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

Ibrahim-Verbaas, C. A. and Bressler, J. and Debette, S. and Schuur, M. and Smith, A. V. and Bis, J. C. and Davies, G. and Trompet, S. and Smith, J. A. and Wolf, C. and Chibnik, L. B. and Liu, Y. and Vitart, V. and Kirin, M. and Petrovic, K. and Polasek, O. and Zgaga, L. and Fawns-Ritchie, C. and Hoffmann, P. and Karjalainen, J. and Lahti, J. and Llewellyn, D. J. and Schmidt, C. O. and Mather, K. A. and Chouraki, V. and Sun, Q. and Resnick, S. M. and Rose, L. M. and Oldmeadow, C. and Stewart, M. and Smith, B. H. and Gudnason, V. and Yang, Q. and Mirza, S. S. and Jukema, J. W. and deJager, P. L. and Harris, T. B. and Liewald, D. C. and Amin, N. and Coker, L. H. and Stegle, O. and Lopez, O. L. and Schmidt, R. and Teumer, A. and Ford, I. and Karbalai, N. and Becker, J. T. and Jonsdottir, M. K. and Au, R. and Fehrmann, R. S. and Herms, S. and Nalls, M. and Zhao, W. and Turner, S. T. and Yaffe, K. and Lohman, K. and van Swieten, J. C. and Kardia, S. L. and Knopman, D. S. and Meeks, W. M. and Heiss, G. and Holliday, E. G. and Schofield, P. W. and Tanaka, T. and Stott, D. J. and Wang, J. and Ridker, P. and Gow, A. J. and Pattie, A. and Starr, J. M. and Hocking, L. J. and Armstrong, N. J. and McLachlan, S. and Shulman, J. M. and Pilling, L. C. and Eiriksdottir, G. and Scott, R. J. and Kochan, N. A. and Palotie, A. and Hsieh, Y. C. and Eriksson, J. G. and Penman, A. and Gottesman, R. F. and Oostra, B. A. and Yu, L. and DeStefano, A. L. and Beiser, A. and Garcia, M. and Rotter, J. I. and Nothen, M. M. and Hofman, A. and Slagboom, P. E. and Westendorp, R. G. and Buckley, B. M. and Wolf, P. A. and Uitterlinden, A. G. and Psaty, B. M. and Grabe, H. J. and Bandinelli, S. and Chasman, D. I. and Grodstein, F. and Raikkonen, K. and Lambert, J. C. and Porteous, D. J. and Generation, Scotland and Price, J. F. and Sachdev, P. S. and Ferrucci, L. and Attia, J. R. and Rudan, I. and Hayward, C. and Wright, A. F. and Wilson, J. F. and Cichon, S. and Franke, L. and Schmidt, H. and Ding, J. and de Craen, A. J. and Fornage, M. and Bennett, D. A. and Deary, I. J. and Ikram, M. A. and Launer, L. J. and Fitzpatrick, A. L. and Seshadri, S. and van Duijn, C. M. and Mosley, T. H.. (2016) GWAS for executive function and processing speed suggests involvement of the CADM2 gene. Molecular Psychiatry, 21 (2). pp. 189-197.

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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.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Human Genetics (Cichon)
UniBasel Contributors:Cichon, Sven
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:23 Apr 2019 17:38
Deposited On:23 Apr 2019 17:38

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