Is the time right for translation research in genomics?

Abstract

Genome-wide association studies are rapidly unraveling genetic susceptibility variants that are implicated in the etiology of common multifactorial diseases such as coronary heart disease, type 2 diabetes, non-familial forms of breast cancer and age-related macular degeneration [1]. Expectations about the future impact of these discoveries on preventive and clinical health care practice are high [2, 3]. Future use of genetic tests is foreseen for the prediction of disease susceptibility, targeting pharmacotherapy and tailoring lifestyle and health behavior recommendations. Fueled by the enormous progress in gene discovery, many researchers are already investigating the prediction of common diseases based on genetic profiling, the simultaneous testing of multiple susceptibility variants [4], and an increasing number of companies already offer personalized lifestyle health recommendations and nutritional supplements based on clients’ genetic profiles [5]. Despite the current euphoria, the predictive value of genetic profiling is still limited for most disorders, with only some promising exceptions. [4, 6–9] The major limitation to date is that only a fraction of the genetic factors involved have been identified, for most disorders less than 20 [1], explaining not more than a few percentages of the heritability. While we may expect that a large number of genetic variants will be discovered in the next few years, establishing a solid evidence base for genomics applications in clinical and public health care may take longer given the number of steps to be taken. Khoury and colleagues have described a framework for the continuum of translation research that is required to move genomics research findings to clinical and public health applications that benefit population health [10]. The four phases of translation researches include (1) translation of basic genomics research into a potential health care application; (2) evaluation of the application for the development of evidencebased guidelines; (3) evaluation of the implementation and use of the application in health care practice; and (4) evaluation of the achieved population health impact [10]. Translation research in genomics starts after gene discovery [10]. In common diseases, where numerous genetic factors may be implicated, genes are discovered by demonstrating robust genetic association, not in a single study but in meta-analyses or pooled analyses of large-scale studies [11–13]. A major challenge in common diseases is to decide when we have discovered sufficient genetic variants to begin translation research. One may argue that now the time is right because the studies so far likely have identified the common variants with the strongest effects and that further studies will only add weak susceptibility variants. For instance the complement factor H gene was the first common gene discovered to be involved in agerelated macular degeneration (AMD) using not more than 100 patients and 50 controls [14]. Typical gene discovery studies include 1,000s of patients and are able to detect variants with odds ratios as low as 1.05–1.10. Yet, also a very large number of weak susceptibility variants may further improve risk prediction [15]. Furthermore, stronger genetic effects may still be found for gene-gene and gene– environment interactions. Many groups of researchers are currently pooling their data in large consortia, which together will have sufficient power to model and detect interactions. Another avenue to pursue is to target more rare variants with strong genetic effects in specific populations. Genetic associations may not only differ between A. C. J. W. Janssens (&) Department of Epidemiology, Erasmus University Medical Center Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands e-mail: a.janssens@erasmusmc.nl