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GWAS for executive function and processing speed suggests involvement of the CADM2 gene
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
ID
4377214
Author(s)
Ibrahim-Verbaas, C. A.; Bressler, J.; Debette, S.; Schuur, M.; Smith, A. V.; Bis, J. C.; Davies, G.; Trompet, S.; Smith, J. A.; Wolf, C.; Chibnik, L. B.; Liu, Y.; Vitart, V.; Kirin, M.; Petrovic, K.; Polasek, O.; Zgaga, L.; Fawns-Ritchie, C.; Hoffmann, P.; Karjalainen, J.; Lahti, J.; Llewellyn, D. J.; Schmidt, C. O.; Mather, K. A.; Chouraki, V.; Sun, Q.; Resnick, S. M.; Rose, L. M.; Oldmeadow, C.; Stewart, M.; Smith, B. H.; Gudnason, V.; Yang, Q.; Mirza, S. S.; Jukema, J. W.; deJager, P. L.; Harris, T. B.; Liewald, D. C.; Amin, N.; Coker, L. H.; Stegle, O.; Lopez, O. L.; Schmidt, R.; Teumer, A.; Ford, I.; Karbalai, N.; Becker, J. T.; Jonsdottir, M. K.; Au, R.; Fehrmann, R. S.; Herms, S.; Nalls, M.; Zhao, W.; Turner, S. T.; Yaffe, K.; Lohman, K.; van Swieten, J. C.; Kardia, S. L.; Knopman, D. S.; Meeks, W. M.; Heiss, G.; Holliday, E. G.; Schofield, P. W.; Tanaka, T.; Stott, D. J.; Wang, J.; Ridker, P.; Gow, A. J.; Pattie, A.; Starr, J. M.; Hocking, L. J.; Armstrong, N. J.; McLachlan, S.; Shulman, J. M.; Pilling, L. C.; Eiriksdottir, G.; Scott, R. J.; Kochan, N. A.; Palotie, A.; Hsieh, Y. C.; Eriksson, J. G.; Penman, A.; Gottesman, R. F.; Oostra, B. A.; Yu, L.; DeStefano, A. L.; Beiser, A.; Garcia, M.; Rotter, J. I.; Nothen, M. M.; Hofman, A.; Slagboom, P. E.; Westendorp, R. G.; Buckley, B. M.; Wolf, P. A.; Uitterlinden, A. G.; Psaty, B. M.; Grabe, H. J.; Bandinelli, S.; Chasman, D. I.; Grodstein, F.; Raikkonen, K.; Lambert, J. C.; Porteous, D. J.; Generation, Scotland; Price, J. F.; Sachdev, P. S.; Ferrucci, L.; Attia, J. R.; Rudan, I.; Hayward, C.; Wright, A. F.; Wilson, J. F.; Cichon, S.; Franke, L.; Schmidt, H.; Ding, J.; de Craen, A. J.; Fornage, M.; Bennett, D. A.; Deary, I. J.; Ikram, M. A.; Launer, L. J.; Fitzpatrick, A. L.; Seshadri, S.; van Duijn, C. M.; Mosley, T. H.
GWAS for executive function and processing speed suggests involvement of the CADM2 gene
Journal
Molecular Psychiatry
Volume
21
Number
2
Pages / Article-Number
189-197
Keywords
Aged; Aged, 80 and over; Cell Adhesion Molecules/*genetics/physiology; Cognition/physiology; Cohort Studies; European Continental Ancestry Group/genetics; Executive Function/*physiology; Female; Genetic Association Studies; Genetic Variation/genetics; Genome-Wide Association Study; Genomics; Humans; Introns; Male; Middle Aged; Neuropsychological Tests; Polymorphism, Single Nucleotide; gamma-Aminobutyric Acid
Mesh terms
Aged; Aged, 80 and over; Cell Adhesion Molecules, physiology; Cognition, physiology; Cohort Studies; European Continental Ancestry Group, genetics; Executive Function, physiology; Female; Genetic Association Studies; Genetic Variation, genetics; Genome-Wide Association Study; Genomics; Humans; Introns; Male; Middle Aged; Neuropsychological Tests; Polymorphism, Single Nucleotide; gamma-Aminobutyric Acid
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 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=4 x 10(-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.
