Genetic epidemiologic methods for common, complex diseases: application to cardiovascular disease

Historically, genes harboring causative mutations for rare Mendelian diseases have been relatively easy to identify. Recent attempts to discover the genetic causes of complex diseases that are relatively common in human populations have, however, not been as successful. The difficulties encountered in the genetic study of common diseases include problems with study design, study population, definition of phenotype, and statistical approach. Genetic studies of cardiovascular disease phenotypes provide a prime example of these problems. Specifically, coronary heart disease is a prevalent disease with multiple risk factors including many potential environmental and inherited contributors. Unfortunately, the deciphering of the genetic component for coronary disease has experienced many promising findings that have not been corroborated. The aims of this dissertation project were to evaluate genetic contributions to cardiovascular diseases, and coronary heart disease in particular, using large populations with well-defined phenotypes and well-characterized genetic factors, and to explore improved methods of genetic analysis that account for the complexity of genetics and environment. These aims were accomplished through application to the three primary areas of genetic epidemiology: population genetic analysis, linkage analysis of phenotypes to genetic loci, and candidate genes association analysis.