Epistasis Blog

From the Computational Genetics Laboratory at the University of Pennsylvania (www.epistasis.org)

Monday, September 20, 2010

Towards a complete resolution of the genetic architecture of disease

How is it possible to discuss the 'complete resolution of genetic architecture' while completely ignoring gene-gene and gene-environment interaction? I am not at all convinced, as these authors are, that a majority of the missing heritability can be explained by rare variants. I also completely disagree with the last sentence of their abstract: "Whereas major challenges undoubtedly remain, particularly regarding data handling and the functional classification of variants, we suggest that these will be largely practical and not conceptual". How is it possible that the major challenges are practical rather that conceptual when we do not yet fully understand the complexity of the human genome?

Singleton AB, Hardy J, Traynor BJ, Houlden H. Towards a complete resolution of the genetic architecture of disease. Trends Genet. 2010 Aug 31. [PubMed]

Abstract

After years of linear gains in the genetic dissection of human disease we are now in a period of exponential discovery. This is particularly apparent for complex disease. Genome-wide association studies (GWAS) have provided myriad associations between common variability and disease, and have shown that common genetic variability is unlikely to explain the entire genetic predisposition to disease. Here we detail how one can expand on this success and systematically identify genetic risks that lead or predispose to disease using next-generation sequencing. Geneticists have had for many years a protocol to identify Mendelian disease. A similar set of tools is now available for the identification of rare moderate-risk loci and common low-risk variants. Whereas major challenges undoubtedly remain, particularly regarding data handling and the functional classification of variants, we suggest that these will be largely practical and not conceptual.

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