Gene × Physical Activity Interactions in Obesity: Combined Analysis of 111,421 Individuals of European Ancestry

Numerous obesity loci have been identified using genome-wide association studies. A UK study indicated that physical activity may attenuate the cumulative effect of 12 of these loci, but replication studies are lacking. Therefore, we tested whether the aggregate effect of these loci is diminished in adults of European ancestry reporting high levels of physical activity. Twelve obesity-susceptibility loci were genotyped or imputed in 111,421 participants. A genetic risk score (GRS) was calculated by summing the BMI-associated alleles of each genetic variant. Physical activity was assessed using self-administered questionnaires. Multiplicative interactions between the GRS and physical activity on BMI were tested in linear and logistic regression models in each cohort, with adjustment for age, age2, sex, study center (for multicenter studies), and the marginal terms for physical activity and the GRS. These results were combined using meta-analysis weighted by cohort sample size. The meta-analysis yielded a statistically significant GRS × physical activity interaction effect estimate (Pinteraction = 0.015). However, a statistically significant interaction effect was only apparent in North American cohorts (n = 39,810, Pinteraction = 0.014 vs. n = 71,611, Pinteraction = 0.275 for Europeans). In secondary analyses, both the FTO rs1121980 (Pinteraction = 0.003) and the SEC16B rs10913469 (Pinteraction = 0.025) variants showed evidence of SNP × physical activity interactions. This meta-analysis of 111,421 individuals provides further support for an interaction between physical activity and a GRS in obesity disposition, although these findings hinge on the inclusion of cohorts from North America, indicating that these results are either population-specific or non-causal.

既往通过全基因组关联研究（Genome-Wide Association Studies, GWAS）已鉴定出多个肥胖易感基因座（obesity loci）。一项英国队列研究指出，体力活动或许可缓解其中12个基因座的累积效应，但目前尚缺乏相关重复验证研究。因此，本研究旨在探究：在报告高水平体力活动的欧洲血统成年人群中，上述肥胖易感基因座的整体效应是否会被削弱。本研究对111421名受试者的12个肥胖易感基因座进行了基因分型或基因型填充（imputation），通过累加每个遗传变异体的体质量指数（Body Mass Index, BMI）相关等位基因，计算得到遗传风险评分（Genetic Risk Score, GRS）；体力活动水平通过自填式问卷进行评估。本研究在每个队列中分别采用线性回归与逻辑回归模型，检验遗传风险评分与体力活动对体质量指数的乘积交互作用，并校正年龄、年龄平方、性别、研究中心（针对多中心研究）以及体力活动与遗传风险评分的边际效应项，后续以队列样本量为权重进行荟萃分析整合各队列研究结果。荟萃分析结果显示，遗传风险评分与体力活动的交互作用具有统计学意义（交互检验P值=0.015），但该显著交互作用仅在北美队列中得以观测（北美队列：n=39810，交互检验P=0.014；欧洲队列：n=71611，交互检验P=0.275）。后续次级分析显示，FTO基因rs1121980位点（交互检验P=0.003）与SEC16B基因rs10913469位点（交互检验P=0.025）均存在单核苷酸多态性（Single Nucleotide Polymorphism, SNP）与体力活动的交互效应。这项纳入111421名受试者的荟萃分析进一步证实，体力活动与遗传风险评分在肥胖易感性方面存在交互作用；但该研究结论高度依赖北美队列的纳入，提示上述结果可能仅适用于特定人群，或并非因果关联。