title: Genome-wide studies of verbal declarative memory in nondemented older people: the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium.
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.
authors: 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.
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authors: 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.
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authors: 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.
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authors: Institut National de la Santé et de la Recherche Médicale, Epidemiology, University of Bordeaux; University Bordeaux Segalen, Bordeaux, France.
authors: Christophe
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authors: Psychiatric University Clinics and Department of Psychology, Division of Molecular Neuroscience, University of Basel, Basel, Switzerland; Department Biozentrum, Life Sciences Training Facility, Basel, Switzerland.
authors: Andreas
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authors: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois.
authors: David A
authors: DA
authors: Bennett
authors: 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.
authors: M Arfan
authors: MA
authors: Ikram
authors: Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh; Department of Psychology, The University of Edinburgh.
authors: Ian J
authors: IJ
authors: Deary
authors: 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.
authors: Cornelia M
authors: CM
authors: van Duijn
authors: Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, Maryland.
authors: Lenore
authors: L
authors: Launer
authors: Epidemiology, University of Washington.
authors: Annette L
authors: AL
authors: Fitzpatrick
authors: 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.
authors: Sudha
authors: S
authors: Seshadri
authors: Department of Medicine and Neurology, University of Mississippi Medical Center, Jackson, Mississippi.
authors: Thomas H
authors: TH
authors: Mosley
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics; D062507:Claudin-5 / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008569:Memory Disorders / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011506:Proteins / Q000235:genetics; D011509:Proteoglycans / Q000235:genetics; D012044:Regression Analysis; D015238:Sulfotransferases / Q000235:genetics; D014706:Verbal Learning / Q000502:physiology*; D009687:Nuclear Proteins
chemical_list: D001057:Apolipoproteins E; D062507:Claudin-5; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D011509:Proteoglycans; D015238:Sulfotransferases; C107466:CLDN5 protein, human; C504409:SPOCK3 protein, human; C021350:heparitin sulfotransferase; C526165:WDR48 protein, human; D009687:Nuclear Proteins
keywords: Alzheimer disease; Dementia; Epidemiology; Genetics; Population-based; Verbal declarative memory
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