Rosenquist James Niels, Lehrer Steven F, O'Malley A James, Zaslavsky Alan M, Smoller Jordan W, Christakis Nicholas A
Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114;
School of Policy Studies and Department of Economics, Queens University, Kingston, Ontario, Canada K7L 3N6; National Bureau of Economic Research USA, Cambridge, MA 02138;
Proc Natl Acad Sci U S A. 2015 Jan 13;112(2):354-9. doi: 10.1073/pnas.1411893111. Epub 2014 Dec 29.
A substantial body of research has explored the relative roles of genetic and environmental factors on phenotype expression in humans. Recent research has also sought to identify gene-environment (or g-by-e) interactions, with mixed success. One potential reason for these mixed results may relate to the fact that genetic effects might be modified by changes in the environment over time. For example, the noted rise of obesity in the United States in the latter part of the 20th century might reflect an interaction between genetic variation and changing environmental conditions that together affect the penetrance of genetic influences. To evaluate this hypothesis, we use longitudinal data from the Framingham Heart Study collected over 30 y from a geographically relatively localized sample to test whether the well-documented association between the rs993609 variant of the FTO (fat mass and obesity associated) gene and body mass index (BMI) varies across birth cohorts, time period, and the lifecycle. Such cohort and period effects integrate many potential environmental factors, and this gene-by-environment analysis examines interactions with both time-varying contemporaneous and historical environmental influences. Using constrained linear age-period-cohort models that include family controls, we find that there is a robust relationship between birth cohort and the genotype-phenotype correlation between the FTO risk allele and BMI, with an observed inflection point for those born after 1942. These results suggest genetic influences on complex traits like obesity can vary over time, presumably because of global environmental changes that modify allelic penetrance.
大量研究探讨了遗传和环境因素在人类表型表达中的相对作用。近期研究也试图确定基因-环境（或基因与环境相互作用），但结果好坏参半。这些结果不一的一个潜在原因可能与以下事实有关：随着时间的推移，环境变化可能会改变遗传效应。例如，20世纪后期美国肥胖率的显著上升可能反映了基因变异与不断变化的环境条件之间的相互作用，二者共同影响了遗传影响的外显率。为了评估这一假设，我们使用了来自弗雷明汉心脏研究的纵向数据，这些数据是在30多年间从一个地理上相对集中的样本中收集的，以测试FTO（脂肪量和肥胖相关）基因的rs993609变体与体重指数（BMI）之间已被充分记录的关联是否会因出生队列、时间段和生命周期的不同而有所变化。这种队列和时期效应整合了许多潜在的环境因素，而这种基因与环境分析考察了与随时间变化的同期和历史环境影响的相互作用。使用包含家庭对照的受限线性年龄-时期-队列模型，我们发现出生队列与FTO风险等位基因和BMI之间的基因型-表型相关性之间存在稳健的关系，1942年以后出生的人存在一个明显的转折点。这些结果表明，对肥胖等复杂性状的遗传影响可能会随时间变化，大概是由于全球环境变化改变了等位基因的外显率。
