Can we apply the Mendelian randomization methodology without considering epigenetic effects?
Can we apply the Mendelian randomization methodology without considering epigenetic effects?
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DOI：
10.1186/1742-7622-6-3
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发表时间：
2009-05-11
影响因子：
2.3
通讯作者：
Karmaus, Wilfried
中科院分区：
文献类型：
--
作者：
Ogbuanu, Ikechukwu U.;Zhang, Hongmei;Karmaus, Wilfried
简介：工具变量（IV）方法已在计量经济学中使用了几十年，但直到最近才被引入流行病学研究框架。类似地，孟德尔随机化研究，使用IV方法进行流行病学的分析和推断，只是在过去的十年间才被引入流行病学家的工具箱。分析：使用工具变量（IV）的孟德尔随机化研究有可能避免观察流行病学的一些局限性（混淆，反向因果关系，回归稀释偏倚）进行因果推断。随机对照试验的某些局限性，如某些暴露的普遍性，可行性和伦理问题，以及高昂的成本，也使孟德尔随机化在观察性研究中的使用具有吸引力。与传统的随机对照试验（randomized controlled trials，RCTs）不同，孟德尔随机化研究可以在一个代表性样本中进行，而不需要任何排除标准或要求志愿者服从随机治疗分配。在过去的十年中，表观遗传学作为一个独立的研究领域得到了认可，并似乎是未来复杂疾病遗传学研究的新方向。虽然以前的文章已经解决了孟德尔随机化的一些局限性（如缺乏合适的遗传变异，不可靠的关联，人口分层，连锁不平衡（LD），多效性，发育渠道化，需要大样本量和二元结果的一些潜在问题），没有直接表征表观遗传学对孟德尔随机化的影响。表观遗传效应的可能性（非孟德尔的，基因表达的可遗传变化不伴随DNA序列的改变）可能改变孟德尔随机化的核心工具变量假设。本文应用概念考虑，代数推导和数据模拟来质疑当表观遗传修饰存在时孟德尔随机化方法的适当性。由于基因表达遗传自父母，孟德尔随机化研究不仅需要假设后代中等位基因的随机分布，而且还需要假设表观遗传变化的随机分布（例如基因表达），以使孟德尔随机化方法的核心假设保持有效。随着越来越多的流行病学家在他们的研究中采用孟德尔随机化方法，因此，如果这些假设不满足，则需要谨慎地从这些研究中得出结论。
Introduction: Instrumental variable (IV) methods have been used in econometrics for several decades now, but have only recently been introduced into the epidemiologic research frameworks. Similarly, Mendelian randomization studies, which use the IV methodology for analysis and inference in epidemiology, were introduced into the epidemiologist's toolbox only in the last decade.Analysis: Mendelian randomization studies using instrumental variables (IVs) have the potential to avoid some of the limitations of observational epidemiology (confounding, reverse causality, regression dilution bias) for making causal inferences. Certain limitations of randomized controlled trials, such as problems with generalizability, feasibility and ethics for some exposures, and high costs, also make the use of Mendelian randomization in observational studies attractive. Unlike conventional randomized controlled trials (RCTs), Mendelian randomization studies can be conducted in a representative sample without imposing any exclusion criteria or requiring volunteers to be amenable to random treatment allocation.Within the last decade, epigenetics has gained recognition as an independent field of study, and appears to be the new direction for future research into the genetics of complex diseases. Although previous articles have addressed some of the limitations of Mendelian randomization (such as the lack of suitable genetic variants, unreliable associations, population stratification, linkage disequilibrium (LD), pleiotropy, developmental canalization, the need for large sample sizes and some potential problems with binary outcomes), none has directly characterized the impact of epigenetics on Mendelian randomization. The possibility of epigenetic effects (non-Mendelian, heritable changes in gene expression not accompanied by alterations in DNA sequence) could alter the core instrumental variable assumptions of Mendelian randomization.This paper applies conceptual considerations, algebraic derivations and data simulations to question the appropriateness of Mendelian randomization methods when epigenetic modifications are present.Conclusion: Given an inheritance of gene expression from parents, Mendelian randomization studies not only need to assume a random distribution of alleles in the offspring, but also a random distribution of epigenetic changes (e.g. gene expression) at conception, in order for the core assumptions of the Mendelian randomization methodology to remain valid. As an increasing number of epidemiologists employ Mendelian randomization methods in their research, caution is therefore needed in drawing conclusions from these studies if these assumptions are not met.