Genetic aetiology of obesity

Lead Research Organisation: MRC Epidemiology Unit

Abstract

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.

Publications

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Brandys MK (2010) Are recently identified genetic variants regulating BMI in the general population associated with anorexia nervosa? in American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics

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Böger CA (2011) CUBN is a gene locus for albuminuria. in Journal of the American Society of Nephrology : JASN

 
Description A genome-wide association study for weight gain in large population-based cohorts
Amount £191,000 (GBP)
Organisation Unilever 
Sector Private
Country United Kingdom
Start 02/2006 
End 02/2011
 
Description BHF Project Grant
Amount £279,688 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2008 
End 01/2012
 
Description Diet, obesity and Genes 'DIOGenes' (14.5m euros across 37 participants)
Amount £162,020 (GBP)
Funding ID 513946 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 01/2005 
End 12/2009
 
Description MRC/GSK Pilot programme to identify new targets and biomarkers
Amount £1,000,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 02/2008 
End 01/2010
 
Description Collaborations with the Chinese Academy of Science (Professor Huaixing Li) 
Organisation Chinese Academy of Sciences
Department Laboratory of Signal Transduction and Nutrition-related Diseases
Country China 
Sector Academic/University 
PI Contribution We work together with prfoessor Huaixing Li to examine wehther observations/associations in white Europeans can be confirmed in East Asians.
Collaborator Contribution This collaboration has results in a number of papers published in good to high impact papers.
Impact We have already published many papers together and various others are in progress.
Start Year 2008
 
Description GIANT (Genetic Investigation of Anthropometric Traits) consortium 
Organisation Broad Institute
Country United States 
Sector Charity/Non Profit 
PI Contribution This consortium brings together genome-wide association data from 44 cohorts. Scientist in this programme have lead the meta-analysis on BMI (one of the 3 traits studied). We have contributed genome-wide association from EPIC-GWA study and Fenland study and also replication data on the the full EPIC-Norfolk study.
Collaborator Contribution Discovery of genes for height, BMI and waist. We have published various high impact papers (Nature Genetics and PLoS Genetics) together on height, BMI and waist and we are in the process to writing a new series of papers on these traits.
Impact We have published various high impact papers (Nature Genetics and PLoS Genetics) together on height, BMI and waist and we are in the process to writing a new series of papers on these traits. PMID: 18454148; PMID: 19079261; PMID: 19557161
Start Year 2007
 
Description GIANT Consortium 
Organisation Mount Sinai Hospital (USA)
Country United States 
Sector Hospitals 
PI Contribution GIANT is a consortium of cohort studies with GWAS data which are used to examine the genetic basis of obesity and anthropometric traits.
Collaborator Contribution Multiple cohort partners.
Impact Multiple collaborative papers on the genetic determinants of obesity and related traits.
Start Year 2008
 
Description Article in WeightWatcher's Magazine 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Publication in a popular magazine, covering a paper that had been published in 2010.

Reaching a large lay audience
Year(s) Of Engagement Activity 2011
 
Description Article in popular women's magazine 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Publication of an article on the work done in my research group.

No notable recognition other publicity for our unit
Year(s) Of Engagement Activity 2011
 
Description Documentary 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Television documentary on causes of obesity for Channel 4 called Gok Wan: too fat too young.

Awareness of genetic susceptibility for obesity
Year(s) Of Engagement Activity 2009
 
Description Press Release 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Press release following the publication of a paper on the discovery of genes for body fat percentage.

The press release was widely covered by many media.
Year(s) Of Engagement Activity 2011
 
Description Press release 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact We led the GIANT collaboration that identified 18 new obesity susceptibility loci and 14 new fat distribution loci.

Our work was reported in many newspapers and websites worldwide and I gave interviews for radio.
Year(s) Of Engagement Activity 2010
 
Description Press release 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact We showed that the genetic susceptibility to obesity was reduced by 40% when people are physical active for around 30min per day.

Our work was published in mainy newspapers in the UK (in cluding The Sun and Daily Mail) and worldwide; and on many websites. I also gave radio presentations for BBC, and for South African and Belgian radio.
Year(s) Of Engagement Activity 2010
 
Description Press release 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Press release following a paper on the fact that physical activity can reduce the effects of FTO on BMI

reaching a large lay audience via various media.
Year(s) Of Engagement Activity 2011