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Original Investigation
November 2014

Effects of Multiple Genetic Loci on Age at Onset in Late-Onset Alzheimer Disease: A Genome-Wide Association Study

Adam C. Naj, PhD1; Gyungah Jun, PhD3,4,5; Christiane Reitz, MD, PhD6,7,8; et al Brian W. Kunkle, PhD2; William Perry, MPH2; Yo Son Park, BS9; Gary W. Beecham, PhD2,9; Ruchita A. Rajbhandary, MPH2; Kara L. Hamilton-Nelson, MPH2; Li-San Wang, PhD10; John S. K. Kauwe, PhD11; Matthew J. Huentelman, PhD12; Amanda J. Myers, PhD13; Thomas D. Bird, MD14,15; Bradley F. Boeve, MD16; Clinton T. Baldwin, PhD3; Gail P. Jarvik, MD, PhD17,18; Paul K. Crane, MD, MPH19; Ekaterina Rogaeva, PhD20; M. Michael Barmada, PhD21; F. Yesim Demirci, MD21; Carlos Cruchaga, PhD22; Patricia L. Kramer, PhD23,24; Nilufer Ertekin-Taner, MD, PhD25,26; John Hardy, PhD27; Neill R. Graff-Radford, MD25,26; Robert C. Green, MD, MPH28; Eric B. Larson, MD, MPH19,29; Peter H. St. George-Hyslop, MD, FRCP20,30; Joseph D. Buxbaum, PhD31,32,33; Denis A. Evans, MD34; Julie A. Schneider, MD35,36; Kathryn L. Lunetta, PhD4; M. Ilyas Kamboh, PhD21,37; Andrew J. Saykin, PsyD38,39; Eric M. Reiman, MD12,40,41,42; Philip L. De Jager, MD, PhD43,44; David A. Bennett, MD35,45; John C. Morris, MD46,47; Thomas J. Montine, MD, PhD48; Alison M. Goate, DPhil22; Deborah Blacker, MD49,50; Debby W. Tsuang, MD15,51; Hakon Hakonarson, MD, PhD52; Walter A. Kukull, PhD53; Tatiana M. Foroud, PhD38; Eden R. Martin, PhD2,9; Jonathan L. Haines, PhD54,55; Richard P. Mayeux, MD56,57,58; Lindsay A. Farrer, PhD3,4,5,59,60; Gerard D. Schellenberg, PhD10; Margaret A. Pericak-Vance, PhD2,9; and the Alzheimer Disease Genetics Consortium
Author Affiliations
  • 1Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia
  • 2John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida
  • 3Genetics Program, Department of Medicine, Boston University, Boston, Massachusetts
  • 4Department of Biostatistics, Boston University, Boston, Massachusetts
  • 5Department of Ophthalmology, Boston University, Boston, Massachusetts
  • 6Taub Institute on Alzheimer’s Disease and the Aging Brain, Department of Neurology, Columbia University, New York, New York
  • 7Gertrude H. Sergievsky Center, Columbia University, New York, New York
  • 8Department of Neurology, Columbia University, New York, New York
  • 9The Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, Florida
  • 10Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia
  • 11Department of Biology, Brigham Young University, Provo, Utah
  • 12Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona
  • 13Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, Florida
  • 14Department of Neurology, University of Washington, Seattle
  • 15Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington
  • 16Department of Neurology, Mayo Clinic, Rochester, Minnesota
  • 17Department of Genome Sciences, University of Washington, Seattle
  • 18Division of Medical Genetics, Department of Medicine, University of Washington, Seattle
  • 19Department of Medicine, University of Washington, Seattle
  • 20Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada
  • 21Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania
  • 22Department of Psychiatry and Hope Center Program on Protein Aggregation and Neurodegeneration, School of Medicine, Washington University in St Louis, St Louis, Missouri
  • 23Department of Neurology, Oregon Health & Science University, Portland
  • 24Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland
  • 25Department of Neuroscience, Mayo Clinic, Jacksonville, Florida
  • 26Department of Neurology, Mayo Clinic, Jacksonville, Florida
  • 27Institute of Neurology, University College London, London, England
  • 28Division of Genetics, Department of Medicine, and Partners Center for Personalized Genetic Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 29Group Health Research Institute, Group Health Cooperative, Seattle, Washington
  • 30Cambridge Institute for Medical Research, Department of Clinical Neurosciences, University of Cambridge, Cambridge, England
  • 31Department of Neuroscience, Mount Sinai School of Medicine, New York, New York
  • 32Department of Psychiatry, Mount Sinai School of Medicine, New York, New York
  • 33Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York
  • 34Rush Institute for Healthy Aging, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois
  • 35Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois
  • 36Neuropathology, Department of Pathology, Rush University Medical Center, Chicago, Illinois
  • 37Alheimer Disease Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania
  • 38Department of Medical and Molecular Genetics, Indiana University, Indianapolis
  • 39Department of Radiology and Imaging Sciences, Indiana University, Indianapolis
  • 40Arizona Alzheimer’s Consortium, Phoenix
  • 41Department of Psychiatry, University of Arizona, Phoenix
  • 42Banner Alzheimer’s Institute, Phoenix, Arizona
  • 43Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology and Psychiatry, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 44Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts
  • 45Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, Illinois
  • 46Department of Pathology and Immunology, Washington University in St Louis, St Louis, Missouri
  • 47Department of Neurology, Washington University in St Louis, St Louis, Missouri
  • 48Department of Pathology, University of Washington, Seattle
  • 49Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts
  • 50Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston
  • 51Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle
  • 52Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
  • 53Department of Epidemiology, University of Washington, Seattle
  • 54Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee
  • 55Vanderbilit Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee
  • 56Taub Institute on Alzheimer’s Disease and the Aging Brain, Columbia University, New York, New York
  • 57Gertrude H. Sergievsky Center, Columbia University, New York, New York
  • 58Department of Neurology, Columbia University, New York, New York
  • 59Department of Epidemiology, Boston University, Boston, Massachusetts
  • 60Department of Neurology, Boston University, Boston, Massachusetts
JAMA Neurol. 2014;71(11):1394-1404. doi:10.1001/jamaneurol.2014.1491
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 (R2 = 0.256) over baseline (R2 = 0.221), whereas the other 9 loci together contribute to 2.2% of the variation (R2 = 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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