Don’t throw the baby out with the bathwater: Enabling a bottom-up approach in genome-wide association studies
- Sean E. McGuire1,2 and
- Amy L. McGuire3,4
- 1 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA;
- 2 Division of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
- 3 Center for Medical Ethics and Health Policy, Baylor College of Medicine, Houston, Texas 77030, USA
This extract was created in the absence of an abstract.
The current model for conducting genome-wide association studies (GWAS) is primarily phenotype-driven. In this “top-down” approach, the model is the case-control study, where participants are enrolled based on the presence or absence of a clinical phenotype, for example, cardiovascular disease or breast cancer (Pennisi 2007; Wellcome Trust Case Control Consortium 2007). The International HapMap Project has identified a large number of single nucleotide polymorphisms (SNPs) in the human population that enable investigators to genotype subjects for these various polymorphisms and determine associations with a phenotype of interest (Fig. 1A) (International HapMap Consortium et al. 2007).
Top-down and bottom-up approaches to genome-wide association studies. (A) In the top-down approach, clinical investigators assemble cases and controls based on a particular phenotype. Genotypic information is then acquired and deposited in dbGaP. (B) In the bottom-up approach, basic investigators identify in vitro phenotypes based on SNP data in dbSNP. They then access clinical populations and controls with whom they are able to conduct “targeted phenotyping.”
Commercially available SNP arrays allow researchers to easily genotype from 100,000 to 1,000,000 SNPs per individual, providing “whole-genome” coverage (Affymetrix GeneChip System, http://www.affymetrix.com/products/system.affx; Illumina, Inc., http://www.illumina.com/pages.ilmn?=39). Typically, only a handful of these SNPs are associated with the particular phenotype under study and are present in only a small fraction of the study population because the minor alleles (variants) tend to be present at low frequencies. The vast majority of SNPs are not associated with the phenotype under study and are ignored because they are not relevant to the phenotype under investigation in the GWAS. For example, the Wellcome Trust Case Control Consortium genotyped 500,000 SNPs in 14,000 cases representing seven common diseases and an additional 3000 controls. From this extensive genotyping (17,000 × 500,000), they identified 24 independent associations (Wellcome Trust Case Control Consortium 2007). The …
