Mapping of susceptibility genes for obesity, type 2 diabetes, and the metabolic syndrome in human populations

Obesity, type 2 diabetes (T2D), and metabolic syndrome (MS) are complex diseases causing considerable morbidity and mortality worldwide. These traits or diseases have multifactorial or oligogenic inheritance patterns, and are influenced by multiple genes, environmental factors, and their interactions. There have been continued efforts to localize and identify genetic variants that contribute to susceptibility to these diseases, although knowledge on actual causal variants influencing these traits is extremely limited. In this chapter, we first present an epidemiological overview on obesity, T2D, and MS, followed by a brief overview on the three genetic mapping approaches: candidate gene association study, and hypothesis-free genome-wide linkage and association approaches that have been widely used to decipher the genetic architectures of these complex diseases. We will then provide a comprehensive review on the common susceptibility loci localized to date, ~ 80 loci for obesity-related traits, ~90 loci for T2D and its related metabolic traits, and ~50 loci for MS and its component traits with a brief discussion on replication studies, lessons learned beyond GWAS, and potential sources of missing heritability. Finally, we provide a brief review of follow-up and fine-mapping studies, including next-generation sequencing studies, and their role in the discovery of rare variants with potential large effect sizes, which may contribute to the issue of missing heritability and facilitate further biological insights. Ultimately, susceptibility gene discovery efforts could help develop novel preventive and treatment strategies for obesity, T2D, and MS, and may eventually lead to personalized medicine.