‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease?*

Abstract

Associations between modifiable exposures and disease seen in observational epidemiology are sometimes confounded and thus misleading, despite our best efforts to improve the design and analysis of studies. Mendelian randomization—the random assortment of genes from parents to offspring that occurs during gamete formation and conception—provides one method for assessing the causal nature of some environmental exposures. The association between a disease and a polymorphism that mimics the biological link between a proposed exposure and disease is not generally susceptible to the reverse causation or confounding that may distort interpretations of conventional observational studies. Several examples where the phenotypic effects of polymorphisms are well documented provide encouraging evidence of the explanatory power of Mendelian randomization and are described. The limitations of the approach include confounding by polymorphisms in linkage disequilibrium with the polymorphism under study, that polymorphisms may have several phenotypic effects associated with disease, the lack of suitable polymorphisms for studying modifiable exposures of interest, and canalization—the buffering of the effects of genetic variation during development. Nevertheless, Mendelian randomization provides new opportunities to test causality and demonstrates how investment in the human genome project may contribute to understanding and preventing the adverse effects on human health of modifiable exposures. Genetic epidemiology—the theme of this issue of the International Journal of Epidemiology—is seen by many to be the only future for epidemiology, perhaps reflecting a growing awareness of the limitations of observational epidemiology1 (Box 1). Genetic epidemiology is concerned with understanding heritable aspects of disease risk, individual susceptibility to disease, and ultimately with contributing to a comprehensive molecular understanding of pathogenesis. The massive investment and expansion of human genetics, if it is to return value for the common good, must be integrated into public health functions. The human genome epidemiology network (HuGE Net—http://www.cdc.gov/genetics/huge.htm) has been established to promote the use of genetic knowledge—in terms of genetic tests and services—for disease prevention and health promotion.2,3 A broad taxonomy of human genome studies of public health relevance has been developed4 (Box 2). In this issue of the IJE, we publish a paper by Miguel Porta,5 who highlights the need for a more rational approach to genetic testing, given the likely low penetrance of many genes associated with cancers,6 likening the role of the genome to a jazz score that is interpreted and developed through experience and context—and is seldom predictable. Such insights may well temper enthusiasm for genetic testing in populations. However, in parallel to the approaches advocated by HuGE, genetic epidemiology can lead to a more robust understanding of environmental determinants of disease (e.g. dietary factors, occupational exposures, and health-related behaviours) relevant to whole populations (and not simply to genetically susceptible sub-populations).7–10 This approach has recently been referred to as ‘Mendelian randomization’.11–15 Here we begin by briefly reviewing reasons for current concerns about aetiological findings generated by conventional observational epidemiology and then we outline the potential contribution (and limitations) of Mendelian randomization. ‘Epidemiology set to get fast-track treatment’ ‘A consortium of leading European research centres and pharmaceutical companies will this week announce a plan to transform epidemiology by combining it with the new techniques of high-throughput biology. They plan to create a new field of study—genomic epidemiology—by using screening technologies derived from the human genome project … We think it is important to expand classical epidemiology and genetic epidemiology to take it to this high-throughput mode, says Esper Boel, vice-president of biotechnology research at Novo Nordisk. We want to use post-genomic technologies to create a new clinical science, to turn functional genomics into real clinical chemistry.’ From: Butler D. Epidemiology set to get fast-track treatment. Nature 2001;414:139. Reprinted with permission. Surveillance Population frequency of gene variants predisposing to specific diseases Population frequency of morbidity and mortality from such diseases Population frequency and effects of environmental factors known to interact with gene variants Economic costs of genetic components of diseases Coverage, access, and uptake of genetic tests and services Aetiology Magnitude of disease risk associated with gene variants in different populations Contribution of gene variants to the overall level of disease in different populations Magnitude of disease risk associated with gene–gene and gene–environment interactions in different populations Heal