Chapter 11: Genome-wide association studies.

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.

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.

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.