期刊
MOLECULAR PSYCHIATRY
卷 21, 期 2, 页码 189-197出版社
SPRINGERNATURE
DOI: 10.1038/mp.2015.37
关键词
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资金
- National Foundation for Alzheimer's disease and related disorders
- Institut Pasteur de Lille
- Centre National de Genotypage
- Inserm
- FRC (fondation pour la recherche sur le cerveau)
- Rotary
- LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease)
- MEDIALZ Project - ERDF (European Regional Development Fund) [11001003]
- Conseil Regional Nord Pas de Calais
- Fondation pour la Recherche Medicale
- Caisse Nationale Maladie des Travailleurs Salaries
- Direction Generale de la Sante
- MGEN
- Institut de la Longevite
- Agence Francaise de Securite Sanitaire des Produits de Sante
- Aquitaine and Bourgogne Regional Councils
- Fondation de France
- joint French Ministry of Research/INSERM 'Cohortes et collections de donnees biologiques' program
- Eisai
- Wellcome Trust
- British Heart Foundation
- Chief Scientist Office of the Scottish Executive
- NIA [N01-AG-12100]
- National Heart, Lung and Blood Institute Contracts [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL70825, R01HL087641, R01HL59367, R01HL086694]
- National Human Genome Research Institute [U01HG004402]
- NIH Roadmap for Medical Research
- Austrian Science Fond (FWF) [P20545-P05, P13180]
- Intramural Research Program of the NIH, National Institute on Aging
- NHLBI [HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC850863, U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393]
- National Institute of Neurological Disorders and Stroke (NINDS)
- National Institute on Aging (NIA) [R01AG023629, R01AG15928, R01AG20098, R01AG027058]
- National Center for Advancing Translational Sciences
- CTSI [UL1TR000124]
- National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) [DK063491]
- Medical Research Council (UK)
- European Commission Framework 6 project EUROSPAN [LSHG-CT-2006-018947]
- Republic of Croatia Ministry of Science, Education and Sports [108-1080315-0302]
- Netherlands Organization for Scientific Research (NWO)
- Internationale Stichting Alzheimer Onderzoek (ISAO)
- Hersenstichting Nederland (HSN)
- Centre for Medical Systems Biology (CMSB) in the framework of the Netherlands Genomics Initiative (NGI)
- Russian Foundation for Basic Research (RFBR)
- National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195]
- Affymetrix, Inc [N02-HL-6-4278, U01 HL096917, R01 HL093029]
- Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine
- Boston Medical Center
- National Institute of Neurological Disorders and Stroke [NS17950]
- National Institute of Aging [U01 AG049505, AG033193, AG008122, AG16495]
- Agence National de la Recherche
- Leducq Foundation
- National Heart, Lung and Blood Institute [HL054464, HL054457, HL054481, HL071917, HL87660, HL043851, HL080467]
- National Institute of Neurological Disorders and Stroke of the National Institutes of Health [NS041558]
- Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6]
- Scottish Funding Council [HR03006]
- Academy of Finland
- Finnish Diabetes Research Society
- Folkhalsan Research Foundation
- Novo Nordisk Foundation
- Finska Lakaresallskapet
- Signe and Ane Gyllenberg Foundation
- University of Helsinki
- Ministry of Education
- Ahokas Foundation
- Emil Aaltonen Foundation
- Juho Vainio Foundation
- Wellcome Trust [WT089062]
- University of Newcastle's Strategic Initiative Fund
- Vincent Fairfax Family Foundation
- Hunter Medical Research Institute
- Italian Ministry of Health [ICS 110.1RS97.71]
- US National Institute on Aging [N01[AG]916413, N01[AG]821336, 263 MD 9164 13, 263 MD 821336]
- Intramural Research Program, National Institute on Aging, National Institutes of Health
- BBSRC
- Royal Society
- Chief Scientist Office of the Scottish Government
- Research Into Ageing
- UK Biotechnology and Biological Sciences Research Council (BBSRC)
- Engineering and Physical Sciences Research Council (EPSRC)
- Economic and Social Research Council (ESRC)
- MRC
- NHMRC [401184]
- Australian National Health & Medical Research Council [350833, 568969]
- Capacity Building Grant [568940]
- NHMRC Project [525453]
- National Institutes of Health [CA87969, CA49449, HL34594, U01HG004399, DK058845, CA65725, CA67262, CA50385, 5UO1CA098233, EY09611, EY015473, HG004728, HL35464, CA55075, CA134958, DK070756]
- MRC Human Genetics Unit
- Arthritis Research UK
- European Union [LSHG-CT-2006-018947]
- Bristol-Myers Squibb
- Netherlands Heart Foundation [2001 D 032]
- European commission [223004]
- Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging) [050-060-810]
- Netherlands Organisation of Scientific Research NWO Investments [175.010.2005.011, 911-03-012]
- Research Institute for Diseases in the Elderly [014-93-015]
- Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project [050-060-810]
- Erasmus Medical Center
- Erasmus University, Rotterdam
- Netherlands Organization for the Health Research and Development (ZonMw)
- Research Institute for Diseases in the Elderly (RIDE)
- Ministry of Education, Culture and Science
- Ministry for Health, Welfare and Sports
- European Commission 49 (DG XII)
- Municipality of Rotterdam
- ZonMW Veni Grant [916.13.054]
- NIA Grants [P30AG10161, R01AG15819, R01AG17917, R01AG30146, K08AG34290, K25AG41906]
- Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403]
- Ministry of Cultural Affairs
- Social Ministry of the Federal State of Mecklenburg-West Pomerania
- National Cancer Institute [CA047988]
- Donald W Reynolds Foundation
- Fondation Leducq
- Amgen
- Biotechnology and Biological Sciences Research Council [BB/F019394/1] Funding Source: researchfish
- Chief Scientist Office [CZB/4/710, CZB/4/505, ETM/55, CZD/16/6/4] Funding Source: researchfish
- Medical Research Council [MC_PC_U127561128, G0700704, MR/K026992/1] Funding Source: researchfish
- BBSRC [BB/F019394/1] Funding Source: UKRI
- MRC [MC_PC_U127561128, G0700704] Funding Source: UKRI
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 x 10(-8)) and in the joint discovery and replication meta-analysis (P-value = 3.28 x 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= 4x10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value = 7.22 x 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value = 1.36 x 10(-11)) and neuron cell-cell adhesion (P-value = 1.48 x 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.
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