The use of animal models in the study of complex disease: all else is never equal or why do so many human studies fail to replicate animal findings?

Abstract

The study of the genetics of complex human disease has met with limited success. Many findings with candidate genes fail to replicate despite seemingly overwhelming physiological data implicating the genes. In contrast, animal model studies of the same genes and disease models usually have more consistent results. We propose that one important reason for this is the ability to control genetic background in animal studies. The fact that controlling genetic background can produce more consistent results suggests that the failure to replicate human findings in the same diseases is due to variation in interacting genes. Hence, the contrasting nature of the findings from the different study designs indicates the importance of non-additive genetic effects on human disease. We discuss these issues and some methodological approaches that can detect multilocus effects, using hypertension as a model disease. This article contains supplementary material, which may be viewed at the BioEssays website at http://www.interscience.wiley.com/jpages/0265-9247/suppmat/index.html.

Association of copy number variation in the FCGR3B gene with risk of autoimmune diseases

“…However, the exact biological mechanisms by which CCL3L1 CNV might influence the effects of FCGR3B are currently unknown. Nevertheless, there is a growing recognition for both the importance of gene-gene interactions in influencing disease phenotype 30,31 and the presence of many well-described and unknown gene networks that may influence different disease states. 32 In this context, we surmise that CCL3L1-FCGR3B may participate in key immunopathogenic networks that influence autoimmune diseases.…”

Replication in genetic studies of complex traits

“…In such cases, single-locus approaches might not find the underlying loci (Frankel & Schork, 1996;Williams et al 2004). In general, to capture effects of gene-gene interaction one needs an extremely large sample, and specific statistical methods and designs, as well as consideration of the population history.…”

“…Thus, it might be more cost-effective to focus research efforts on deciphering genetic architecture and pathophysiology using experimental animal models. These provide better control of environmental and genetical conditions (Frankel, 1995;Moore & Nagle, 2000;McPeek, 2000;Williams et al 2004). Benefits of controlled conditions are many, and include: high statistical power in well-designed experiments; genetic homogeneity; predictable dependence between linkage disequilibrium and genetic distance in controlled matings; availability of special crossing designs in the study of epistasis (Frankel & Schork, 1996;Cockerham & Zeng, 1996;Jannink & Jansen, 2001); and control of mapping accuracy (map expansion) by increasing the number of generations, e.g.…”

“…For example, one concern is to ensure that the phenotypes in the model organism and human fully correspond to each other at the molecular level. Moreover, use of animal models is sometimes discouraged because the genetic background may substantially differ between humans and cross-bred animals (Williams et al 2004). Because of these difficulties, use of model organisms should be seen as a complementary, rather than competing, research strategy for human studies.…”

The Collaborative Cross, a community resource for the genetic analysis of complex traits

“…Progress toward treatment and prevention will require new approaches to the genetic analysis of complex systems 1 . We believe that computational, statistical and genomic resources are now sufficiently mature to address these mechanisms in the context of an experimental model system that more accurately reflects the genetic structure of human populations 2,3 . Global analysis of complex biological systems can be implemented most efficiently using experimental designs that employ multifactorial perturbations 4,5 .…”