Abstract
The past decade has been proclaimed as a hugely successful era of gene discovery through the high yields of many genome-wide association studies (GWAS). However, much of the perceived benefit of such discoveries lies in the promise that the identification of genes that influence disease would directly translate into the identification of potential therapeutic targets, but this has yet to be realized at a level reflecting expectation. One reason for this, we suggest, is that GWAS, to date, have generally not focused on phenotypes that directly relate to the progression of disease and thus speak to disease treatment.
Highlights
In contrast to the large body of research on the genetic risk of disease incidence, only a small proportion of genome-wide association studies (GWAS) have attempted to identify variants associated with disease progression or severity, and those that have are mostly small (90% have n < 5,000)
With its emphasis on causality, it is important to appreciate that the challenges we present here apply to Mendelian randomization (MR)
In S1 Table, we summarize the 28 MR studies of progression that we identified in a systematic search
Summary
In contrast to the large body of research on the genetic risk of disease incidence, only a small proportion of GWAS (approximately 8% of associations curated in the GWAS Catalog [p < 1 x 10−5]) have attempted to identify variants associated with disease progression or severity, and those that have are mostly small (90% have n < 5,000). This is most likely due to a research focus on mechanisms of the underlying causes of disease, as well as the limitation of available disease progression data, partly because measures of progression are harder to define and collect than more straightforward case/control phenotypes.
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