Aims

Genome Wide Complex Trait Analysis (GCTA) has been applied to Genome Wide Association Study (GWAS) data sets of cognitive ability to show that around half of the phenotypic variation is tagged by common variants (Davies et al., 2011). However, GCTA cannot provide information regarding which variants are more important. This study aims to find regions in the genome that make a significant contribution to the GCTA heritability estimate. Three groups of single nucleotide polymorphisms (SNPs) will be formed; the first group will consist of all SNPs available for use, the second set will consist of SNPs found in genes, whereas the third will be formed from SNPs that are found between genes. GCTA will be perfomed on each group allowing for both the genic and intergenic SNP-sets to be tested against 0 in order to determine if they each make a significant contribution toward intelligence differences. In addition the two groups will be compared against each other to show which regions matter most to human intelligence differences. Using GCTA in this way will help to show that variants within genes account for a significant proportion of the heritability of human intelligence. This will justify the use of gene and gene-set based analyses well as indicate which areas of the genome are of particular importance to cognitive ability.

Hypothesis

It is expected that for general cognitive ability both the geneic and the intergenic SNPs will make significant contributions to the total heritiability estimate. It is also expected that SNPs found within genes will also make a greater contribution toward the heritability estimates than SNPs found between genes as has been demonstrated for height (Yang et al., 2011) and indicated for schizophrenia (Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014).

Exposure variables

GCTA has been performed previously on general cognitive ability in The Avon Longitudinal Study of Parents and Children (ALSPAC) group (Benyamin et al., 2013) as it has a suitably large sample size (5517 at age 9) and an execellent test to derive an Intelligence Quotent (IQ) estimate, namely the Wecshler Intelligence Scale for Children-III (WISC-III). For the proposed analyses to take place, the genotype data along with Verbal (Information, similarities, arithmetic, vocabulary, and comprehenssion) and Performance (picture completion, coding, picture arrangement. Block design, and object assembly) subscales of the WISC-III will be used to form an IQ score. GCTA analysis will be performed on this IQ score using all SNPs available for analysis. Next, the total set of SNPs will be divided into genic and intergenic SNP-sets before GCTA is performed on both SNP-sets.

Outcome variables

The proportion of phenotypic varainace attributable to the genetic variation in each of the three groups will form the outcome variable.

Confounding variables

One potential source of confounding would be that the two SNP-sets could tag the same variants due to the existence of linkage disequilibrium.