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

Ibrahim-Verbaas, C. A. et al. (2016) GWAS for executive function and processing speed suggests involvement of the CADM2 gene. Molecular Psychiatry, 21(2), pp. 189-197. (doi:10.1038/mp.2015.37) (PMID:25869804) (PMCID:PMC4722802)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Stott, Professor David J and Ford, Professor Ian
Authors: 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. N., Herms, S., Nalls, M., Zhao, W., Turner, S. T., Yaffe, K., Lohman, K., van Swieten, J. C., Kardia, S. L. R., Knopman, D. S., Meeks, W. M., Heiss, G., Holliday, E. G., Schofield, P. W., Tanaka, T., Stott, D., 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., Nöthen, M. M., Hofman, A., Slagboom, P. E., Westendorp, R. G. J., Buckley, B. M., Wolf, P. A., Uitterlinden, A. G., Psaty, B. M., Grabe, H. J., Bandinelli, S., Chasman, D. I., Grodstein, F., Räikkönen, K., Lambert, J.-C., Porteous, D. J., 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. M., Fornage, M., Bennett, D. A., Deary, I. J., Ikram, M. A., Launer, L. J., Fitzpatrick, A. L., Seshadri, S., van Duijn, C. M., and Mosley, T. H.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Robertson Centre
Journal Name:Molecular Psychiatry
Publisher:Nature Publishing Group
ISSN:1359-4184
ISSN (Online):1476-5578
Copyright Holders:Copyright © 2016 Nature Publications
First Published:First published in Molecular Psychiatry 21(2):189-197
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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