Distilling pathophysiology from complex disease genetics

Abstract

Technologies for genome-wide sequence interrogation have dramatically improved our ability to identify loci associated with complex human disease. However, a chasm remains between correlations and causality that stems, in part, from a limiting theoretical framework derived from Mendelian genetics and an incomplete understanding of disease physiology. Here we propose a set of criteria, akin to Koch's postulates for infectious disease, for assigning causality between genetic variants and human disease phenotypes.

Figure 1

Complementary approaches for proving genetic causality and understanding pathophysiology of complex disease. Genetic association studies in humans combined with prior knowledge about biological pathways generate testable hypotheses. Prior knowledge and systems-level quantitative analysis can help predict where (anatomically) and when (developmentally) disruptions to a particular pathway will lead a to a specific morphological or biochemical phenotype, which can then be tested in an appropriate model system while adhering to the postulates outlined in Box 1.