Genetics of complex disease: approaches, problems, and solutions.

Complex or multifactorial diseases are defined as diseases that are ultimately determined by a number of genetic and environmental factors. Although there are many technologies and strategies that can be used to detect genetic factors influencing complex diseases, these technologies and strategies have inherent limitations. In fact, the very name "complex disease" suggests that the results from relevant studies will not be simple to decipher. Ultimately, both the detection and precise characterization of a factor's contribution to a complex disease are difficult undertakings, because the effect of any one factor may be obscured or confounded by other factors. However, the genetic dissection of complex diseases can be greatly facilitated by paying heed to two very basic distinctions. The first distinction is between complexity at the level of individuals and complexity at the level of populations. The second distinction is between the two sequentially pursued components of gene discovery paradigms: gene identification and gene effect characterization. Although genetic epidemiology, as a research field, is oriented to both components of gene discovery for complex diseases, it is suited to gene effect characterization at the population level more than anything else. This paper reviews the origins of the genetic basis of complex traits, as well as the problems plaguing genetic epidemiologic analysis strategies, with the hope of showing how greater attention to these distinctions, as well as a greater integration of relevant knowledge, can alleviate confusion and shape future investigations. In addition, a new discipline, "phenomics" or "phenometrics," could be initiated that would complement genomic research as presently performed.