Select: GWAS Gets Functional

By identifying regions of the human genome linked to complex traits, genome-wide association studies (GWAS) are revolutionizing how researchers investigate common diseases, such as cancer and cardiovascular disease. However, as with many great scientific breakthroughs, skeptics have questioned the usefulness of this approach and whether GWAS can provide insights into the molecular mechanisms underlying these diseases. This Select highlights recent research showing that common DNA variations identified by GWAS can indeed contribute to a disease phenotype, and investigating the function of these variants can be highly rewarding, yielding insights of both clinical and biological importance. Approximately 30% of Americans suffer from cardiovascular disease, and high levels of low-density lipoprotein (LDL) cholesterol in the blood is one major risk factor for this common disease. Therefore, a major goal of the pharmaceutical industry is to identify new approaches for lowering LDL cholesterol. Previous GWAS pinpointed a noncoding region on chromosome 1, the 1p13 locus, as strongly associated with increased risk of heart disease and high levels of LDL cholesterol. Now Musunuru et al. (2010) determine the function of these DNA variants and, in the process, uncover a new pathway that regulates cholesterol metabolism. Moreover, they identify a protein, sortilin 1 (SORT1), that directly reduces the blood levels of LDL cholesterol in mice. Sequence variations outside coding regions often modulate the expression of nearby genes. Therefore, Musunuru et al. first profile the expression of seven genes surrounding the 1p13 locus in human tissue samples. Interestingly, although SORT1 is not the closest gene to the risk allele, its gene expression was most strongly affected by sequence variations in the disease locus; the allele associated with low levels of LDL cholesterol boosts SORT1 gene expression by almost 4-fold in the liver. Sequencing and DNA-binding assays reveal that this protective allele, which is 120 kb upstream of the SORT1 promoter, creates a binding site for C/EBPa, a transcription factor that regulates numerous metabolic processes in the liver. SORT1 is a membrane receptor in the Golgi network that controls intracellular trafficking. To confirm its importance in cholesterol metabolism, Musunuru and colleagues silence the expression of Sort1 in the liver of mice, which increases LDL cholesterol by 2-fold. In contrast, overexpressing Sort1 reduces total plasma cholesterol levels by 70%. These results elegantly demonstrate that characterizing the function of risk alleles from a GWAS can have huge payoffs—the discovery of critical components contributing to a common disease and new …