Background: Obesity is a multifactorial disease caused by the interplay of environmental and genetic risk factors. With the prevalence of obesity more than doubling since 1980, this disease has become a global epidemic. The objectives of this research were to (1) review the current evidence of gene-environment interactions (GEI) in the field of obesity, (2) investigate novel GEI involving sedentary behaviour, sleep duration and alcohol consumption, (3) assess GEI using a cumulative environmental risk score, and (4) provide an overview of methodological weaknesses in GEI studies and provide suggestions for future directions.
Methods: The data for the gene-environment interaction analyses were collected from the EpiDREAM study: a cohort study including participants of six ethnic backgrounds from 17 countries worldwide. A subset of 17 423 participants with complete genotype and phenotype information was included in the analysis. Twenty-three obesity predisposing single nucleotide polymorphisms (SNPs) were analyzed independently and as a genetic risk score (GRS). Linear regression models were used to analyze these interactions.
Results: Heritability, monogenic and polygenic obesity studies provide converging evidence that obesity-predisposing genes interact with a variety of environmental exposures including physical activity and diet patterns. In the EpiDREAM cohort, we found that increased sedentary time did not interact with obesity predisposing SNPs or the GRS to modulate BMI. The interaction between sedentary time and physical activity was also not significant. We observed a U-shaped association between sleep duration and BMI and sleep duration did not appear to moderate the impact of the obesity predisposing SNPs or the GRS. However, we did observe an alcohol x FTO rs1421085 interaction, whereby increased alcohol consumption attenuated the impact of FTO rs1421085 variation on BMI. We also found that the combined effect of several environmental risk factors significantly modified the effect of FTO rs3751812 on BMI. Specifically, we found that the effect of the FTO rs3751812 SNP on BMI was over two times greater among those in the highest quartile of environmental risk compared to those in the lowest quartile. The GRS did not interact with any of the exposures tested.
Discussion: Our results indicate that sedentary behaviour did not moderate the impact of obesity predisposing genes, while alcohol consumption decreased the impact of variation in FTO rs3751812 on BMI. We also observed that variation in FTO rs3751812 interacted with a cumulative environmental risk score to moderate BMI. The growing body of GEI evidence has provided a deeper understanding of obesity aetiology and may have tremendous applications in the emerging field of personalized medicine and individualized lifestyle recommendations. Although the number of gene-environment interaction analyses has increased rapidly across multiple disciplines, addressing methodological concerns such as statistical modeling, confounding, biological assumptions and measurement precision will be necessary to fully exploit the potential of the GEI field. With the development of new methodological and measurement techniques such as hypothesis-free genome wide interaction studies and deep phenotyping, it may be possible to translate the information from GEI studies into public health policy and personalized medicine for obesity and other complex human diseases. / Thesis / Doctor of Philosophy (PhD)
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/22062 |
| Date | January 2017 |
| Creators | Reddon, Hudson |
| Contributors | Meyre, David, Health Research Methodology |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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