Effect of interaction between obesity-promoting genetic variants and behavioral factors on the risk of obese phenotypes

Mol Genet Genomics. 2021 Jul;296(4):919-938. doi: 10.1007/s00438-021-01793-y. Epub 2021 May 9.


The studies investigating gene-gene and gene-environment (or gene-behavior) interactions provide valuable insight into the pathomechanisms underlying obese phenotypes. The Pakistani population due to its unique characteristics offers numerous advantages for conducting such studies. In this view, the current study was undertaken to examine the effects of gene-gene and gene-environment/behavior interactions on the risk of obesity in a sample of Pakistani population. A total of 578 adult participants including 290 overweight/obese cases and 288 normal-weight controls were involved. The five key obesity-associated genetic variants namely MC4R rs17782313, BDNF rs6265, FTO rs1421085, TMEM18 rs7561317, and NEGR1 rs2815752 were genotyped using the TaqMan allelic discrimination assays. The data related to behavioral factors, such as eating pattern, diet consciousness, the tendency toward fat-dense food (TFDF), sleep duration, sleep-wake cycle (SWC), shift work (SW), and physical activity levels were collected via a questionnaire. Gene-gene and gene-behavior interactions were analyzed by multifactor dimensionality reduction and linear regression, respectively. In our study, only TMEM18 rs7561317 was found to be significantly associated with anthropometric traits with no significant effect of gene-gene interactions were observed on obesity-related phenotypes. However, the genetic variants were found to interact with the behavioral factors to significantly influence various obesity-related anthropometric traits including BMI, waist circumference, hip circumference, waist-to-hip ratio, waist-to-height ratio, and percentage of body fat. In conclusion, the interaction between genetic architecture and behavior/environment determines the outcome of obesity-related anthropometric phenotypes. Thus, gene-environment/behavior interaction studies should be promoted to explore the risk of complex and multifactorial disorders, such as obesity.

Keywords: Gene × behavior interactions; Gene × gene interaction; Low physical activity; Obesity; Pakistanis.

MeSH terms

  • Adult
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO / genetics
  • Body Mass Index
  • Body Weight / genetics
  • Case-Control Studies
  • Feeding Behavior / physiology
  • Female
  • Food Preferences / physiology
  • Gene-Environment Interaction*
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Health Behavior* / physiology
  • Humans
  • Life Style
  • Male
  • Middle Aged
  • Obesity* / epidemiology
  • Obesity* / etiology
  • Obesity* / genetics
  • Overweight / epidemiology
  • Overweight / etiology
  • Overweight / genetics
  • Pakistan / epidemiology
  • Polymorphism, Single Nucleotide
  • Risk Factors
  • Young Adult


  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO
  • FTO protein, human