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Biol Psychiatry. 2015 Apr 15;77(8):749-63. doi: 10.1016/j.biopsych.2014.08.027. Epub 2014 Nov 25.

Genome-wide studies of verbal declarative memory in nondemented older people: the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium.

Debette S1, Ibrahim Verbaas CA2, Bressler J3, Schuur M2, Smith A4, Bis JC5, Davies G6, Wolf C7, Gudnason V4, Chibnik LB8, Yang Q9, deStefano AL10, de Quervain DJ11, Srikanth V12, Lahti J13, Grabe HJ14, Smith JA15, Priebe L16, Yu L17, Karbalai N7, Hayward C18, Wilson JF19, Campbell H20, Petrovic K20, Fornage M21, Chauhan G22, Yeo R22, Boxall R23, Becker J24, Stegle O25, Mather KA26, Chouraki V27, Sun Q28, Rose LM29, Resnick S30, Oldmeadow C31, Kirin M19, Wright AF19, Jonsdottir MK32, Au R33, Becker A34, Amin N35, Nalls MA36, Turner ST37, Kardia SL15, Oostra B38, Windham G39, Coker LH40, Zhao W15, Knopman DS41, Heiss G42, Griswold ME43, Gottesman RF44, Vitart V18, Hastie ND18, Zgaga L18, Rudan I19, Polasek O45, Holliday EG46, Schofield P47, Choi SH48, Tanaka T49, An Y30, Perry RT50, Kennedy RE51, Sale MM52, Wang J48, Wadley VG53, Liewald DC54, Ridker PM55, Gow AJ54, Pattie A23, Starr JM56, Porteous D57, Liu X48, Thomson R58, Armstrong NJ59, Eiriksdottir G32, Assareh AA60, Kochan NA61, Widen E62, Palotie A63, Hsieh YC64, Eriksson JG65, Vogler C66, van Swieten JC67, Shulman JM68, Beiser A10, Rotter J69, Schmidt CO70, Hoffmann W71, Nöthen MM72, Ferrucci L49, Attia J73, Uitterlinden AG74, Amouyel P75, Dartigues JF76, Amieva H76, Räikkönen K77, Garcia M78, Wolf PA33, Hofman A79, Longstreth WT Jr80, Psaty BM81, Boerwinkle E82, DeJager PL8, Sachdev PS61, Schmidt R83, Breteler MM84, Teumer A85, Lopez OL86, Cichon S87, Chasman DI55, Grodstein F88, Müller-Myhsok B89, Tzourio C90, Papassotiropoulos A91, Bennett DA17, Ikram MA92, Deary IJ54, van Duijn CM93, Launer L78, Fitzpatrick AL94, Seshadri S10, Mosley TH Jr95; Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium.

Author information

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.

KEYWORDS:

Alzheimer disease; Dementia; Epidemiology; Genetics; Population-based; Verbal declarative memory

PMID:
25648963
PMCID:
PMC4513651
DOI:
10.1016/j.biopsych.2014.08.027
[Indexed for MEDLINE]
Free PMC Article

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