Population Genetics and Pharmacogenetics

Genome-wide association studies (GWAS) have been hugely successful in identifying thousands of genetic loci robustly associated with hundreds of disease and other human traits. Since the first GWAS publication in an endocrinology-related topic, obesity in 2007, these studies have very rapidly increased in size and productivity. In 2011, this chapter is now largely dominated by a number of ‘mega’ or greatly-expanded GWAS papers, each involving over 100,000 participants in the combined initial discovery and replication phases. Hundreds of new genes, or genetic loci, are reported for adult height, lipids, BMI, waist-hip ratio, type 2 diabetes (T2DM), and age at menarche. New topics for GWAS are also described, including polycystic ovary syndrome (PCOS) and hypospadias. Prior to this wave of expanded studies, some commentators had criticized the relatively minor effect sizes of common genetic variants. They argued that the previous GWAS papers, already involving tens of thousands of individuals, would have already found the loci with the strongest effects, and that further expansion would only find variants with effects that are too small to be of biological interest. In addition to simple identification of genetic loci, many of the current papers describe key applications and supporting experimental data that underline the new biological advances. The GWAS locus at HMGCR is held up as an important illustration of the potential application of these novel findings, being associated with only a very modest change in LDL cholesterol levels, yet it encodes the target of statins that currently benefit tens of millions of patients. We should not forget that prior to the GWAS era we had to endure barren decades of linkage mapping and weakly replicable candidate genotyping studies. Eric Lander’s review article published in February 2011 on the 10th anniversary of the Human Genome Project describes the remarkable extent of achievements in the last decade and the rapid pace of current research efforts towards the routine use of sequencing as ‘a simple and inexpensive general-purpose tool throughout biomedicine’.