Chapter 11: Genome-wide association studies

Abstract

Genome-wide association studies (GWAS) have evolved over the last ten years into a powerful tool for investigating the genetic architecture of human disease. In this work, we review the key concepts underlying GWAS, including the architecture of common diseases, the structure of common human genetic variation, technologies for capturing genetic information, study designs, and the statistical methods used for data analysis. We also look forward to the future beyond GWAS.

Figure 1. Spectrum of Disease Allele Effects.

Disease associations are often conceptualized in two dimensions: allele frequency and effect size. Highly penetrant alleles for Mendelian disorders are extremely rare with large effect sizes (upper left), while most GWAS findings are associations of common SNPs with small effect sizes (lower right). The bulk of discovered genetic associations lie on the diagonal denoted by the dashed lines.

Figure 2. Linkage and Linkage Disequilibrium.

Within a family, linkage occurs when two genetic markers (points on a chromosome) remain linked on a chromosome rather than being broken apart by recombination events during meiosis, shown as red lines. In a population, contiguous stretches of founder chromosomes from the initial generation are sequentially reduced in size by recombination events. Over time, a pair of markers or points on a chromosome in the population move from linkage disequilibrium to linkage equilibrium, as recombination events eventually occur between every possible point on the chromosome.

Figure 3. Indirect Association.

Genotyped SNPs often lie in a region of high linkage disequilibrium with an influential allele. The genotyped SNP will be statistically associated with disease as a surrogate for the disease SNP through an indirect association.