General Aims : Our objective in this project is to use individual genotyping and genome-wide association studies (GWAS) in two UK population cohorts , one a family-based adult cohort (twins) and the second a prospective study of children with parental information (ALSPAC). Both have overlapping multiple intermediate phenotypes useful to uncover novel susceptibility genes, explore gene-gene and gene-environment interactions and advance understanding about gene networks which influence disease susceptibility. The other wider aim is to provide a UK resource of several finely genotyped and complimentary population cohorts with overlapping phenotypes for replication.

Specific Aims: The specific project aim is to use existing DNA from a sub-cohort of heavily phenotyped 1,500 dizygous (DZ) twins and 1500 unrelated MZ twins to perform individual genotyping using 300k Illumina Bead Chip Array. We will then conduct a genome-wide association analysis of this data using both total association and family-based statistics to test for associations with extensive existing phenotype and environmental data (i.e. greater than 1000 phenotypes) we have collected over the past 15 years GWAS projects survey common genetic variation by testing a dense set of single nucleotide polymorphisms (SNP) across the genome and we expect this will be an efficient method to uncover novel genes, gene-gene interactions and gene-environment interactions that are relevant to common chronic diseases

Specific Aim 1: Genotype approximately 317,000 SNPs (Illumina Hap300 beadChip) in each of 1,000 female Caucasian twin individuals (500 pairs) and 1000 ALPAC children starting October 2006. Test for association with 20 primary phenotypes related to cardiovascular, metabolic, respiratory and bone and other common complex genetic diseases. Test for stratification and perform test for total and family-based association with the primary phenotypes (First phase).

Specific Aim 2: Compare results of overlapping phenotypes with other genotyped cohorts (EPIC and 1958BC) to obtain replications and between adult and child populations to examine age-gene interactions for the same phenotype. Note these other cohorts will initially have been genotyped with 500,000 Affymetrix SNPs. In addition, the 1958BC will have also been typed with the Illumina 550K chip and the EPIC with the 317K chip. Thus all samples will have data on the 317K SNP set but some comparisons will be region rather than SNP specific.

Specific Aim 3: Use the data from the second wave of genotyping in TwinsUK and ALSPAC for further confirmatory association studies. The added power will allow detection of gene effects of more modest influence and again replicated in the other cohorts. In any gene shown to have compelling association from first and second phase, resequence the promoter (+2kb up stream), 5'UTR exons and 3'UTR (+2kb down stream), in 50 individuals selected from opposite ends of the associated trait distribution. This will fully characterise genetic variation in any genes showing compelling association and confirm the pattern of linkage disequilibrium and the HT-SNPs.

Specific Aim 4: Share the data with other investigators - as the amount of data generated in this multiple phenotype approach will be immense, it will be impossible for any single group to analyse. The nature of the cohorts makes it ideal to be used as a control group for female Caucasian case series and children.

Specific Aim 5: Use the results after phase 1 and 2 to assess value of extending the genotyping to the whole twin and ALSPAC sample..