Gene-environment interaction explains a part of missing heritability in human body mass index

Gene-environment (G×E) interaction could partially explain missing heritability in traits; however, the magnitudes of G×E interaction effects remain unclear. Here, we estimate the heritability of G×E interaction for body mass index (BMI) by subjecting genome-wide interaction study data of 331,282 participants in the UK Biobank to linkage disequilibrium score regression (LDSC) and linkage disequilibrium adjusted kinships–software for estimating SNP heritability from summary statistics (LDAK-SumHer) analyses. Among 14 obesity-related lifestyle factors, MET score, pack years of smoking, and alcohol intake frequency significantly interact with genetic factors in both analyses, accounting for the partial variance of BMI. The G×E interaction heritability (%) and standard error of these factors by LDSC and LDAK-SumHer are as follows: MET score, 0.45% (0.12) and 0.65% (0.24); pack years of smoking, 0.52% (0.13) and 0.93% (0.26); and alcohol intake frequency, 0.32% (0.10) and 0.80% (0.17), respectively. Moreover, these three factors are partially validated for their interactions with genetic factors in other obesity-related traits, including waist circumference, hip circumference, waist-to-hip ratio adjusted with BMI, and body fat percentage. Our results suggest that G×E interaction may partly explain the missing heritability in BMI, and two G×E interaction loci identified could help in understanding the genetic architecture of obesity.基因-环境（G×E）互作可部分解释性状的缺失遗传力，但目前G×E互作效应的大小仍不明确。本研究针对英国生物库（UK Biobank）中331282名参与者的全基因组互作研究数据，采用连锁不平衡得分回归（LDSC）与基于汇总统计量估算单核苷酸多态性（SNP）遗传力的连锁不平衡校正亲缘矩阵软件（LDAK-SumHer）两种方法，对体重指数（BMI）的G×E互作遗传力进行估算。在14种肥胖相关生活方式因素中，代谢当量（MET）评分、吸烟包年数及饮酒频率在两种分析中均与遗传因素存在显著互作，可解释BMI的部分方差。上述因素的G×E互作遗传力（%）及标准误经LDSC与LDAK-SumHer估算结果如下：代谢当量评分分别为0.45%（0.12）与0.65%（0.24）；吸烟包年数分别为0.52%（0.13）与0.93%（0.26）；饮酒频率分别为0.32%（0.10）与0.80%（0.17）。此外，针对腰围、臀围、校正BMI的腰臀比及体脂百分比等其他肥胖相关性状，本研究验证了上述三种因素与遗传因素的互作效应。本研究结果表明，G×E互作可部分解释BMI的缺失遗传力，且本研究鉴定出的两个G×E互作位点有助于解析肥胖的遗传结构。