What lies behind the causal impact of body mass index level and change on human health? Added value from complementary study design and deep metabolomic phenotyping.

PhD project (3/4 yr research project leading to independent research at the doctorate level)

Nicholas Timpson, George Davey Smith, Laura Corbin


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Rationale

There is strong evidence that BMI causally influences a wide range of health outcomes, but there is little understanding of the mechanisms driving BMI effects and at the level of the population we are limited in our ability to alter BMI. Targeted lifestyle and pharmaceutical interventions have failed to deliver large reductions in BMI and the only effective intervention is surgery. The proposal here is that metabolomic measurements can be used to understand the mechanisms by which BMI contributes to disease. Circulating metabolites are the product of genetic and non-genetic factors and are a useful read-out of physiological function. Despite the similarity of metabolites to complex health outcomes, it remains possible to map metabolites to genotypes and translatable biological pathways. Consequently, identifying metabolites important in the link between BMI and disease is a promising approach to further understanding BMI as a risk factor.

Aims & objectives

To better understand how body mass index (BMI) exerts an effect on human health and disease using metabolomics in complementary study designs and through applied genetic epidemiology. This is a PhD which will be coodrinated with a Wellcome Trust funded programme of research that explicitly seeks to use the most contemporary and powerful study designs, metabolic data capture and analytical techniques to explore BMI as a risk factor.

Methods

To show this and address the most promising and contested areas, we have assembled a unique set of experiments to examine this. We will address five key research questions by testing the hypotheses that:

(1) Specific circulating metabolites are affected by BMI change

(2) BMI has a causal effect on the human metabolite response to feeding

(3) BMI has a causal effect on the on the human faecal microbiome

(4) It is possible to causally map the human faecal microbiome onto the metabolome to extend the study of the microbiome

(5) Metabolites identified through population based causal analysis of BMI, intervention studies of BMI change, the effect of BMI on metabolic response and investigation of the microbiome (“BMI-metabolites”) have a causal effect on disease risk

Analyses for this PhD could pick up on any one of these target areas and aim to develop and explore it or a combination of evidence sources. All work will be carried out at the MRC Integrative Epidemiology Unit

References

Dombrowski et al BMJ 348, g2646 (2014).

Wake et al BMJ 346, f3092 (2013).

Corbin & Timpson Obesity. 2016 Aug;24(8):1630-8. doi: 10.1002/oby.21554.

Varbo et al Circ Res. 2015 Feb 13;116(4):665-73. doi: 10.1161/CIRCRESAHA.116.304846. Epub 2014 Nov 19.


Created on Nov. 14, 2016, 5:52 p.m.