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

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.

SUBMITTER: Ibrahim-Verbaas CA

PROVIDER: S-EPMC4722802 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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

Ibrahim-Verbaas C A CA Bressler J J Debette S S Schuur M M Smith A V AV Bis J C JC Davies G G Trompet S S Smith J A JA Wolf C C Chibnik L B LB Liu Y Y Vitart V V Kirin M M Petrovic K K Polasek O O Zgaga L L Fawns-Ritchie C C Hoffmann P P Karjalainen J J Lahti J J Llewellyn D J DJ Schmidt C O CO Mather K A KA Chouraki V V Sun Q Q Resnick S M SM Rose L M LM Oldmeadow C C Stewart M M Smith B H BH Gudnason V V Yang Q Q Mirza S S SS Jukema J W JW deJager P L PL Harris T B TB Liewald D C DC Amin N N Coker L H LH Stegle O O Lopez O L OL Schmidt R R Teumer A A Ford I I Karbalai N N Becker J T JT Jonsdottir M K MK Au R R Fehrmann Rsn R Herms S S Nalls M M Zhao W W Turner S T ST Yaffe K K Lohman K K van Swieten J C JC Kardia Slr S Knopman D S DS Meeks W M WM Heiss G G Holliday E G EG Schofield P W PW Tanaka T T Stott D J DJ Wang J J Ridker P P Gow A J AJ Pattie A A Starr J M JM Hocking L J LJ Armstrong N J NJ McLachlan S S Shulman J M JM Pilling L C LC Eiriksdottir G G Scott R J RJ Kochan N A NA Palotie A A Hsieh Y-C YC Eriksson J G JG Penman A A Gottesman R F RF Oostra B A BA Yu L L DeStefano A L AL Beiser A A Garcia M M Rotter J I JI Nöthen M M MM Hofman A A Slagboom P E PE Westendorp Rgj R Buckley B M BM Wolf P A PA Uitterlinden A G AG Psaty B M BM Grabe H J HJ Bandinelli S S Chasman D I DI Grodstein F F Räikkönen K K Lambert J-C JC Porteous D J DJ Price J F JF Sachdev P S PS Ferrucci L L Attia J R JR Rudan I I Hayward C C Wright A F AF Wilson J F JF Cichon S S Franke L L Schmidt H H Ding J J de Craen Ajm A Fornage M M Bennett D A DA Deary I J IJ Ikram M A MA Launer L J LJ Fitzpatrick A L AL Seshadri S S van Duijn C M CM Mosley T H TH

Molecular psychiatry 20150414 2

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 ...[more]

PMID: 25869804

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Project description:IntroductionProcessing speed and executive function are often impaired after stroke and in typical aging. However, there are no reliable neurological markers of these cognitive impairments. The trail making test (TMT) is a common index of processing speed and executive function. Here, we tested candidate MRI markers of TMT performance in a cohort of older adults and individuals with chronic stroke.MethodsIn 61 older adults and 32 individuals with chronic stroke, we indexed white matter structure with region-specific lesion load (of white matter hyperintensities (WMHs) and stroke lesions) and diffusion tensor imaging (DTI) from four regions related to TMT performance: the anterior thalamic radiations (ATR), superior longitudinal fasciculus (SLF), forceps minor, and cholinergic pathways. Regression modelling was used to identify the marker(s) that explained the most variance in TMT performance.ResultsDTI metrics of the ATR related to processing speed in both the older adult (TMT A: β = -3.431, p < 0.001) and chronic stroke (TMT A: β = 11.282, p < 0.001) groups. In the chronic stroke group executive function was best predicted by a combination of ATR and forceps minor DTI metrics (TMT B: adjustedR2 = 0.438, p < 0.001); no significant predictors of executive function (TMT B) emerged in the older adult group. No imaging metrics related to set shifting (TMT B-A). Regional DTI metrics predicted TMT performance above and beyond whole-brain stroke and WMH volumes and removing whole-brain lesion volumes improved model fits.ConclusionsIn this comprehensive assessment of candidate imaging markers, we demonstrate an association between ATR microstructure and processing speed and executive function performance. Regional DTI metrics provided better predictors of cognitive performance than whole-brain lesion volumes or regional lesion load, emphasizing the importance of lesion location in understanding cognition. We propose ATR DTI metrics as novel candidate imaging biomarker of post-stroke cognitive impairment.

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

Publications

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

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