Mapping complex disease genes using linkage disequilibrium and genome-wide association scans

Remarkable advances have occurred recently in our ability to detect genetic polymorphisms contributing to susceptibility to complex human disease. The technology for detecting and scoring single nucleotide polymorphisms (SNPs) has undergone rapid development, yielding extensive catalogues of these polymorphisms across the genome. Population-based maps of the correlations among SNPs (linkage disequilibrium) have been developed to accelerate the discovery of variants contributing to complex diseases in humans, and have been applied in genome-wide association studies. These advances coincide with an increasing recognition of the importance of very large sample sizes for studying genetic effects and have resulted in the discovery of over 150 validated new genes for complex phenotypes since early 2007. This chapter reviews the state of knowledge about the structure of the human genome as related to SNPs and linkage disequilibrium, discusses the application of this knowledge to mapping complex disease genes using genome-wide association studies, considers related methodological and study design issues, and considers the future of genetic association studies.