Genetic and Environmental Interactions in Human Obesity

Abstract

Obesity is a rising global problem, clinically defined as having a body mass index (BMI) > 30 or a waist-to-hip ratio >0.9 for males and >0.85 for females. It is a complex disease with both genetic and environmental factors affecting its development and progression. However, although BMI is highly heritable (60-90% according to twin studies), only ~6% of the variance is explained by additive genetic variation discovered in large genome-wide association studies. Possible sources of unexplained BMI variance are gene-gene (GxG) and gene-environment (GxE) interactions, but to date, only a few studies have addressed this question, and mostly focused on the UK biobank and data from smaller longitudinal studies This study used data from the Estonian biobank to investigate the potential of using the Brown-Forsythe (BF) test to detect heteroscedasticity in BMI based on the genotype and phenotype groups. Moreover, in this work, the BF test was used to select genotypes and environmental variables that were significantly associated with BMI and WHR variance. The study demonstrated sex and age-dependent differences in heteroscedasticity, with higher levels of heteroscedasticity in females compared to males and decreasing heteroscedasticity with increasing age for both sexes. Next, the gene-environment interactions for the outcome variables BMI and WHR were modeled and studied for two genes (FTO and MC4R) and environmental factors, such as physical activity, smoking, and education level. The study found evidence for significant interaction of FTO with smoking for the age group of 31-50 years for males, along with significant interaction of FTO with physical activity for Females (18-30 age group) and males (31-50 age group) in the case of BMI as the outcome variable. Moreover, the evidence for significant interaction of FTO and physical activity was found for females (age group 18-30) for the WHR as the outcome variable. Furthermore, the significant interaction was observed in the case of MC4R and physical activity for BMI in males (18-30 year old group). Additionally, it was shown that the significant interaction between MC4R and education level for males (31-50 age group) was present for BMI. Finally, the study outlined the ground for future research work in the area of gene-environment interactions and statistical modeling, indicating potential environmental factors that can be studied for possible gene-environment interactions.