department of Ophthalmology, Boston University, Boston, Massachusetts59Department of Epidemiology, Bos.
⁴⁴ Department of Neurology, Johns Hopkins University, Baltimore, Maryland.
⁴⁵ Department of Neurology, University of Michigan, Ann Arbor63Geriatric Research, Education and Clinical Center (GRECC), VA Ann Arbor Healthcare System (VAAAHS), Ann Arbor, Michigan64Michigan Alzheimer Disease Center, Ann Arbor.
⁴⁶ Department of Neurology, University of California Los Angeles, Los Angeles.
⁴⁷ Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia.
⁴⁸ Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth.
⁴⁹ Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois68Department of Behavioral Sciences, Rush University Medical Center, Chicago, Illinois.
⁵⁰ Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Phoenix, Arizona.
⁵¹ Departments of Psychiatry, Neurology, and Psychology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
⁵² National Alzheimer's Coordinating Center, University of Washington, Seattle.
⁵³ Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois73Cognitive Neurology and Alzheimer's Disease Center, Northwestern University, Chicago, Illinois.
⁵⁴ Swedish Medical Center, Seattle, Washington.
⁵⁵ Department of Neurology, University of California San Francisco, San Francisco.
⁵⁶ Department of Medicine, Duke University, Durham, North Carolina.
⁵⁷ Department of Pathology and Immunology, Washington University in St Louis, St Louis, Missouri.
⁵⁸ USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa.
⁵⁹ Fred Hutchinson Cancer Research Center, Seattle, Washington.
⁶⁰ Department of Neuroscience, Mayo Clinic, Jacksonville, Florida.
⁶¹ Department of Pathology, University of Alabama at Birmingham, Birmingham.
⁶² Department of Neurology, University of Southern California, Los Angeles.
⁶³ Department of Neurology, University of Alabama at Birmingham, Birmingham.
⁶⁴ Department of Neurology, University of California Irvine, Irvine.
⁶⁵ Department of Neurology, University of California Davis, Sacramento.
⁶⁶ University of Virginia School of Medicine, Charlottesville.
⁶⁷ Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine.
⁶⁸ Wien Center for Alzheimer's Disease and Memory Disorders, Mount Sinai Medical Center, Miami Beach, Florida.
⁶⁹ Department of Neurology, Indiana University, Indianapolis.
⁷⁰ Department of Psychiatry, New York University, New York.
⁷¹ C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Charlestown.
⁷² Department of Neurosciences, University of California San Diego, La Jolla.
⁷³ Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania.
⁷⁴ Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia93Emory Alzheimer's Disease Center, Emory University, Atlanta, Georgia.
⁷⁵ Neurogenetics Program, University of California Los Angeles, Los Angeles.
⁷⁶ Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis.
⁷⁷ Department of Neurology, Emory University, Atlanta, Georgia.
⁷⁸ Department of Neurology, Massachusetts General Hospital/Harvard Medical School, Boston.
⁷⁹ Department of Pathology (Neuropathology), University of Pittsburgh, Pittsburgh, Pennsylvania.
⁸⁰ Sanders-Brown Center on Aging, Department of Molecular and Biomedical Pharmacology, University of Kentucky, Lexington.
⁸¹ Taub Institute on Alzheimer's Disease and the Aging Brain, Department of Neurology, Columbia University, New York, New York.
⁸² Department of Pathology, Duke University, Durham, North Carolina.
⁸³ Sanders-Brown Center on Aging, Department Neurology, University of Kentucky, Lexington.
⁸⁴ Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento.
⁸⁵ Department of Neurology, Oregon Health & Science University, Portland103Department of Neurology, Portland Veterans Affairs Medical Center, Portland, Oregon.
⁸⁶ Department of Pathology and Laboratory Medicine, University of California Irvine, Irvine.
⁸⁷ Department of Neurology, Boston University, Boston, Massachusetts105Department of Pathology, Boston University, Boston, Massachusetts.
⁸⁸ Department of Neuropsychology, University of California San Francisco, San Francisco.
⁸⁹ Department of Neurobiology and Behavior, University of California Irvine, Irvine.
⁹⁰ Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle.
⁹¹ Department of Pathology, University of Michigan, Ann Arbor.
⁹² Alheimer Disease Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania.
⁹³ Department of Psychiatry, Johns Hopkins University, Baltimore, Maryland.
⁹⁴ Department of Preventive Medicine, University of Southern California, Los Angeles.
⁹⁵ Department of Medicine - Pulmonary, New York University, New York.
⁹⁶ Department of Neurology, University of Miami, Miami, Florida.
⁹⁷ Department of Neurosciences, University of California San Diego, La Jolla113Department of Pathology, University of California San Diego, La Jolla.
⁹⁸ School of Nursing Northwest Research Group on Aging, University of Washington, Seattle.
⁹⁹ Cognitive Neurology and Alzheimer's Disease Center, Northwestern University, Chicago, Illinois115Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
¹⁰⁰ Department of Pathology, University of Southern California, Los Angeles.
¹⁰¹ Department of Medical and Molecular Genetics, Indiana University, Indianapolis95Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis.
¹⁰² Department of Biostatistics, Mayo Clinic, Rochester, Minnesota.
¹⁰³ Department of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota119Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
¹⁰⁴ Department of Neurology, University of Michigan, Ann Arbor.
¹⁰⁵ Department of Neurology, Oregon Health & Science University, Portland.
¹⁰⁶ Department of Psychiatry, New York University, New York120Alzheimer's Disease Center, New York University, New York.
¹⁰⁷ Department of Neurology, University of Texas Southwestern, Dallas.
¹⁰⁸ Department of Psychiatry, Mount Sinai School of Medicine, New York, New York.
¹⁰⁹ Department of Neurology, University of Southern California, Los Angeles122Department of Psychiatry, University of Southern California, Los Angeles.
¹¹⁰ Department of Neurology, Boston University, Boston, Massachusetts.
¹¹¹ Vanderbilit Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee.
¹¹² Department of Pathology, Johns Hopkins University, Baltimore, Maryland.
¹¹³ Sanders-Brown Center on Aging, Department of Anatomy and Neurobiology, University of Kentucky, Lexington.
¹¹⁴ Department of Neurology, Columbia University, New York, New York.
¹¹⁵ Department of Neurology, University of California Los Angeles, Los Angeles125Department of Pathology & Laboratory Medicine, University of California Los Angeles, Los Angeles.
¹¹⁶ Taub Institute on Alzheimer's Disease and the Aging Brain, Department of Pathology, Columbia University, New York, New York.
¹¹⁷ Cognitive Neurology and Alzheimer's Disease Center, Northwestern University, Chicago, Illinois127Department of Psychiatry, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
¹¹⁸ Department of Medicine, Duke University, Durham, North Carolina128Department of Psychiatry & Behavioral Sciences, Duke University, Durham, North Carolina.
¹¹⁹ Department of Pathology, Oregon Health & Science University, Portland.
¹²⁰ Evelyn F. McKnight Brain Institute, Department of Neurology, Miller School of Medicine, University of Miami, Miami, Florida.
¹²¹ Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois.

PMID: 25199842
PMCID: PMC4314944
DOI: 10.1001/jamaneurol.2014.1491

Meta-Analysis

Effects of multiple genetic loci on age at onset in late-onset Alzheimer disease: a genome-wide association study

Adam C Naj et al. JAMA Neurol. 2014 Nov.

. 2014 Nov;71(11):1394-404.

doi: 10.1001/jamaneurol.2014.1491.

Authors

Affiliations

¹ Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia.
² Genetics Program, Department of Medicine, Boston University, Boston, Massachusetts4Department of Biostatistics, Boston University, Boston, Massachusetts5Department of Ophthalmology, Boston University, Boston, Massachusetts.
³ Taub Institute on Alzheimer's Disease and the Aging Brain, Department of Neurology, Columbia University, New York, New York7Gertrude H. Sergievsky Center, Columbia University, New York, New York8Department of Neurology, Columbia University, New York, New.
⁴ John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida.
⁵ The Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, Florida.
⁶ John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida9The Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, Florida.
⁷ Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia.
⁸ Department of Biology, Brigham Young University, Provo, Utah.
⁹ Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona.
¹⁰ Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, Florida.
¹¹ Department of Neurology, University of Washington, Seattle15Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington.
¹² Department of Neurology, Mayo Clinic, Rochester, Minnesota.
¹³ Genetics Program, Department of Medicine, Boston University, Boston, Massachusetts.
¹⁴ Department of Genome Sciences, University of Washington, Seattle18Division of Medical Genetics, Department of Medicine, University of Washington, Seattle.
¹⁵ Department of Medicine, University of Washington, Seattle.
¹⁶ Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada.
¹⁷ Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania.
¹⁸ Department of Psychiatry and Hope Center Program on Protein Aggregation and Neurodegeneration, School of Medicine, Washington University in St Louis, St Louis, Missouri.
¹⁹ Department of Neurology, Oregon Health & Science University, Portland24Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland.
²⁰ Department of Neuroscience, Mayo Clinic, Jacksonville, Florida26Department of Neurology, Mayo Clinic, Jacksonville, Florida.
²¹ Institute of Neurology, University College London, London, England.
²² Division of Genetics, Department of Medicine, and Partners Center for Personalized Genetic Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
²³ Department of Medicine, University of Washington, Seattle29Group Health Research Institute, Group Health Cooperative, Seattle, Washington.
²⁴ Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada30Cambridge Institute for Medical Research, Department of Clinical Neurosciences, University of Cambridge, Cambridge, England.
²⁵ Department of Neuroscience, Mount Sinai School of Medicine, New York, New York32Department of Psychiatry, Mount Sinai School of Medicine, New York, New York33Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York.
²⁶ Rush Institute for Healthy Aging, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois.
²⁷ Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois36Neuropathology, Department of Pathology, Rush University Medical Center, Chicago, Illinois.
²⁸ Department of Biostatistics, Boston University, Boston, Massachusetts.
²⁹ Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania37Alheimer Disease Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania.
³⁰ Department of Medical and Molecular Genetics, Indiana University, Indianapolis39Department of Radiology and Imaging Sciences, Indiana University, Indianapolis.
³¹ Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona40Arizona Alzheimer's Consortium, Phoenix41Department of Psychiatry, University of Arizona, Phoenix42Banner Alzheimer's Institute, Phoenix, Arizona.
³² Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology and Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts44Program in Medical and Population Genetics, Broad Ins.
³³ Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois45Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois.
³⁴ Department of Pathology and Immunology, Washington University in St Louis, St Louis, Missouri47Department of Neurology, Washington University in St Louis, St Louis, Missouri.
³⁵ Department of Pathology, University of Washington, Seattle.
³⁶ Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts50Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston.
³⁷ Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington51Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle.
³⁸ Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
³⁹ Department of Epidemiology, University of Washington, Seattle.
⁴⁰ Department of Medical and Molecular Genetics, Indiana University, Indianapolis.
⁴¹ Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee55Vanderbilit Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee.
⁴² Taub Institute on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York57Gertrude H. Sergievsky Center, Columbia University, New York, New York58Department of Neurology, Columbia University, New York, New York.
⁴³ Genetics Program, Department of Medicine, Boston University, Boston, Massachusetts4Department of Biostatistics, Boston University, Boston, Massachusetts5Department of Ophthalmology, Boston University, Boston, Massachusetts59Department of Epidemiology, Bos.
⁴⁴ Department of Neurology, Johns Hopkins University, Baltimore, Maryland.
⁴⁵ Department of Neurology, University of Michigan, Ann Arbor63Geriatric Research, Education and Clinical Center (GRECC), VA Ann Arbor Healthcare System (VAAAHS), Ann Arbor, Michigan64Michigan Alzheimer Disease Center, Ann Arbor.
⁴⁶ Department of Neurology, University of California Los Angeles, Los Angeles.
⁴⁷ Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia.
⁴⁸ Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth.
⁴⁹ Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois68Department of Behavioral Sciences, Rush University Medical Center, Chicago, Illinois.
⁵⁰ Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Phoenix, Arizona.
⁵¹ Departments of Psychiatry, Neurology, and Psychology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
⁵² National Alzheimer's Coordinating Center, University of Washington, Seattle.
⁵³ Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois73Cognitive Neurology and Alzheimer's Disease Center, Northwestern University, Chicago, Illinois.
⁵⁴ Swedish Medical Center, Seattle, Washington.
⁵⁵ Department of Neurology, University of California San Francisco, San Francisco.
⁵⁶ Department of Medicine, Duke University, Durham, North Carolina.
⁵⁷ Department of Pathology and Immunology, Washington University in St Louis, St Louis, Missouri.
⁵⁸ USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa.
⁵⁹ Fred Hutchinson Cancer Research Center, Seattle, Washington.
⁶⁰ Department of Neuroscience, Mayo Clinic, Jacksonville, Florida.
⁶¹ Department of Pathology, University of Alabama at Birmingham, Birmingham.
⁶² Department of Neurology, University of Southern California, Los Angeles.
⁶³ Department of Neurology, University of Alabama at Birmingham, Birmingham.
⁶⁴ Department of Neurology, University of California Irvine, Irvine.
⁶⁵ Department of Neurology, University of California Davis, Sacramento.
⁶⁶ University of Virginia School of Medicine, Charlottesville.
⁶⁷ Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine.
⁶⁸ Wien Center for Alzheimer's Disease and Memory Disorders, Mount Sinai Medical Center, Miami Beach, Florida.
⁶⁹ Department of Neurology, Indiana University, Indianapolis.
⁷⁰ Department of Psychiatry, New York University, New York.
⁷¹ C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Charlestown.
⁷² Department of Neurosciences, University of California San Diego, La Jolla.
⁷³ Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania.
⁷⁴ Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia93Emory Alzheimer's Disease Center, Emory University, Atlanta, Georgia.
⁷⁵ Neurogenetics Program, University of California Los Angeles, Los Angeles.
⁷⁶ Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis.
⁷⁷ Department of Neurology, Emory University, Atlanta, Georgia.
⁷⁸ Department of Neurology, Massachusetts General Hospital/Harvard Medical School, Boston.
⁷⁹ Department of Pathology (Neuropathology), University of Pittsburgh, Pittsburgh, Pennsylvania.
⁸⁰ Sanders-Brown Center on Aging, Department of Molecular and Biomedical Pharmacology, University of Kentucky, Lexington.
⁸¹ Taub Institute on Alzheimer's Disease and the Aging Brain, Department of Neurology, Columbia University, New York, New York.
⁸² Department of Pathology, Duke University, Durham, North Carolina.
⁸³ Sanders-Brown Center on Aging, Department Neurology, University of Kentucky, Lexington.
⁸⁴ Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento.
⁸⁵ Department of Neurology, Oregon Health & Science University, Portland103Department of Neurology, Portland Veterans Affairs Medical Center, Portland, Oregon.
⁸⁶ Department of Pathology and Laboratory Medicine, University of California Irvine, Irvine.
⁸⁷ Department of Neurology, Boston University, Boston, Massachusetts105Department of Pathology, Boston University, Boston, Massachusetts.
⁸⁸ Department of Neuropsychology, University of California San Francisco, San Francisco.
⁸⁹ Department of Neurobiology and Behavior, University of California Irvine, Irvine.
⁹⁰ Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle.
⁹¹ Department of Pathology, University of Michigan, Ann Arbor.
⁹² Alheimer Disease Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania.
⁹³ Department of Psychiatry, Johns Hopkins University, Baltimore, Maryland.
⁹⁴ Department of Preventive Medicine, University of Southern California, Los Angeles.
⁹⁵ Department of Medicine - Pulmonary, New York University, New York.
⁹⁶ Department of Neurology, University of Miami, Miami, Florida.
⁹⁷ Department of Neurosciences, University of California San Diego, La Jolla113Department of Pathology, University of California San Diego, La Jolla.
⁹⁸ School of Nursing Northwest Research Group on Aging, University of Washington, Seattle.
⁹⁹ Cognitive Neurology and Alzheimer's Disease Center, Northwestern University, Chicago, Illinois115Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
¹⁰⁰ Department of Pathology, University of Southern California, Los Angeles.
¹⁰¹ Department of Medical and Molecular Genetics, Indiana University, Indianapolis95Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis.
¹⁰² Department of Biostatistics, Mayo Clinic, Rochester, Minnesota.
¹⁰³ Department of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota119Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
¹⁰⁴ Department of Neurology, University of Michigan, Ann Arbor.
¹⁰⁵ Department of Neurology, Oregon Health & Science University, Portland.
¹⁰⁶ Department of Psychiatry, New York University, New York120Alzheimer's Disease Center, New York University, New York.
¹⁰⁷ Department of Neurology, University of Texas Southwestern, Dallas.
¹⁰⁸ Department of Psychiatry, Mount Sinai School of Medicine, New York, New York.
¹⁰⁹ Department of Neurology, University of Southern California, Los Angeles122Department of Psychiatry, University of Southern California, Los Angeles.
¹¹⁰ Department of Neurology, Boston University, Boston, Massachusetts.
¹¹¹ Vanderbilit Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee.
¹¹² Department of Pathology, Johns Hopkins University, Baltimore, Maryland.
¹¹³ Sanders-Brown Center on Aging, Department of Anatomy and Neurobiology, University of Kentucky, Lexington.
¹¹⁴ Department of Neurology, Columbia University, New York, New York.
¹¹⁵ Department of Neurology, University of California Los Angeles, Los Angeles125Department of Pathology & Laboratory Medicine, University of California Los Angeles, Los Angeles.
¹¹⁶ Taub Institute on Alzheimer's Disease and the Aging Brain, Department of Pathology, Columbia University, New York, New York.
¹¹⁷ Cognitive Neurology and Alzheimer's Disease Center, Northwestern University, Chicago, Illinois127Department of Psychiatry, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
¹¹⁸ Department of Medicine, Duke University, Durham, North Carolina128Department of Psychiatry & Behavioral Sciences, Duke University, Durham, North Carolina.
¹¹⁹ Department of Pathology, Oregon Health & Science University, Portland.
¹²⁰ Evelyn F. McKnight Brain Institute, Department of Neurology, Miller School of Medicine, University of Miami, Miami, Florida.
¹²¹ Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois.

PMID: 25199842
PMCID: PMC4314944
DOI: 10.1001/jamaneurol.2014.1491

Erratum in

JAMA Neurol. 2014 Nov;71(11):1457

Abstract

Importance: Because APOE locus variants contribute to risk of late-onset Alzheimer disease (LOAD) and to differences in age at onset (AAO), it is important to know whether other established LOAD risk loci also affect AAO in affected participants.

Objectives: To investigate the effects of known Alzheimer disease risk loci in modifying AAO and to estimate their cumulative effect on AAO variation using data from genome-wide association studies in the Alzheimer Disease Genetics Consortium.

Design, setting, and participants: The Alzheimer Disease Genetics Consortium comprises 14 case-control, prospective, and family-based data sets with data on 9162 participants of white race/ethnicity with Alzheimer disease occurring after age 60 years who also had complete AAO information, gathered between 1989 and 2011 at multiple sites by participating studies. Data on genotyped or imputed single-nucleotide polymorphisms most significantly associated with risk at 10 confirmed LOAD loci were examined in linear modeling of AAO, and individual data set results were combined using a random-effects, inverse variance-weighted meta-analysis approach to determine whether they contribute to variation in AAO. Aggregate effects of all risk loci on AAO were examined in a burden analysis using genotype scores weighted by risk effect sizes.

Main outcomes and measures: Age at disease onset abstracted from medical records among participants with LOAD diagnosed per standard criteria.

Results: Analysis confirmed the association of APOE with earlier AAO (P = 3.3 × 10(-96)), with associations in CR1 (rs6701713, P = 7.2 × 10(-4)), BIN1 (rs7561528, P = 4.8 × 10(-4)), and PICALM (rs561655, P = 2.2 × 10(-3)) reaching statistical significance (P < .005). Risk alleles individually reduced AAO by 3 to 6 months. Burden analyses demonstrated that APOE contributes to 3.7% of the variation in AAO (R(2) = 0.256) over baseline (R(2) = 0.221), whereas the other 9 loci together contribute to 2.2% of the variation (R(2) = 0.242).

Conclusions and relevance: We confirmed an association of APOE (OMIM 107741) variants with AAO among affected participants with LOAD and observed novel associations of CR1 (OMIM 120620), BIN1 (OMIM 601248), and PICALM (OMIM 603025) with AAO. In contrast to earlier hypothetical modeling, we show that the combined effects of Alzheimer disease risk variants on AAO are on the scale of, but do not exceed, the APOE effect. While the aggregate effects of risk loci on AAO may be significant, additional genetic contributions to AAO are individually likely to be small.

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Figures

**Figure 1. Boxplots for age-at-onset (AAO) by ADGC dataset**

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References

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Effects of multiple genetic loci on age at onset in late-onset Alzheimer disease: a genome-wide association study

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Effects of multiple genetic loci on age at onset in late-onset Alzheimer disease: a genome-wide association study

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Erratum in

Abstract

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Miscellaneous