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Mol Psychiatry. 2016 Feb;21(2):189-197. doi: 10.1038/mp.2015.37. Epub 2015 Apr 14.

GWAS for executive function and processing speed suggests involvement of the CADM2 gene.

Ibrahim-Verbaas CA1,2,3, Bressler J4,3, Debette S5,6,7,3, Schuur M1,2,3, Smith AV8,9,3, Bis JC10,3, Davies G11,3, Trompet S12,13, Smith JA14, Wolf C15, Chibnik LB16, Liu Y17, Vitart V18, Kirin M19, Petrovic K20, Polasek O21, Zgaga L22, Fawns-Ritchie C11, Hoffmann P23,24,25, Karjalainen J26, Lahti J27,28, Llewellyn DJ29, Schmidt CO30, Mather KA31, Chouraki V32, Sun Q33, Resnick SM34, Rose LM35, Oldmeadow C36, Stewart M19, Smith BH37, Gudnason V8,9, Yang Q38,39, Mirza SS40,41, Jukema JW12, deJager PL16, Harris TB42, Liewald DC11,43, Amin N1, Coker LH44, Stegle O45, Lopez OL46, Schmidt R20, Teumer A47, Ford I48, Karbalai N15, Becker JT46,49,50, Jonsdottir MK51, Au R5,38, Fehrmann R26, Herms S24,25, Nalls M52, Zhao W14, Turner ST53, Yaffe K54, Lohman K17, van Swieten JC2, Kardia S14, Knopman DS55, Meeks WM56, Heiss G57, Holliday EG36, Schofield PW58, Tanaka T59, Stott DJ60, Wang J39, Ridker P35, Gow AJ11,43, Pattie A11, Starr JM11,61, Hocking LJ62, Armstrong NJ31,63,64, McLachlan S19, Shulman JM65,66, Pilling LC67, Eiriksdottir G8, Scott RJ36, Kochan NA31,68, Palotie A69,70,71, Hsieh YC72, Eriksson JG28,73,74,75,76, Penman A77, Gottesman RF78, Oostra BA1, Yu L79, DeStefano AL5,38,39, Beiser A5,38,39, Garcia M42, Rotter JI80,81,82, Nöthen MM25,83, Hofman A40,41, Slagboom PE84, Westendorp R85, Buckley BM86, Wolf PA5,38, Uitterlinden AG40,41,87, Psaty BM10,88,89,90, Grabe HJ91, Bandinelli S3, Chasman DI35, Grodstein F33, Räikkönen K27, Lambert JC32, Porteous DJ92; Generation Scotland, Price JF19, Sachdev PS31,68, Ferrucci L59, Attia JR36, Rudan I19, Hayward C18, Wright AF18, Wilson JF19, Cichon S24,25,93, Franke L26, Schmidt H20, Ding J94, de Craen A13, Fornage M95, Bennett DA#79, Deary IJ#11,43, Ikram MA#2,40,41,96, Launer LJ#42, Fitzpatrick AL#88, Seshadri S#5,38, van Duijn CM#1,41, Mosley TH#97.

Author information

1
Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
2
Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands.
3
Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence, Italy.
4
Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA.
5
Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
6
Institut National de la Santé et de la Recherche Médicale (INSERM), U897, Epidemiology and Biostatistics, University of Bordeaux, Bordeaux, France.
7
Department of Neurology, Bordeaux University Hospital, Bordeaux, France.
8
Icelandic Heart Association, Kopavogur, Iceland.
9
Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
10
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
11
Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK.
12
Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
13
Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
14
Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA.
15
RG Statistical Genetics, Max Planck Institute of Psychiatry, Munich, Germany.
16
Program in Translational Neuropsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
17
Department of Epidemiology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
18
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
19
Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.
20
Department of Neurology, Medical University and General Hospital of Graz, Graz, Austria.
21
Department of Public Health, University of Split, Split, Croatia.
22
Department of Public Health and Primary Care, Trinity College Dublin, Dublin, Ireland.
23
Institute of Neuroscience and Medicine (INM -1), Research Center Juelich, Juelich, Germany.
24
Division of Medical Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland.
25
Department of Genomics, Life and Brain Research Center, Institute of Human Genetics, University of Bonn, Bonn, Germany.
26
Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
27
Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland.
28
Folkhälsan Research Centre, Helsinki, Finland.
29
Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Exeter, UK.
30
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
31
Centre for Healthy Brain Ageing, School of Psychiatry, UNSW Medicine, University of New South Wales, Sydney, Australia.
32
Inserm, U1167, Institut Pasteur de Lille, Université Lille-Nord de France, Lille, France.
33
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
34
Laboratory of Behavioral Neuroscience, National Institute on Aging, NIH, Baltimore, MD, USA.
35
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.
36
Hunter Medical Research Institute and Faculty of Health, University of Newcastle, Newcastle, NSW, Australia.
37
Medical Research Institute, University of Dundee, Dundee, UK.
38
The National Heart Lung and Blood Institute's Framingham Heart Study, Framingham, MA, USA.
39
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
40
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
41
Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands.
42
Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, MD, USA.
43
Department of Psychology, University of Edinburgh, Edinburgh, UK.
44
Division of Public Health Sciences and Neurology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
45
Max Planck Institute for Developmental Biology, Max Planck Institute for Intelligent Systems, Tübingen, Germany.
46
Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
47
Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
48
Robertson Center for biostatistics, University of Glasgow, Glasgow, UK.
49
Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
50
Department of Psychology, University of Pittsburgh, Pittsburgh, PA, USA.
51
Landspitali Hospital, Reykjavik, Iceland.
52
Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
53
Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
54
Departments of Psychiatry, Neurology and Epidemiology, University of California, San Francisco and San Francisco VA Medical Center, San Francisco, CA, USA.
55
Department of Neurology, Mayo Clinic, Rochester, MN, USA.
56
Department of Medicine, Division of Geriatrics, University of Mississippi Medical Center, Jackson, MS, USA.
57
Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
58
School of Medicine and Public Health, Faculty of Health, University of Newcastle, Newcastle, SW, Australia.
59
Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA.
60
Department of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
61
Alzheimer Scotland Research Centre, Edinburgh, UK.
62
Division of Applied Medicine, University of Aberdeen, Aberdeen, UK.
63
Cancer Research Program, Garvan Institute of Medical Research, Sydney, NSW, Australia.
64
School of Mathematics & Statistics and Prince of Wales Clinical School, University of New South Wales, Sydney, NSW, Australia.
65
Department of Neurology, Baylor College of Medicine, Houston, TX, USA.
66
Department of Molecular and Human Genetics, The Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
67
Epidemiology and Public Health Group, University of Exeter Medical School, Exeter, UK.
68
Neuropsychiatric Institute, The Prince of Wales Hospital, Sydney, NSW, Australia.
69
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
70
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
71
Department of Medical Genetics, University of Helsinki and University Central Hospital, Helsinki, Finland.
72
School of Public Health, Taipei Medical University, Taipei, Taiwan.
73
Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland.
74
National Institute for Health and Welfare, Helsinki, Finland.
75
Helsinki University Central Hospital, Unit of General Practice, Helsinki, Finland.
76
Vasa Central Hospital, Vasa, Finland.
77
Center of Biostatistics and Bioinformatics, University of Mississippi Medical Center, Jackson, MS, USA.
78
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
79
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
80
Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
81
Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
82
Division of Genetic Outcomes, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, USA.
83
German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
84
Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
85
Leiden Academy of Vitality and Ageing, Leiden, The Netherlands.
86
Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland.
87
Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
88
Department of Epidemiology, University of Washington, Seattle, WA, USA.
89
Department of Health Services, University of Washington, Seattle, WA, USA.
90
Group Health Research Institute, Group Health, Seattle, WA, USA.
91
Department of Psychiatry and Psychotherapy, University Medicine Greifswald, HELIOS-Hospital Stralsund, Stralsund, Germany.
92
Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
93
Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany.
94
Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
95
Institute for Molecular Medicine and Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX, USA.
96
Department of Radiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
97
Department of Medicine and Neurology, University of Mississippi Medical Center, Jackson, MS, USA.
#
Contributed equally

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.

PMID:
25869804
PMCID:
PMC4722802
DOI:
10.1038/mp.2015.37
[Indexed for MEDLINE]
Free PMC Article

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