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.

研究基因-基因和基因-环境（或基因-行为）相互作用的研究为肥胖表型背后的病理机制提供了有价值的见解。巴基斯坦人口因其独特的特征为开展此类研究提供了许多优势。鉴于此，当前的研究旨在检验基因-基因和基因-环境/行为相互作用对巴基斯坦人口样本肥胖风险的影响。共有 578 名成年参与者参与，其中包括 290 名超重/肥胖病例和 288 名正常体重对照。使用 TaqMan 等位基因区分分析对五个关键的肥胖相关遗传变异（即MC4R rs17782313、BDNF rs6265、FTO rs1421085、TMEM18 rs7561317 和NEGR1 rs2815752）进行基因分型。与行为因素相关的数据，如饮食模式、饮食意识、高脂肪食物倾向（TFDF）、睡眠持续时间、睡眠-觉醒周期（SWC）、轮班工作（SW）和体力活动水平通过一份调查问卷。分别通过多因素降维和线性回归分析基因-基因和基因-行为相互作用。在我们的研究中，仅发现TMEM18 rs7561317 与人体测量特征显着相关，但未观察到基因-基因相互作用对肥胖相关表型的显着影响。然而，发现遗传变异与行为因素相互作用，显着影响各种与肥胖相关的人体测量特征，包括体重指数、腰围、臀围、腰臀比、腰高比和体脂百分比。总之，遗传结构与行为/环境之间的相互作用决定了肥胖相关人体测量表型的结果。因此，应促进基因-环境/行为相互作用研究，以探索复杂和多因素疾病（例如肥胖）的风险。