title: GWAS for executive function and processing speed suggests involvement of the CADM2 gene.
abstract: To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32,070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.
authors: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.|Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands.|Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence, Italy.
authors: C A
authors: CA
authors: Ibrahim-Verbaas
authors: Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA.|Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence, Italy.
authors: J
authors: J
authors: Bressler
authors: Department of Neurology, Boston University School of Medicine, Boston, MA, USA.|Institut National de la Santé et de la Recherche Médicale (INSERM), U897, Epidemiology and Biostatistics, University of Bordeaux, Bordeaux, France.|Department of Neurology, Bordeaux University Hospital, Bordeaux, France.|Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence, Italy.
authors: S
authors: S
authors: Debette
authors: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.|Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands.|Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence, Italy.
authors: M
authors: M
authors: Schuur
authors: Icelandic Heart Association, Kopavogur, Iceland.|Faculty of Medicine, University of Iceland, Reykjavik, Iceland.|Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence, Italy.
authors: A V
authors: AV
authors: Smith
authors: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.|Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence, Italy.
authors: J C
authors: JC
authors: Bis
authors: Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK.|Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence, Italy.
authors: G
authors: G
authors: Davies
authors: Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.|Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
authors: S
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authors: Trompet
authors: Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA.
authors: J A
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authors: Smith
authors: RG Statistical Genetics, Max Planck Institute of Psychiatry, Munich, Germany.
authors: C
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authors: Program in Translational Neuropsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
authors: L B
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authors: Department of Epidemiology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors: Y
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authors: Liu
authors: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
authors: V
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authors: Vitart
authors: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.
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authors: Kirin
authors: Department of Neurology, Medical University and General Hospital of Graz, Graz, Austria.
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authors: Petrovic
authors: Department of Public Health, University of Split, Split, Croatia.
authors: O
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authors: Polasek
authors: Department of Public Health and Primary Care, Trinity College Dublin, Dublin, Ireland.
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authors: Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK.
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authors: Fawns-Ritchie
authors: Institute of Neuroscience and Medicine (INM -1), Research Center Juelich, Juelich, Germany.|Division of Medical Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland.|Department of Genomics, Life and Brain Research Center, Institute of Human Genetics, University of Bonn, Bonn, Germany.
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authors: Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
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authors: Karjalainen
authors: Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland.|Folkhälsan Research Centre, Helsinki, Finland.
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authors: Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Exeter, UK.
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authors: Centre for Healthy Brain Ageing, School of Psychiatry, UNSW Medicine, University of New South Wales, Sydney, Australia.
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authors: Inserm, U1167, Institut Pasteur de Lille, Université Lille-Nord de France, Lille, France.
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authors: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
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authors: Laboratory of Behavioral Neuroscience, National Institute on Aging, NIH, Baltimore, MD, USA.
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authors: Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.
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authors: Hunter Medical Research Institute and Faculty of Health, University of Newcastle, Newcastle, NSW, Australia.
authors: C
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authors: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.
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authors: Medical Research Institute, University of Dundee, Dundee, UK.
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authors: Icelandic Heart Association, Kopavogur, Iceland.|Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors: V
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authors: The National Heart Lung and Blood Institute's Framingham Heart Study, Framingham, MA, USA.|Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
authors: Q
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authors: Yang
authors: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.|Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands.
authors: S S
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authors: Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
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authors: Program in Translational Neuropsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
authors: P L
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authors: Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, MD, USA.
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authors: Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK.|Department of Psychology, University of Edinburgh, Edinburgh, UK.
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authors: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
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authors: Division of Public Health Sciences and Neurology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors: L H
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authors: Max Planck Institute for Developmental Biology, Max Planck Institute for Intelligent Systems, Tübingen, Germany.
authors: O
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authors: Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
authors: O L
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authors: Department of Neurology, Medical University and General Hospital of Graz, Graz, Austria.
authors: R
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authors: Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
authors: A
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authors: Robertson Center for biostatistics, University of Glasgow, Glasgow, UK.
authors: I
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authors: Ford
authors: RG Statistical Genetics, Max Planck Institute of Psychiatry, Munich, Germany.
authors: N
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authors: Karbalai
authors: Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.|Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.|Department of Psychology, University of Pittsburgh, Pittsburgh, PA, USA.
authors: J T
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authors: Landspitali Hospital, Reykjavik, Iceland.
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authors: Department of Neurology, Boston University School of Medicine, Boston, MA, USA.|The National Heart Lung and Blood Institute's Framingham Heart Study, Framingham, MA, USA.
authors: R
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authors: Au
authors: Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
authors: Rsn
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authors: Fehrmann
authors: Division of Medical Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland.|Department of Genomics, Life and Brain Research Center, Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors: S
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authors: Herms
authors: Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
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authors: Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA.
authors: W
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authors: Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
authors: S T
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authors: Departments of Psychiatry, Neurology and Epidemiology, University of California, San Francisco and San Francisco VA Medical Center, San Francisco, CA, USA.
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authors: Department of Epidemiology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
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authors: Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors: J C
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authors: Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA.
authors: Slr
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authors: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
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authors: Department of Medicine, Division of Geriatrics, University of Mississippi Medical Center, Jackson, MS, USA.
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authors: Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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authors: Hunter Medical Research Institute and Faculty of Health, University of Newcastle, Newcastle, NSW, Australia.
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authors: School of Medicine and Public Health, Faculty of Health, University of Newcastle, Newcastle, SW, Australia.
authors: P W
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authors: Department of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
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authors: Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
authors: J
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authors: Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors: P
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authors: Ridker
authors: Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK.|Department of Psychology, University of Edinburgh, Edinburgh, UK.
authors: A J
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authors: Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK.
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authors: Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK.|Alzheimer Scotland Research Centre, Edinburgh, UK.
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authors: L J
authors: LJ
authors: Hocking
authors: Centre for Healthy Brain Ageing, School of Psychiatry, UNSW Medicine, University of New South Wales, Sydney, Australia.|Cancer Research Program, Garvan Institute of Medical Research, Sydney, NSW, Australia.|School of Mathematics & Statistics and Prince of Wales Clinical School, University of New South Wales, Sydney, NSW, Australia.
authors: N J
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authors: Armstrong
authors: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.
authors: S
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authors: McLachlan
authors: Department of Neurology, Baylor College of Medicine, Houston, TX, USA.|Department of Molecular and Human Genetics, The Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
authors: J M
authors: JM
authors: Shulman
authors: Epidemiology and Public Health Group, University of Exeter Medical School, Exeter, UK.
authors: L C
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authors: Eiriksdottir
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authors: R J
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authors: Scott
authors: Centre for Healthy Brain Ageing, School of Psychiatry, UNSW Medicine, University of New South Wales, Sydney, Australia.|Neuropsychiatric Institute, The Prince of Wales Hospital, Sydney, NSW, Australia.
authors: N A
authors: NA
authors: Kochan
authors: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.|Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.|Department of Medical Genetics, University of Helsinki and University Central Hospital, Helsinki, Finland.
authors: A
authors: A
authors: Palotie
authors: School of Public Health, Taipei Medical University, Taipei, Taiwan.
authors: Y-C
authors: YC
authors: Hsieh
authors: Folkhälsan Research Centre, Helsinki, Finland.|Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland.|National Institute for Health and Welfare, Helsinki, Finland.|Helsinki University Central Hospital, Unit of General Practice, Helsinki, Finland.|Vasa Central Hospital, Vasa, Finland.
authors: J G
authors: JG
authors: Eriksson
authors: Center of Biostatistics and Bioinformatics, University of Mississippi Medical Center, Jackson, MS, USA.
authors: A
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authors: Penman
authors: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: R F
authors: RF
authors: Gottesman
authors: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors: B A
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authors: Oostra
authors: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
authors: L
authors: L
authors: Yu
authors: Department of Neurology, Boston University School of Medicine, Boston, MA, USA.|The National Heart Lung and Blood Institute's Framingham Heart Study, Framingham, MA, USA.|Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
authors: A L
authors: AL
authors: DeStefano
authors: Department of Neurology, Boston University School of Medicine, Boston, MA, USA.|The National Heart Lung and Blood Institute's Framingham Heart Study, Framingham, MA, USA.|Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
authors: A
authors: A
authors: Beiser
authors: Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, MD, USA.
authors: M
authors: M
authors: Garcia
authors: Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.|Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.|Division of Genetic Outcomes, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, USA.
authors: J I
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authors: Department of Genomics, Life and Brain Research Center, Institute of Human Genetics, University of Bonn, Bonn, Germany.|German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors: M M
authors: MM
authors: Nöthen
authors: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.|Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands.
authors: A
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authors: Hofman
authors: Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
authors: P E
authors: PE
authors: Slagboom
authors: Leiden Academy of Vitality and Ageing, Leiden, The Netherlands.
authors: Rgj
authors: R
authors: Westendorp
authors: Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland.
authors: B M
authors: BM
authors: Buckley
authors: Department of Neurology, Boston University School of Medicine, Boston, MA, USA.|The National Heart Lung and Blood Institute's Framingham Heart Study, Framingham, MA, USA.
authors: P A
authors: PA
authors: Wolf
authors: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.|Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands.|Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors: A G
authors: AG
authors: Uitterlinden
authors: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.|Department of Epidemiology, University of Washington, Seattle, WA, USA.|Department of Health Services, University of Washington, Seattle, WA, USA.|Group Health Research Institute, Group Health, Seattle, WA, USA.
authors: B M
authors: BM
authors: Psaty
authors: Department of Psychiatry and Psychotherapy, University Medicine Greifswald, HELIOS-Hospital Stralsund, Stralsund, Germany.
authors: H J
authors: HJ
authors: Grabe
authors: Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence, Italy.
authors: S
authors: S
authors: Bandinelli
authors: Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors: D I
authors: DI
authors: Chasman
authors: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors: F
authors: F
authors: Grodstein
authors: Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland.
authors: K
authors: K
authors: Räikkönen
authors: Inserm, U1167, Institut Pasteur de Lille, Université Lille-Nord de France, Lille, France.
authors: J-C
authors: JC
authors: Lambert
authors: Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
authors: D J
authors: DJ
authors: Porteous
authors: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.
authors: J F
authors: JF
authors: Price
authors: Centre for Healthy Brain Ageing, School of Psychiatry, UNSW Medicine, University of New South Wales, Sydney, Australia.|Neuropsychiatric Institute, The Prince of Wales Hospital, Sydney, NSW, Australia.
authors: P S
authors: PS
authors: Sachdev
authors: Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA.
authors: L
authors: L
authors: Ferrucci
authors: Hunter Medical Research Institute and Faculty of Health, University of Newcastle, Newcastle, NSW, Australia.
authors: J R
authors: JR
authors: Attia
authors: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.
authors: I
authors: I
authors: Rudan
authors: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
authors: C
authors: C
authors: Hayward
authors: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
authors: A F
authors: AF
authors: Wright
authors: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.
authors: J F
authors: JF
authors: Wilson
authors: Division of Medical Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland.|Department of Genomics, Life and Brain Research Center, Institute of Human Genetics, University of Bonn, Bonn, Germany.|Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany.
authors: S
authors: S
authors: Cichon
authors: Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
authors: L
authors: L
authors: Franke
authors: Department of Neurology, Medical University and General Hospital of Graz, Graz, Austria.
authors: H
authors: H
authors: Schmidt
authors: Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
authors: J
authors: J
authors: Ding
authors: Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
authors: Ajm
authors: A
authors: de Craen
authors: Institute for Molecular Medicine and Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors: M
authors: M
authors: Fornage
authors: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
authors: D A
authors: DA
authors: Bennett
authors: Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK.|Department of Psychology, University of Edinburgh, Edinburgh, UK.
authors: I J
authors: IJ
authors: Deary
authors: Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands.|Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.|Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands.|Department of Radiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors: M A
authors: MA
authors: Ikram
authors: Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, MD, USA.
authors: L J
authors: LJ
authors: Launer
authors: Department of Epidemiology, University of Washington, Seattle, WA, USA.
authors: A L
authors: AL
authors: Fitzpatrick
authors: Department of Neurology, Boston University School of Medicine, Boston, MA, USA.|The National Heart Lung and Blood Institute's Framingham Heart Study, Framingham, MA, USA.
authors: S
authors: S
authors: Seshadri
authors: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.|Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands.
authors: C M
authors: CM
authors: van Duijn
authors: Department of Medicine and Neurology, University of Mississippi Medical Center, Jackson, MS, USA.
authors: T H
authors: TH
authors: Mosley
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000502:physiology; D003071:Cognition / Q000502:physiology; D015331:Cohort Studies; D056344:Executive Function / Q000502:physiology*; D005260:Female; D056726:Genetic Association Studies; D014644:Genetic Variation / Q000235:genetics; D055106:Genome-Wide Association Study; D023281:Genomics; D006801:Humans; D007438:Introns; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics; D005680:gamma-Aminobutyric Acid
chemical_list: C556123:CADM2 protein, human; D015815:Cell Adhesion Molecules; D005680:gamma-Aminobutyric Acid