Introduction to Genetic Association Studies Hensin Tsao, Jose C. Florez  Journal of Investigative Dermatology  Volume 127, Issue 10, Pages 2283-2287 (October 2007) DOI: 10.1038/sj.jid.5701054 Copyright © 2007 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 General schema for genetic association studies. All genetic association studies have two arms: a phenotype arm and a genotype arm. Clinicians are often engaged in the phenotyping arm in an effort to define the distinguishing features of common diseases. Because medical diagnoses rarely capture all phenotypes attendant to a disorder, not all clinical traits are documented. For instance, if blood pressure is not ascertained in melanoma cases, a relationship between hypertension and melanoma risk may not be discernible. The genotyping arm, as it pertains to contemporary association studies, starts with the decisive nomination of markers, in particular, singlenucleotide polymorphisms (SNPs). Prior to SNPs, restriction fragment length polymorphisms, ABO blood groups, and microsatellite repeats were all commonly used. If there are specific candidate genes known to be involved in the pathogenesis of the disorder (e.g., BRAF in melanoma), a targeted sampling of SNPs (e.g., SNPs in the BRAF locus) may be a reasonable hypothesis-derived search for risk alleles. If one assumes a more agnostic approach, then a “genome-wide association study” (GWAS) that systematically surveys representative SNPs across all chromosomes would be appropriate. The central engine of all GWASs is a determination of the prevalence of a certain SNP allele in both cases and controls. Conceptually, overrepresentation of any allele among the cases represents a candidate risk allele, whereas increased prevalence among controls defines a protective allele. These initial putative risk alleles are then further filtered by statistical adjustments for multiple hypothesis testing. SNPs can be tabulated by P value if limited in number or displayed across the entire genome if it is a GWAS. Journal of Investigative Dermatology 2007 127, 2283-2287DOI: (10.1038/sj.jid.5701054) Copyright © 2007 The Society for Investigative Dermatology, Inc Terms and Conditions