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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 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.
