Testing replication of a 5-SNP set for general cognitive ability in six population samples

Abstract

A 5-single nucleotide polymorphism (SNP) set has been associated with general cognitive ability in 5000 7-year-old children from the Twins Early Development Study (TEDS). Four of these SNPs were identified through a 10 K microarray analysis and one was identified through a targeted analysis of brain-expressed genes. The present study tested this association with general cognitive ability in six population samples of varying size and age from Australia, the UK (Scotland and England) and the Netherlands. Results from the largest sample (N ¼ 1310) approached significance (P ¼ 0.06) in the direction of the original finding, but results from the other samples (N ¼ 205 -758) were mixed. A meta-analysis of the results -allowing for effect size heterogeneity between samples -yielded a non-significant correlation (r ¼ À0.01, P ¼ 0.57), indicating that this SNP set was not associated with general cognitive ability in the populations studied.

Challenges in phenotype definition in the whole-genome era: multivariate models of memory and intelligence

“…Five of the 10,000 typed single nucleotide polymorphisms (SNPs) (located on chromosomes 2, 6, 7, 11, and 18) showed replicable association but together accounted for less than 1% of ability variance. Though these associations were confirmed by individual genotyping, a meta-analysis across six population samples did not support an association between the 5-SNP set and (g); (Luciano et al, 2008). Of course, at the time this study was conducted, the prevailing technology was far less developed than today, thus prompting both the use of the pooled DNA method and genotyping at “only” 10,000 SNPs, while today GWAS routinely genotype each individual case at more than 350,000 SNPs.…”

The Impact of Genetic Research on our Understanding of Normal Cognitive Ageing: 1995 to 2009

“…The group also created composite SNP sets from the associated SNPs that accounted for between 0.76 and 1% of the variance and which would require smaller numbers for replication (sample sizes of 700 to 800 for 80% power). However, a collaboration of four independent groups (total n=3539) failed to replicate the 5 SNP set or the composite set results derived from the 10 K platform (Luciano et al 2008). Hence, we can only conclude that the 10 k microarray/pooling technique may be inadequate to find polymorphisms associated with cognition and that replication of the 100 and 500 k findings is required to confirm the small effect sizes.…”

“…The use of principal component analysis and genotype-imputation (Huang et al 2009b) means that research groups with diverse cognitive measures and genotypes from different microarrays can combine data. These collaborations are beginning to emerge for the study of individual genes (Luciano et al 2008;Luciano et al 2009a), and several large cognitive groups in the UK will soon be combining their microarray data for joint analysis. Whether this proves sufficient remains to be seen and a global call for collaboration should be encouraged in order to increase power and provide additional conformation.…”

Meeting the Challenges of Neuroimaging Genetics

“…Moreover, the sample has already been employed to test the replicability of genetic effects on cognition reported by other groups around the world (e.g., Bates et al, 2007; Luciano et al, 2008). Of course, there might be cultural factors unique to the Australian study that could conceivably impact upon the imaging results, introducing environmental variability when comparing the sample with others around the world.…”