1. A quantitative trait locus not associated with cognitive ability in children: a failure to replicate Hill, L. et al.

2. In 1998, the authors had reported results suggesting that the Insulin-like growth factor-2 receptor, IGF2R was associated with general cognitive ability (g) in two independent case-control samples of children selected for very high g (cases) or for average g (controls).

3. The authors genotyped 47 simple- sequence repeat (SSR) DNA markers in a region of Chromosome 6. In two independent samples, they found significant associations for one of the SSR markers, which was in the gene IGF2R.

4. The SSR marker in the IGF2R gene involved two nucleotide base pairs (TG in this case) that repeated several times; the number of repeats varies and is stably inherited. One allele (allele 5) for this TG repeat marker yielded frequencies of about 30% in the two high-g groups and about 15% in the two control groups with average g, with a p-value of 0.02 in each of the two samples and a combined p- value of 0.001.

5. They also found higher than average allele 5 frequencies in two groups high in mathematics ability or especially high in verbal ability (p =0.06 and 0.08). The authors concluded that their results suggested IGF2R is associated with high g. Note: A Bonferroni correction for 47 comparisons would suggest that an appropriate p-value for a significant results might be –0.1 / 47 = 0.002.

6. Replication of the original study The authors stated that they hoped another group would independently attempt to replicate their results in another study population. They were aware of the likelihood of false positive results when looking for quantitative trait loci (QTLs), particularly as the effect size was small and their study used many DNA markers. However, no other group performed such a study, so they did one themselves.

7. The new sample was as large as the original two studies combined, and was obtained using the same procedures. The samples were restricted to non- Hispanic Caucasian participants. This restriction was applied to reduce the likelihood that differences in marker allele frequencies between the groups would be due to ethnic stratification.

8. The results for the original studies gave a frequency of allele 5 of 32% in the high-g group and 16% in the control group. In the replication study, the frequency of allele 5 was 19% in the high-g group and 24% in the control group (p = 0.22). Tests of other alleles and genotypic comparisons also failed to replicate the previous results.

9. Discussion The replication study had as many subjects as the original studies combined, and had 98% power to detect a QTL association with an effect size as small as 1%. The authors conclude that the TG repeat polymorphism is not associated with high g. This results joins a list of many reported associations that have failed to be replicated in different study populations.

10. The most likely reasons for failure to replicate Complex traits such as cognitive ability are due to many genes and many variations of each gene, each having a very small effect on the trait. Different study populations may not have the same variations.

11. The individual genes and the individual variations within genes may interact, so that no one variation will affect the trait uniformly. Looking at variants one at a time will not detect such interactions, and the sample size available will usually be inadequate to examine interactions.