Topic Introduction Introduction to Genetic Association Studies

Genetic association studies test for a correlation between disease status and genetic variation to identify candidate genes or genome regions that contribute to a specific disease. A higher frequency of a singlenucleotide polymorphism (SNP) allele or genotype in a series of individuals affected with a disease can be interpreted as meaning that the tested variant increases the risk of a specific disease (although several other interpretations are also valid; see the following sections). SNPs are the most widely tested markers in association studies (and this term will be used throughout), but microsatellite markers, insertion/deletions, variable-number tandem repeats (VNTRs), and copy-number variants (CNVs) are also used. Association studies are a major tool for identifying genes conferring susceptibility to complex disorders. These traits and diseases are termed “complex” because both genetic and environmental factors contribute to the susceptibility risk. Extensive experience in genetic studies for many complex disorders (such as diabetes, heart disease, autoimmune diseases, and psychiatric traits) confirms that many different genetic variants control disease risk, with each variant having only a subtle effect. Associations with polymorphisms in candidate genes have been confirmed in many different diseases (Lohmueller et al. 2003), and genome-wide association studies (GWAS) are identifying many novel associations in genes that had not been strong a priori candidates for the disease under test (Wellcome Trust Case Control Consortium 2007). However, the modest increase in risk implies that large well-designed and analyzed studies are required to detect and confirm signals for association. This article outlines the design and analysis of genetic association studies, but it focuses specifically on case–control studies in candidate genes or regions. Even in this era of genome-wide studies, case– control studies still form the majority of published reports. We illustrate the importance of quality control in performing these studies, describe basic analytical strategies for a SNP, and point the reader toward methods for analyzing haplotypes or multiple markers. We also highlight some of the pitfalls of performing powerful, accurate association studies and discuss how these challenges are reflected in the contradictory literature for many disease–gene investigations. In addition to GWAS, other approaches to genetic association studies include family-based association studies and quantitative trait locus studies; these approaches are not addressed in any detail here.