Genome-Wide Approaches to Finding Novel Genes for Lipid Traits

he sequencing of the human genome and identification of common human genetic variations have made high- throughput interrogation of the human genome possible. Genome-wide association studies (GWASs) are now an exciting new approach to discovering the genetic variations underlying complex diseases and phenotypes.1 These studies allow "hypothesis-free" interrogation of the entire genome without the biases of candidate gene approaches. The GWAS approach has both highlighted candidate genes previously identified by the study of mendelian disorders or by basic biological investigation and illuminated novel genomic loci clearly associated with the phenotype or disease of interest that were previously unsuspected. These studies are only the beginning of a shift in genetics and genomics that has the potential to alter our understanding of physiology and patho- physiology and to profoundly affect clinical medicine for generations to come. However, relatively few genes identi- fied through GWASs have been rigorously assessed for their function in physiological processes, used for clinical risk assessment and prediction, or validated as bona fide targets for drug development. Articles see pp 10 and 21 The plasma lipid phenotypes of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides have been a fertile early testing ground for GWASs. They are quantitative heritable traits strongly associated with cardiovascular risk and widely mea- sured in clinical practice, making them methodologically, clinically, and logistically attractive for investigation with genome-wide approaches. In the lipid GWASs reported to date, many genes previously identified with mendelian lipid disorders (Table 1) have been significantly associated with lipid phenotypes,2-7 confirming that these genes also are