From association to causality: the new frontier for complex traits

Technological and analytical advances have led to an unprecedented catalog of genomic regions associated with a broad range of clinically relevant phenotypes in humans. However, some examples notwithstanding, the causes of the overwhelming majority of genetic diseases remain obscure. More importantly, an emerging lesson from genome-wide association studies is that, in most instances, the resolution necessary for identifying actual genes that underlie the phenotype is limited, as is our ability to develop mechanistic, testable disease models from such studies. These new realities will probably necessitate a paradigm shift in our approach to complex traits, for which the combinatorial application of genomic and functional studies will be necessary to understand the mechanism and pathology of genetic disease. Here I will discuss these issues and highlight how additional sequencing and genotyping of ever-increasing cohort sizes without functional interpretation is unlikely to improve our ability to dissect the genetic basis of complex traits.