Computational protocol: DNA Evidence for Strong Genome-Wide Pleiotropy of Cognitive and Learning Abilities

Similar protocols

Protocol publication

[…] The sample was drawn from the Twins Early Development Study (TEDS), which is a multivariate longitudinal study that recruited over 11,000 twin pairs born in England and Wales in 1994, 1995 and 1996 (Haworth et al. ; Oliver and Plomin ). TEDS has been shown to be representative of the UK population (Kovas et al. ). The project received approval from the Institute of Psychiatry ethics committee (05/Q0706/228) and parental consent was obtained prior to data collection.Cognitive and DNA data were available for 3,747 11- and 12-year-old children whose first language was English and had no major medical or psychiatric problems. From that sample, 3,665 DNA samples were successfully hybridized to Affymetrix GeneChip 6.0 SNP genotyping arrays using standard experimental protocols as part of the WTCCC2 project (for details see Trzaskowski et al. ). In addition to nearly 700,000 genotyped SNPs, more than one million other SNPs were imputed from HapMap 2, 3 and WTCCC controls using IMPUTE v.2 software (Howie et al. ). 3,152 DNA samples (1,446 males and 1,706 females) survived quality control criteria for ancestry, heterozygosity, relatedness, and hybridization intensity outliers. To control for ancestral stratification, we performed principal component analyses on a subset of 100,000 quality-controlled SNPs after removing SNPs in linkage disequilibrium (r2 > 0.2) (Fellay et al. ). Using the Tracy–Widom test (Patterson et al. ), we identified 8 axes with p < 0.05, which were used as covariates in GCTA analyses.The mean age of the sample was 11.5 years (SD = 0.66). The sample sizes for the GCTA results shown in Table  are 2,325 for ‘g’ and language, 2,238 for ‘g’ and mathematics, 2,250 for ‘g’ and reading, and 2,296 for height and weight. For the twin analyses, cognitive data were available for 5,434 twin pairs (Davis et al. ); however, the twin analyses presented here were based only on twins included in the GCTA analyses in order to provide a more precise comparison between GCTA and twin-study results. The numbers of twin pairs were 2,205, 2,095, 2,104 and 2,162, respectively. [...] Conceptually, the amount of phenotypic variance, or covariance, explained by genetic factors is estimated by a comparison of a matrix of pairwise genomic similarity to a matrix of pairwise phenotypic similarity (Yang et al. ). Before the variance or covariance can be decomposed into genetic and residual components, we need to calculate pairwise genomic similarity between all pairs of individuals in the sample using all genetic markers genotyped on the SNP array. Because the GCTA package uses a random effects model to estimate genetic effects from a sample of unrelated individuals in the population, any pair whose genetic similarity is equal to or greater than a fourth cousin is removed (estimate of pairwise relatedness >0.025). In univariate analysis, the variance of a trait can be partitioned using residual maximum likelihood into genetic and residual components. Detailed description of this method can be found in GCTA publications (Yang et al. , , ). The bivariate method extends the univariate model by relating the pairwise genetic similarity matrix to a phenotypic covariance matrix between traits 1 and 2 (Lee et al. ). The eight principal components described earlier were used as covariates in our bivariate GCTA analyses; as mentioned in the previous section, all phenotypes were age- and sex-regressed prior to analysis.Twin modelling. The twin design and model-fitting is discussed elsewhere (Plomin et al. ). We fit a bivariate Cholesky decomposition using OpenMx (Boker et al. ), which provided a direct comparison with the bivariate GCTA. The correlated factor solution is the least restricted model allowing variables to correlate with one another via genetic, shared environment, and non-shared environment. Because previous analyses of these data indicated nonsignificant differences in model-fitting results between males and females (Kovas et al. ), we combined same-sex and opposite-sex DZ twin pairs in order to increase the power of the analyses. […]

Pipeline specifications

Software tools IMPUTE, GCTA, OpenMx
Applications Miscellaneous, GWAS
Organisms Homo sapiens