Genetic aetiology of obesity

  • Loos, Ruth R. (PI)

Project Details


Almost 61% of adults in the UK are overweight (BMI?25) and 24% are obese (BMI?30). Although rapid globalization of the westernized way of life is fuelling this increasing prevalence, obesity is a common multifactorial disease that arises through the joint actions of multiple genetic and environmental factors.||This programme examines the genetic factors that contribute to the development of obesity and also studies whether lifestyle factors can attenuate the role of these genetic factors. Therefore, we use a range of different epidemiological study designs and apply three main approaches. The first approach is the candidate gene approach that investigates genetic variants on the basis of established biological knowledge from animal studies or extreme case studies. In the second approach, we screen the whole genome for association of any of the 2.2M genetic variants with BMI of obesity risk. This approach does not assume prior knowledge but hoped to discover new loci that may help expand our understanding of the underlying biology of obesity. In the third approach, we study how lifestyle affects the genetic susceptibility of a person and we test whether individuals who may be genetically susceptible to become obese can overcome this susceptibility by living a healthy lifestyle.

Technical Summary

The prevalence of obesity and overweight continues to increase steadily. Although changes in lifestyle are driving this epidemic, not all people become obese. This observation highlights that obesity is a common multifactorial condition that arises through the joint actions of genes and environment. |The aims of this programme are to use epidemiological methods; |[1] to identify genetic variants associated with obesity and related traits through two main approaches; [a] a hypothesis generating approach by GWA studies, and [b] a hypothesis-driven approach by candidate gene studies, and |[2] to determine the mode of action of the newly identified and established obesity-susceptibility loci, [a] by examining traits intermediate to obesity, and [b] by examining the role of the obesity-susceptibility loci in the development of diseases or traits presumed to result from obesity through Mendelian randomisation studies, and|[3] to identify how obesity-susceptibility genes interact with lifestyle factors such as physical activity and diet through gene-environment interaction studies.|The main approach applied in this programme is genome-wide association, a hypothesis-generating approach that aims to discover novel genetic variants that predispose to a disease or a trait. Over the past three years, this programme has contributed to the discovery of nine established obesity-susceptibility loci by leading the analyses of three waves of genome-wide association studies. We are currently leading the fourth wave of genome-wide association studies as part of the GIANT consortium including data on more than 126,000 individuals which promises to identify more obesity-susceptibility loci. Besides testing for association with BMI, we also examine associations with more refined obesity-related traits and with traits intermediate to the development of obesity..|We will continue to identify obesity-susceptibility genes through large-scale meta-analyses of candidate genes variants. Candidate gene studies aim to validate observations from animal models or extreme case studies at the population level. Therefore, our collaboration with colleagues at the MRC CORD and WT Sanger Institute is crucial as they will be the primary source for novel physiological insights.|This programme also studies how obesity-susceptibility genes interact with lifestyle factors such as physical activity and diet. We will examine whether the GWA-identified obesity-susceptibility variants as well as the established candidate genes (based on physiology) interact with lifestyle factors.|By studying the genetics of obesity, we aim to gain insight in the complex physiology that governs the regulation of energy balance. Translation of these new findings into clinical practice will require collaboration with basic, translational and clinical scientists.

Effective start/end date1/10/0730/04/13


  • Medical Research Council: $9,471,864.00


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