Inherited Susceptibility to Complex Diseases

Complex diseases are characterized by a multifactorial (genetic, environmental and developmental) origin. Using primarily asthma as an example, we discuss how genome-wide association studies (GWAS) have advanced our understanding of the inherited (genetic) component of complex disease susceptibility. We highlight the successes of GWAS but also their limitations, revealed by the fact that disease-associated GWAS variants still account for only a fraction of the disease heritability estimated from family studies. We argue that a more comprehensive understanding of the genetic architecture of complex diseases in the post-GWAS era will require the discovery of additional genetic variation through a combination of larger sample sizes, improved phenotyping, more focused study designs, more effective analytical methods and integration with functional information from human and animal models. We also discuss gene–environment interactions, a major challenge in complex disease genetics, and we present examples of cell-based approaches that model these interactions in vitro under controlled conditions. In combination, these novel strategies will help to explain the impact of heritable effects on disease risk—a goal that is not purely academic, because it relates directly to the soundness of our conceptual framework about complex disease susceptibility.