Research Techniques Made Simple: Using Genome-Wide Association Studies to Understand Complex Cutaneous Disorders

Abstract

Complex cutaneous disorders result from the combined effect of many different genes and environmental factors, with individual genetic variants often having only a modest effect on disease risk. The ability to examine large numbers of samples is required for correlating genetic variants with diseases/traits. Technological advances in high-throughput genotyping, along with mapping of the human genome and its associated inter-individual variation, have allowed genetic variants to be analyzed at high density in large case-control cohorts for many diseases, including several major skin diseases. These genome-wide association studies focus on showing differences in the frequencies of variants between case and control groups, rather than co-transmission of a variant and disease through a family, as is done in linkage studies. In this review, we provide overall guidance for genome-wide association study analysis and interpreting the results. Additionally, we discuss challenges and future directions for genome-wide association studies, focusing on translation of findings to provide biological and clinical implications for dermatology.

Figure 1. Basic illustrations for GWAS

a) Chromosomes are 'sliced & diced' by meiosis over thousands of generations, such that only 'small chunks' have been preserved (linkage disequilibrium) - each haplotype is represented by a different color, with the crossing point of the blue and orange haplotypes indicating cross-over (i.e. the exchange of haplotypes during meiosis) - the square brackets indicate a mutation from A to G, which occurs within a small chunk of the blue haplotype; b) Hybridization and fluorescence technologies infer genotypes for each marker across different samples (here represented as dots). The x-axis corresponds to the contrast between the two fluorescent intensities for the two alleles; the y-axis is the average intensity. Samples with homozygous genotypes are colored in red or blue, and the heterozygous genotype is colored purple. Classification of genotypes might not work well if the intensities of the samples do not fall in any one of the three clusters (black); c) GWAS identify significant markers (i.e. where there are considerable differences in alleles between cases and controls) for a particular trait using a statistical model - these markers may lead to a specific phenotype through changes to proteins or regulatory mechanisms.