A recent essay in Cell by University of Washington researchers Jon McClellan and Mary-Claire King has questioned the adequacy of GWAS for finding the genetic causes of human diseases. The authors take an evolutionary approach to human disease, saying that there is strong evidence that "rare mutations of severe effect are responsible for a substantial portion of complex human disease" and that "evolutionary forces generate vast genetic heterogeneity in human illness by introducing many new variants in each generation." They argue that GWAS to date have published hundreds of common variants "whose allele frequencies are statistically correlated with various illnesses and traits." However, they continue, it's become clear that common risk variants fail to explain the majority of genetic heritability for any disease, which renders GWAS findings neutral to our understanding of those diseases.
The Getting Genetics Done blog's Stephen Turner says the paper is "definitely worth a read" and seems to agree with some of McClellan and King's thoughts about the problems in GWAS like population stratification. Turner adds that the authors' assertion that replication in genetic studies should focus on the "identification and confirmation of multiple biologically relevant mutations in the same gene … would provide both biological and epidemiological support for the causality of the gene or pathway in the pathogenesis of the disease."
Other bloggers aren't so convinced, however. The Gene Expression blog's p-ter says that while some of the backlash against GWAS is fair, some of it – like McClellan and King's arguments – is just "bizarre." "How did genome-wide association studies come to be populated by risk variants with no known function?" McClellan and King ask. "Common SNPs are generally nonfunctional," p-ter answers. "The obvious answer is that they influence gene regulation." The evidence suggests that our lack of knowledge about signals coming from GWAS can be attributed to our lack of understanding of the relevant biology, not to some problem with the design of the studies, p-ter concludes. The Genetic Future blog's Daniel MacArthur agrees. "Most of us working in genomics have seen the proliferation of non-coding hits in GWAS studies as a positive, in that it seems to be teaching us something new and unexpected about the underlying biology of human variation," he says.