Heritability and genetic association analysis of two cognition phenotypes in white European adults

Summary

This study examined the genetic contribution to individual differences
of prospective memory and verbal fluency cognition traits in
approximately 5800 phenotyped unrelated adults from the England
Longitudinal Study of Ageing (ELSA). The heritability of the cognitive
traits in unrelated individuals was estimated using the Illumina
HumanOmni2.5 array. A genome-wide association analysis was also carried
out using these data. The estimated heritability following adjustment
for age and gender for memory was h2= 0.17 (0.07) and fluency: h2= 0.38
(0.07). Genome-wide assessment revealed significant evidence of
association with memory for two SNPs: rs77287008 and rs9622280 on
chromosome 22, located near the RBFOX2 (RNA Binding Protein, Fox-1
Homolog), p< 4× 10-8. For verbal fluency, one intergenic SNP rs952684 near IMPAD1 (Inositol Monophosphatase Domain Containing 1) with p < 7 × 10-8 showed suggestive evidence of association. Functional bioinformatics annotation analysis implies that SNP rs77287008 in the RBFOX2 region has a downstream, non-protein-coding effect indicated by a PHRED CADD score (C-score) = 15.0, denoting a pathogenic/deleterious effect. Significant heritabilities for both traits suggest a role for genetic contributors to memory and verbal fluency, and in the case of memory, this is supported by the identification of genetic association signals in a functionally plausible candidate. To replicate these findings, data will be meta-analysed with three additional studies including Understanding Society, resulting in approximately 20000 participants. Additionally, cohorts with cognition phenotypes are available to replicate the most significant SNPs from an extra 7500 samples from studies that have been genotyped using the Illumina CardioMetabochip array.