Stéphanie Debette1, Carla A Ibrahim Verbaas2, Jan Bressler3, Maaike Schuur2, Albert Smith4, Joshua C Bis5, Gail Davies6, Christiane Wolf7, Vilmundur Gudnason4, Lori B Chibnik8, Qiong Yang9, Anita L deStefano10, Dominique J F de Quervain11, Velandai Srikanth12, Jari Lahti13, Hans J Grabe14, Jennifer A Smith15, Lutz Priebe16, Lei Yu17, Nazanin Karbalai7, Caroline Hayward18, James F Wilson19, Harry Campbell20, Katja Petrovic20, Myriam Fornage21, Ganesh Chauhan22, Robin Yeo22, Ruth Boxall23, James Becker24, Oliver Stegle25, Karen A Mather26, Vincent Chouraki27, Qi Sun28, Lynda M Rose29, Susan Resnick30, Christopher Oldmeadow31, Mirna Kirin19, Alan F Wright19, Maria K Jonsdottir32, Rhoda Au33, Albert Becker34, Najaf Amin35, Mike A Nalls36, Stephen T Turner37, Sharon L R Kardia15, Ben Oostra38, Gwen Windham39, Laura H Coker40, Wei Zhao15, David S Knopman41, Gerardo Heiss42, Michael E Griswold43, Rebecca F Gottesman44, Veronique Vitart18, Nicholas D Hastie18, Lina Zgaga18, Igor Rudan19, Ozren Polasek45, Elizabeth G Holliday46, Peter Schofield47, Seung Hoan Choi48, Toshiko Tanaka49, Yang An30, Rodney T Perry50, Richard E Kennedy51, Michèle M Sale52, Jing Wang48, Virginia G Wadley53, David C Liewald54, Paul M Ridker55, Alan J Gow54, Alison Pattie23, John M Starr56, David Porteous57, Xuan Liu48, Russell Thomson58, Nicola J Armstrong59, Gudny Eiriksdottir32, Arezoo A Assareh60, Nicole A Kochan61, Elisabeth Widen62, Aarno Palotie63, Yi-Chen Hsieh64, Johan G Eriksson65, Christian Vogler66, John C van Swieten67, Joshua M Shulman68, Alexa Beiser10, Jerome Rotter69, Carsten O Schmidt70, Wolfgang Hoffmann71, Markus M Nöthen72, Luigi Ferrucci49, John Attia73, Andre G Uitterlinden74, Philippe Amouyel75, Jean-François Dartigues76, Hélène Amieva76, Katri Räikkönen77, Melissa Garcia78, Philip A Wolf33, Albert Hofman79, W T Longstreth80, Bruce M Psaty81, Eric Boerwinkle82, Philip L DeJager8, Perminder S Sachdev61, Reinhold Schmidt83, Monique M B Breteler84, Alexander Teumer85, Oscar L Lopez86, Sven Cichon87, Daniel I Chasman55, Francine Grodstein88, Bertram Müller-Myhsok89, Christophe Tzourio90, Andreas Papassotiropoulos91, David A Bennett17, M Arfan Ikram92, Ian J Deary54, Cornelia M van Duijn93, Lenore Launer78, Annette L Fitzpatrick94, Sudha Seshadri10, Thomas H Mosley95. 1. Department of Neurology, Boston University School of Medicine, Boston, Massachusetts; Institut National de la Santé et de la Recherche Médicale, Epidemiology, University of Bordeaux; Department of Neurology, University Hospital of Bordeaux, Bordeaux, France. Electronic address: sdebette@bu.edu. 2. Genetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands; Department of Neurology, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands. 3. Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas. 4. Icelandic Heart Association, Kopavogur; Faculty of Medicine, University of Iceland, Reykjavik, Iceland. 5. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington. 6. Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh; Department of Psychology, The University of Edinburgh; Medical Genetics Section, Molecular Medicine Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom. 7. Max Planck Institute of Psychiatry, Munich, Germany. 8. Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital, Boston. 9. Department of Biostatistics, Boston University School of Public Health, Boston; The National Heart Lung and Blood Institute's Framingham Heart Study, Framingham, Massachusetts. 10. Department of Neurology, Boston University School of Medicine, Boston, Massachusetts; Department of Biostatistics, Boston University School of Public Health, Boston; The National Heart Lung and Blood Institute's Framingham Heart Study, Framingham, Massachusetts. 11. Psychiatric University Clinics and Department of Psychology, Division of Cognitive Neuroscience, University of Basel, Basel, Switzerland. 12. Stroke and Ageing Research Centre, Southern Clinical School, Department of Medicine, Monash University, Melbourne; Menzies Research Institute Tasmania, University of Tasmania, Hobart, Australia. 13. Institute of Behavioural Sciences, University of Helsinki; Folkhälsan Research Centre, Helsinki, Finland. 14. Department of Psychiatry and Psychotherapy, University Medicine Greifswald, HELIOS-Hospital Stralsund, Stralsund; German Center for Neurodegenerative Diseases, Site Rostock/ Greifswald, Rostock, Germany. 15. Department of Epidemiology, University of Michigan, Ann Arbor, Michigan. 16. Institute of Human Genetics, Universitätsklinikum Bonn, Bonn, Germany. 17. Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois. 18. Medical Research Council Human Genetics Unit. 19. Institute of Genetics and Molecular Medicine, University of Edinburgh, United Kingdom, Centre for Population Health Sciences, University of Edinburgh, United Kingdom. 20. Division of General Neurology, Department of Neurology, Medical University and General Hospital of Graz, Austria. 21. Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas; Institute of Molecular Medicine, University of Texas-Houston Health Science Center, Houston, Texas. 22. Institut National de la Santé et de la Recherche Médicale, Epidemiology, University of Bordeaux. 23. Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh. 24. Departments of Neurology and Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Psychology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. 25. Max Planck Institute for Intelligent Systems, Tübingen, Germany; Max Planck Institute for Developmental Biology, Tübingen, Germany. 26. Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales Medicine, University of New South Wales, Sydney, Australia. 27. Institut National de la Santé et de la Recherche Médicale Unit 744, Institut Pasteur de Lille, and Université Lille Nord de France, Lille, France. 28. Department of Nutrition, Harvard School of Public Health; Channing Division of Network Medicine, Department of Medicine, Brigham and Women׳s Hospital and Harvard Medical School; Harvard Medical School, Brigham and Women׳s Hospital, Boston, Massachusetts. 29. Division of Preventive Medicine, Brigham and Women׳s Hospital, Boston, Massachusetts. 30. Brain Aging and Behavior Section, Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Bethesda, Maryland. 31. Centre for Clinical Epidemiology and Biostatistics, School of Medicine, Newcastle, Australia; Public Health, Faculty of Health, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia. 32. Icelandic Heart Association, Kopavogur. 33. Department of Neurology, Boston University School of Medicine, Boston, Massachusetts; The National Heart Lung and Blood Institute's Framingham Heart Study, Framingham, Massachusetts. 34. Institute of Neuropathology, Universitätsklinikum Bonn, Bonn, Germany. 35. Genetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands. 36. Molecular Genetics Section , Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland. 37. Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota. 38. Genetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands; Department of Clinical Genetics, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands. 39. Department of Medicine, Division of Geriatrics, University of Mississippi Medical Center, Jackson, Mississippi. 40. Division of Public Health Sciences and Neurology, Wake Forest School of Medicine, Winston-Salem, North Carolina. 41. Department of Neurology, Mayo Clinic, Rochester, Minnesota. 42. Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. 43. Center of Biostatistics and Bioinformatics, University of Mississippi Medical Center, Jackson, Mississippi. 44. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland. 45. Department of Public Health, Faculty of Medicine, University of Split, Split, Croatia. 46. Centre for Clinical Epidemiology and Biostatistics, School of Medicine, Newcastle, Australia. 47. Centre for Clinical Epidemiology and Biostatistics, School of Medicine, Newcastle, Australia; Department of Medicine, John Hunter Hospital, Newcastle, Australia. 48. Department of Biostatistics, Boston University School of Public Health, Boston. 49. Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Bethesda, Maryland. 50. Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama. 51. Division of Gerontology, Geriatrics, and Palliative Care, University of Alabama at Birmingham, Birmingham, Alabama. 52. Center for Public Health Genomics, Department of Medicine, Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia. 53. Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama. 54. Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh; Department of Psychology, The University of Edinburgh. 55. Harvard Medical School, Brigham and Women׳s Hospital, Boston, Massachusetts; Division of Preventive Medicine, Brigham and Women׳s Hospital, Boston, Massachusetts. 56. Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh; Alzheimer Scotland Dementia Research Centre, The University of Edinburgh, Edinburgh, United Kingdom. 57. Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh; Medical Genetics Section, Molecular Medicine Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom. 58. Menzies Research Institute Tasmania, University of Tasmania, Hobart, Australia. 59. Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales Medicine, University of New South Wales, Sydney, Australia; Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst; School of Mathematics & Statistics and Prince of Wales Clinical School, University of New South Wales, Sydney. 60. Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales Medicine, University of New South Wales, Sydney, Australia; Neuroscience Research Australia and Primary Dementia Collaborative Research Centre-Assessment and Better Care, University of New South Wales, Sydney. 61. Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales Medicine, University of New South Wales, Sydney, Australia; Neuropsychiatric Institute, Prince of Wales Hospital, Randwick New South Wales, Australia. 62. Institute for Molecular Medicine Finland, University of Helsinki, Finland. 63. Institute for Molecular Medicine Finland, University of Helsinki, Finland; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom; Department of Medical Genetics, University of Helsinki and University Central Hospital, Helsinki, Finland. 64. Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan. 65. Folkhälsan Research Centre, Helsinki, Finland; National Institute for Health and Welfare, Helsinki, Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Helsinki University Central Hospital, Unit of General Practice, Helsinki, Vasa Central Hospital, Vasa, Finland. 66. Psychiatric University Clinics and Department of Psychology, Division of Molecular Neuroscience, University of Basel, Basel, Switzerland. 67. Department of Neurology, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands. 68. Departments of Neurology and Molecular and Human Genetics, Baylor College of Medicine and The Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas. 69. Institute for Translational Genomics and Populaton Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California. 70. Institute for Community Medicine, University Medicine Greifswald. 71. German Center for Neurodegenerative Diseases, Site Rostock/ Greifswald, Rostock, Germany; Section Epidemiology of Health Care and Community Health, Greifswald. 72. Institute of Human Genetics, Department of Genomics, Life & Brain Research Center, University of Bonn, Bonn; German Center for Neurodegenerative Diseases, Bonn, Germany. 73. Centre for Clinical Epidemiology and Biostatistics, School of Medicine, Newcastle, Australia; Public Health, Faculty of Health, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia; Department of Medicine, John Hunter Hospital, Newcastle, Australia. 74. Netherlands Consortium for Healthy Ageing, Leiden, the Netherlands; Department of Internal Medicine, Erasmus Medical Center University Medical Center, Rotterdam, the Netherlands. 75. Institut National de la Santé et de la Recherche Médicale Unit 744, Institut Pasteur de Lille, and Université Lille Nord de France, Lille, France; Centre Hospitalier Régional Universitaire de Lille, Lille. 76. Institut National de la Santé et de la Recherche Médicale, Bordeaux University, Talence, France. 77. Institute of Behavioural Sciences, University of Helsinki. 78. Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, Maryland. 79. Netherlands Consortium for Healthy Ageing, Leiden, the Netherlands; Department of Epidemiology, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands. 80. Departments of Neurology, University of Washington; Epidemiology, University of Washington. 81. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington; Epidemiology, University of Washington; Health Services, University of Washington; Group Health Research Institute, Group Health Cooperative, Seattle, Washington. 82. Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center at Houston, Houston, Texas. 83. Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Graz, Austria. 84. German Center for Neurodegenerative Diseases, Site Rostock/ Greifswald, Rostock, Germany; Netherlands Consortium for Healthy Ageing, Leiden, the Netherlands; Department of Epidemiology, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands; Population Health Sciences, University of Bonn, Bonn, Germany; Department of Epidemiology, Harvard School of Public Health, Harvard University, Boston, Massachusetts. 85. Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany. 86. Departments of Neurology and Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; The Alzheimer׳s Disease Research Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. 87. Institute of Human Genetics, Universitätsklinikum Bonn, Bonn, Germany; Institute of Neuroscience and Medicine, Research Center Julich, Julich, Germany; Division of Medical Genetics, Department of Biomedicine, University of Basel, Switzerland. 88. Channing Division of Network Medicine, Department of Medicine, Brigham and Women׳s Hospital and Harvard Medical School; Department of Epidemiology, Harvard School of Public Health, Harvard University, Boston, Massachusetts. 89. Max Planck Institute of Psychiatry, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. 90. Institut National de la Santé et de la Recherche Médicale, Epidemiology, University of Bordeaux; University Bordeaux Segalen, Bordeaux, France. 91. Psychiatric University Clinics and Department of Psychology, Division of Molecular Neuroscience, University of Basel, Basel, Switzerland; Department Biozentrum, Life Sciences Training Facility, Basel, Switzerland. 92. Netherlands Consortium for Healthy Ageing, Leiden, the Netherlands; Department of Epidemiology, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands; Department of Radiology, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands. 93. Genetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands; Netherlands Consortium for Healthy Ageing, Leiden, the Netherlands; Center for Medical Systems Biology, Netherlands Genomics Initiative, Leiden University Medical Center, Leiden, The Netherlands. 94. Epidemiology, University of Washington. 95. Department of Medicine and Neurology, University of Mississippi Medical Center, Jackson, Mississippi.
Abstract
BACKGROUND: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting. METHODS: We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10(-6)) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults. RESULTS: rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10(-10)) and replication cohorts (p = 5.65 × 10(-8)). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10(-8), and rs6813517 [SPOCK3], p = 2.58 × 10(-8)) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism. CONCLUSIONS: This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.
BACKGROUND: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting. METHODS: We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10(-6)) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults. RESULTS: rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10(-10)) and replication cohorts (p = 5.65 × 10(-8)). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10(-8), and rs6813517 [SPOCK3], p = 2.58 × 10(-8)) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism. CONCLUSIONS: This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.
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