Genomewide association studies- Where is Big Picture

Today’s New York Times health research section carries an interesting article Genes Show Limited Value in Predicting Diseases. Story is based on a set of commentaries appeared recently on online version of The New England Journal of Medicine (1, 2, 3, 4). A genomewide association study (GWA study or GWAS) is an approach that involves rapidly scanning for markers such as SNPs across the genomes of many people to find genetic variations associated with a particular disease. A GWA study normally requires two groups of participants: people with the disease (cases) and similar people without (controls). Generally GWA studies aim to identify genetic variations that contribute to common, complex diseases, such as cancer and diabetes. More than 100 GWA studies have been conducted, resulting the identification of hundreds of genetic variants that are associated with the risk of more than 40 diseases. Hirschhorn hint that the main goal of these studies is not prediction of genetic risks but rather discovery of biological pathways underlying polygenic diseases and traits, and the primary goal of these studies have been always misunderstand. Success of GWA studies relies on much of the risk of common diseases being due to common genetic variants, although there are not very strong evidence to support this. There are examples of rare variants influencing common disease, indicating that both rare and common variants may influence common diseases, although we do not know which one is more influential. Goldstein argue on same line and suggest that the genetic burden of common diseases must be mostly carried by large numbers of rare variants. He also suggests that that GWA studies will not yield too few loci but rather too many and theoretical it would not provide any useful biologic insights (“in pointing at everything, genetics would point at nothing”). He further comments

though genomewide association studies have worked better and faster than expected, they have not explained as much of the genetic component of many diseases and conditions as was anticipated. We must therefore turn more sharply toward the study of rare variants.

Kraft et al. also suggest that “many, rather than few, variant risk alleles are responsible for the majority of the inherited risk of each common disease”, although they disagree with Goldstein’s observation that GWA studies will be contradicted by their own findings. They indicate it is too early to conclude something like that and “many more common variants conferring a risk of disease will be identified in the next several years”.