IJE Advance Access originally published online on March 15, 2006
International Journal of Epidemiology 2006 35(3):590-592; doi:10.1093/ije/dyl007
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Commentary |
Commentary: Understanding sources of complexity in chronic diseases—the importance of integration of genetics and epidemiology
1 Section on Developmental Genetic Epidemiology, National Institutes of Health, National Institute of Mental Health, 35 Convent Drive, MSC#3720, Bethesda, MD 20892, USA
2 Laboratory of Neurogenetics, National Institute of Aging, National Institute of Mental Health, 35 Convent Drive, Bethesda, MD 20892, USA
* Corresponding author. Section on Developmental Genetic Epidemiology, National Institutes of Health, National Institute of Mental Health, 35 Convent Drive, MSC#3720, Bethesda, MD 20892, USA. E-mail: merikank{at}mail.nih.gov
Accepted 5 January 2006
Progress in identifying genes for nearly all known Mendelian diseases spurred by mapping of the human genome generated a nearly universal expectation that the same research strategies would eventually be successful in identifying genes for complex diseases, such as heart disease, obesity, cancer, diabetes, and many common psychiatric conditions. As the failure to identify and replicate genes for complex disorders has become increasingly apparent, enthusiasm for rapid success has waned. In ‘Dissecting Complex Disease: The Quest for the Philosopher's Stone?’ Buchanan et al.1 admonish geneticists and epidemiologists who are engaged in searching for either genetic or environmental risk factors for complex diseases that there may be no gold at the end of the rainbow (or that the philosopher's stone will generate base metals rather than gold; or that there is no ‘fountain of youth’.)2
Although the target readership of this essay is not obvious, chronic disease epidemiologists alone are clearly the wrong audience. The concepts that the authors discuss are well recognized by most serious epidemiologists engaged in research that includes genetic risk factors. The major points raised in this essay on the characteristics of complex human diseases have been described more comprehensively in many of the references that they cite, as well as numerous others.3–8 Many basic textbooks of population and behaviour genetics provide descriptions of the phenomena that lead to a lack of one-to-one correspondence between genotype and phenotype including variable expressivity, gene–environment interaction, epistasis, genotypic and phenotypic heterogeneity, and pleiotropy.9,10 Thus, there is already widespread agreement among population geneticists and epidemiologists, as well as many molecular geneticists, regarding the obstacles to identifying risk factors for complex diseases and the methods for inferring causal associations. Rather, the appropriate target audience for this essay is a small number of highly vocal gene hunters who deny that the above-cited obstacles to gene identification and replication, and instead perpetuate the myth that they are on the verge of cracking the code for many of the diseases through the ever-emerging genomics technologies. Indeed, the message of this small Greek chorus would be more aptly described as having the ‘delusion’ rather than the ‘illusion’ of the Philosopher's Stone!
The nihilist tone of the authors does not reflect a balanced view of successes and failures in the field. They underestimate the importance of the advances in understanding Mendelian disease, which has been the culmination of decades of research. Identifying these genes has been revolutionary in terms of prediction (e.g. Huntington's disease11), comprehension of pathogenesis (e.g. familial hemiplegic migraine12 and Alzheimer's disease13), and, in some cases, prevention (e.g. phenylketonuria14,15). In addition, there have even been some recent successes in gene identification for complex diseases. This is exemplified by the identification of a gene with high attributable risk for macular degeneration in a relatively small case–control study16 using a genome-wide association approach published, with simultaneous replications.17,18 There are replicated findings for other complex diseases, such as rheumatoid arthritis,19–22 that are now emerging as well.
Buchanan et al. also exaggerate the implications of the abundant failures to replicate initial discoveries (i.e. the so-called ‘winner's curse’) for our future ability to identify genetic and environmental causes of complex diseases. Science proceeds as much through rejection of hypotheses as it does through confirmation. Some non-replications have actually been more fruitful in guiding the direction of research than the now regular claims of new associations between single nucleotide polymorphisms and complex diseases.
The authors provide no alternative approaches yet conclude that ‘the lack of an obvious alternative does not justify continuing to invest in what does not work’. They apply the following observations about prevalence rates to support their argument to cease and desist: (1) that rapid changes in prevalence of a disease clearly indicate the major contribution of environmental factors to disease aetiology; and (2) even though genetic factors may be more likely to contribute to a disease if prevalence rates are stable, they will still not be tractable because of the multiple sources of complexity described above. The authors advise complex disease investigators to return research funding and undergo career counselling.
The first conclusion is based on the difficulty in identifying the role of environmental factors that contribute to the aetiology of most of the complex diseases. However, rather than presenting models of some successful strategies employed in identifying environmental risk factors for diseases (e.g. the necessary role of exposure to human papilloma virus for the development of cervical cancer23 or the classic work of an epidemiological study that distinguished between inherited and non-inherited forms of retinoblastoma, with the inherited form attributable to a germline mutation coupled with a somatic mutation24), they perpetuate the dichotomization of genetic versus environmental causes of disease.
The authors also fail to recognize that the traditional case–control family study of unbiased samples may be informative regarding the obstacles to progress that they describe.25–29 Family studies and related designs in genetic epidemiology have largely been abandoned in favour of family study designs that are most potent for gene detection (e.g. family trios). In fact, in order to address the neglect of family studies as both a source of risk identification as well as their relevance to gene-finding, the Center for Disease Control has established an initiative on proper collection and integration of family history in risk estimation.30,31
We addressed Buchanan et al.'s second conclusion in our paper entitled ‘Public Health Priorities and Genomics’, where we proposed that resources for complex diseases be determined only after a comprehensive review of the a priori epidemiological and genetic epidemiological evidence for the validity of the phenotypic definition, knowledge regarding the role and attributable risks of genetic and environmental factors, and potential for intervention at both the population and individual levels.6 For example, public health initiatives to reduce smoking should outweigh (but not replace) studies of the genetic pathways underlying nicotine dependence; whereas, studies of genes underlying autism, which is largely attributable to genetic factors, are likely to be more informative than studies of environmental exposures.31
The most important omission of this essay is the failure to recognize that the lack of progress in understanding complex disorders emanates in part from a lack of integration of the disciplines that have operated independently in identifying genetic and environmental factors. As first described by Morton32 the discipline of genetic epidemiology was established to identify the joint contribution of both genes and environmental factors to the aetiology of complex diseases through integration of the tools of both epidemiology and population genetics.32–36 Yet, few investigators of complex diseases have training in both epidemiology and genetics and actually apply the tools that may be informative for the problems discussed here. Moreover, most genetic epidemiological studies have not yet successfully integrated the new technology emanating from advances in molecular genetics.37–40 Scientists in the truly integrative field of genetic epidemiology have written extensively on this topic36,40–44 but that this important gap is perhaps the most important source of the lack of progress is not reflected in the essay by Buchanan et al. More than 5 years ago in a paper with a remarkably similar title to that of Buchanan et al. paper, namely, ‘Dissecting Human Disease in the Postgenomic Era’, Peltonen and McKusick, came to a diametrically opposite conclusion to that of the present essay: ‘Predictions of ... multiple genes in complex disorders will require efficient collaboration among research groups ... clinicians, epidemiologists, geneticists ... to solve the genetic underpinnings of complex diseases that affect the lives of millions.’45
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