Abstract
While genome-wide association studies (GWAS) and candidate gene approaches have identified many genetic variants that contribute to disease risk as main effects, the impact of genotype by environment (GxE) interactions remains rather under-surveyed. To explore the importance of GxE interactions for diabetes-related traits, a tool for Genome-wide Complex Trait Analysis (GCTA) was used to examine GxE variance contribution of 15 macronutrients and lifestyle to the total phenotypic variance of diabetes-related traits at the genome-wide level in a European American population. GCTA identified two key environmental factors making significant contributions to the GxE variance for diabetes-related traits: carbohydrate for fasting insulin (25.1% of total variance, P-nominal = 0.032) and homeostasis model assessment of insulin resistance (HOMA-IR) (24.2% of total variance, P-nominal = 0.035), n-6 polyunsaturated fatty acid (PUFA) for HOMA-β-cell-function (39.0% of total variance, P-nominal = 0.005). To demonstrate and support the results from GCTA, a GxE GWAS was conducted with each of the significant dietary factors and a control E factor (dietary protein), which contributed a non-significant GxE variance. We observed that GxE GWAS for the environmental factor contributing a significant GxE variance yielded more significant SNPs than the control factor. For each trait, we selected all significant SNPs produced from GxE GWAS, and conducted anew the GCTA to estimate the variance they contributed. We noted the variance contributed by these SNPs is higher than that of the control. In conclusion, we utilized a novel method that demonstrates the importance of genome-wide GxE interactions in explaining the variance of diabetes-related traits.
Highlights
Type 2 diabetes (T2D) is one of the most common chronic diseases in the world, accounting for nearly 90% to 95% of all diabetes cases
After inclusion of GxE in the model, the variance explained by the additive genetic variance varied from 10.9% to 19.5%, and carbohydrate intake contributed significant GxE variance to the total variance of fasting insulin (25.1%, P-nominal = 0.032) (Table 2, Figure 1, 2, 3)
Using Genome-wide Complex Trait Analysis (GCTA), we explored the GxE contribution of 15 macronutrients and lifestyle factors to the total phenotypic variance of four T2D-related traits
Summary
Type 2 diabetes (T2D) is one of the most common chronic diseases in the world, accounting for nearly 90% to 95% of all diabetes cases. [1] and 285 million adults worldwide [2] were affected by diabetes in 2010, and it is estimated that between 2010 and 2030, the number of adult diabetes cases will increase by 69% in developing countries and by 20% in developed countries [2]. For the prevention of T2D, identifying genetic and environmental risk factors has been a primary research focus in the public health arena. More than 100 single-nucleotide polymorphisms (SNP) for T2D and T2D-related traits have been identified via genome-wide association studies (GWAS) Because GxE interactions suggest a way by which genetic risk may be ameliorated, these environmental factors are of great relevance to public health, and are the focus of a growing number of studies [7]
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