B693 - Confirmation of Genome-Wide association findings for obesity and obesity related traits - 01/01/1900

B number: 
Principal applicant name: 
Dr Ruth Loos (University of Cambridge, UK)
Ken Ong (University of Cambridge, UK), Nick Wareham (University of Cambridge, UK)
Title of project: 
Confirmation of Genome-Wide association findings for obesity and obesity related traits
Proposal summary: 

Recent advances in high-throughput genotyping technologies, coupled with the development of massive databases such as the International HapMap Project that catalogues millions of SNPs (single nucleotide polymorphisms), have set the stage for genome-wide association studies. Genome-wide association (GWA) studies are designed as two- or three phased studies. The first phase requires a dense set of hundreds of thousands of SNPs across the human genome, genotyped in a large sample of well-characterised individuals. The second and third phases aim to replicate and fine-map the most significant findings of the first phase in other large cohorts. Eventually, genome-wide association studies will identify new gene variants, previously unanticipated, that will contribute to a better understanding of the etiology of common disease and complex traits.

Our GWA study is designed for the identification of new, unanticipated gene variants that contribute to variation in obesity as well as BMI, and related traits, including age at menarche. This GWA study is undertaken as a collaboration between the MRC Epidemiology Unit and the WT Sanger Institute (Dr Ines Barroso) using a case-cohort design. The 1713 cases (defined as those with a BMI greater than 30kg/m2) and a random control cohort of 2200 individuals have been selected from the EPIC-Norfolk prospective cohort study, a population-based cohort of 25.663 men and women aged 40-79 years recruited in Norfolk, UK between 1993 and 1997. All 3913 individuals have been genotyped for two dense SNP-chips; i.e. the 500K GeneChip Mapping Sets of Affymetrix and the Sentrix HumanHap300 BeadChip of Illumina. We are currently analysing associations of this genome-wide data with obesity as a dichotomous outcome in the case-cohort study and with BMI, age at menarche and various metabolic variables as quantitative traits within the cohort study.

In order to increase the power to detect true positive signals Phase 1 will be expanded by performing a meta-analysis of two other cohorts with similar GWA phenotypic and data. We have recently established a long term collaboration with Vincent Mooser (GSK) and colleagues, who have performed a GWA study in the GSK-Lausanne cohort. The GSK-Lausanne population is comparable to the EPIC data as it is a cohort study of 6,205 Europid men and women from Lausanne, aged 35-75 years. This collaboration has a general aim to identify genes that contribute to various metabolic traits. The summary statistics from these GWA studies on these traits will be shared and meta-analysed at the MRC Epidemiology Unit.

Key to genomewide association studies is replication of the initial findings in more populations with similar characteristics. New genes identified by GWA will be taken forward for rapid confirmation studies in several large cohort studies. In addition to ALSPAC, these include a second equal sized case-cohort study within the EPIC cohort (n=3,900), the MRC-Ely study (n = 1,700), the MRC-Fenland study (currently n = 2,000), the Hertfordshire study (n = Outline 3,000), and the European Youth Heart study (n = 2,700).

Date proposal received: 
Monday, 1 January, 1900
Date proposal approved: 
Monday, 1 January, 1900
Endocrine, Obesity, Weight
Primary keyword: