Richard Sherva1, Alden Gross2, Shubhabrata Mukherjee3, Ryan Koesterer4, Philippe Amouyel5,6,7, Celine Bellenguez5,6,7, Carole Dufouil8, David A Bennett9,10, Lori Chibnik11,12, Carlos Cruchaga13,14,15,16, Jorge Del-Aguila13,14,15,16, Lindsay A Farrer1,17,18,19,20,21, Richard Mayeux22,23,24, Leanne Munsie25, Ashley Winslow26, Stephen Newhouse27,28,29,30,31, Andrew J Saykin32, John S K Kauwe33, Paul K Crane3, Robert C Green34,35,36,37. 1. Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, Massachusetts, USA. 2. Johns Hopkins Bloomberg School of Public Health, Johns Hopkins Center on Aging and Health, Baltimore, Maryland, USA. 3. Department of Medicine, University of Washington, Seattle, Washington, USA. 4. Programs in Metabolism and Medical & Population Genetics, Broad Institute, Cambridge, Massachusetts, USA. 5. Inserm, CHU Lille, Institute Pasteur de Lille, U1167 - RID-AGE - Risk factors and molecular determinants of age-related diseases; Institute Pasteur de Lille, University of Lille, Lille Cedex, France. 6. Institut Pasteur de Lille, Lille, France. 7. DISTALZ Laboratory of Excellence (LabEx), University of Lille, Lille, France. 8. Inserm Unit 1219 Bordeaux Population Health, CIC 1401-EC (Clinical Epidemiology), University of Bordeaux, ISPED (Bordeaux School of Public Health), Bordeaux University Hospital, Bordeaux, France. 9. Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA. 10. Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA. 11. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA. 12. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. 13. Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri, USA. 14. Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA. 15. Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri, USA. 16. NeuroGenomics and Informatics, Washington University School of Medicine, Saint Louis, USA. 17. Bioinformatics Graduate Program, Boston University, Boston, Massachusetts, USA. 18. Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA. 19. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA. 20. Department of Ophthalmology, Boston University School of Medicine, Boston, Massachusetts, USA. 21. Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts, USA. 22. Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA. 23. The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, New York, USA. 24. Department of Neurology, College of Physicians and Surgeons, New York-Presbyterian Hospital, Columbia University Medical Center, New York, New York, USA. 25. Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, USA. 26. Orphan Disease Center, Perelman School of Medicine, University of Pennsylvania, Pennsylvania, Pennsylvania, USA. 27. Department of Biostatistics and Health Informatics, King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK. 28. NIHR BioResource Centre Maudsley, Psychology and Neuroscience (IoPPN), King's College London, NIHR Maudsley Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust (SLaM) & Institute of Psychiatry, London, UK. 29. Health Data Research UK London, University College London, London, UK. 30. Institute of Health Informatics, University College London, London, UK. 31. The National Institute for Health Research University College London Hospitals Biomedical Research Centre, University College London, London, UK. 32. Indiana Alzheimer Disease Center and Department of Radiology and Imaging Sciences, IU Health Neuroscience Center, Indiana University School of Medicine, Indianapolis, Indiana, USA. 33. Department of Biology, Brigham Young University, Provo, Utah, USA. 34. Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. 35. The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. 36. Harvard Medical School, Boston, Massachusetts, USA. 37. Partners HealthCare Personalized Medicine, Boston, Massachusetts, USA.
Abstract
INTRODUCTION: Variability exists in the disease trajectories of Alzheimer's disease (AD) patients. We performed a genome-wide association study to examine rate of cognitive decline (ROD) in patients with AD. METHODS: We tested for interactions between genetic variants and time since diagnosis to predict the ROD of a composite cognitive score in 3946 AD cases and performed pathway analysis on the top genes. RESULTS: Suggestive associations (P < 1.0 × 10-6 ) were observed on chromosome 15 in DNA polymerase-γ (rs3176205, P = 1.11 × 10-7 ), chromosome 7 (rs60465337,P = 4.06 × 10-7 ) in contactin-associated protein-2, in RP11-384F7.1 on chromosome 3 (rs28853947, P = 5.93 × 10-7 ), family with sequence similarity 214 member-A on chromosome 15 (rs2899492, P = 5.94 × 10-7 ), and intergenic regions on chromosomes 16 (rs4949142, P = 4.02 × 10-7 ) and 4 (rs1304013, P = 7.73 × 10-7 ). Significant pathways involving neuronal development and function, apoptosis, memory, and inflammation were identified. DISCUSSION: Pathways related to AD, intelligence, and neurological function determine AD progression, while previously identified AD risk variants, including the apolipoprotein (APOE) ε4 and ε2 variants, do not have a major impact.
INTRODUCTION: Variability exists in the disease trajectories of Alzheimer's disease (AD) patients. We performed a genome-wide association study to examine rate of cognitive decline (ROD) in patients with AD. METHODS: We tested for interactions between genetic variants and time since diagnosis to predict the ROD of a composite cognitive score in 3946 AD cases and performed pathway analysis on the top genes. RESULTS: Suggestive associations (P < 1.0 × 10-6 ) were observed on chromosome 15 in DNA polymerase-γ (rs3176205, P = 1.11 × 10-7 ), chromosome 7 (rs60465337,P = 4.06 × 10-7 ) in contactin-associated protein-2, in RP11-384F7.1 on chromosome 3 (rs28853947, P = 5.93 × 10-7 ), family with sequence similarity 214 member-A on chromosome 15 (rs2899492, P = 5.94 × 10-7 ), and intergenic regions on chromosomes 16 (rs4949142, P = 4.02 × 10-7 ) and 4 (rs1304013, P = 7.73 × 10-7 ). Significant pathways involving neuronal development and function, apoptosis, memory, and inflammation were identified. DISCUSSION: Pathways related to AD, intelligence, and neurological function determine AD progression, while previously identified AD risk variants, including the apolipoprotein (APOE) ε4 and ε2 variants, do not have a major impact.
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