Genome-wide association: which do you want first: the good news, the bad news, or the good news?

TLDR: The strength of the GWA is that it has the potential to identify genes of high genetic effect that were previously unsuspected as candidates, and is not biased by a priori assumptions based on prior observations of the phenotype.

Abstract: It has long been appreciated that there is a genetic component to type 2 diabetes, but progress in gene finding has been slow because the genetic component is complex. Accumulating data on various diabetes-related phenotypes suggest that so-called “type 2 diabetes” is likely a collection of many diseases due to varying but often overlapping underlying mechanisms. As such, the search for the once hoped-for simple genetic basis of type 2 diabetes has proved elusive. This year marks the application of the next gene-finding tool to the study of type 2 diabetes, the genome-wide association study (GWA). This type of study is the logical extension of the candidate gene association study, an approach in which a few (1–20 or so) single nucleotide polymorphisms (SNPs) within a single gene are tested for association with the phenotype of interest. By that approach, the candidate gene is chosen based on biochemistry or physiology related to that phenotype. The candidate gene approach has identified some genes but has not yielded the definitive picture of the genetic contribution to type 2 diabetes (Table 1; reviewed in [1]). In contrast, the GWA approach tests every gene by testing the association of SNPs in every known gene (∼100,000 SNPs) or in both known genes and in regions outside of genes throughout the genome (∼300,000 to 1 million). The GWA is therefore not biased by a priori assumptions based on prior observations of the phenotype (e.g., kinetics of insulin signaling, glucose-mediated insulin secretion, etc). Therefore, the strength of the GWA is that it has the potential to identify genes of high genetic effect that were previously unsuspected as candidates. The latter might be because little was known about the genes previously or because investigators simply had not addressed the action of the products of these genes …