Risch and Merikangas (21) noted that small genetic effects could be detected with greater power by association analyses, and proposed that genomewide LD mapping (GWAS) could be applied if technologies were developed to study SNP frequencies in all genes, contrasting in ill cases vs. control subjects, or cases and their parents (associated alleles are transmitted to ill offspring more often than expected by chance). Lander (9) proposed the common disease common variant (CDCV) hypothesis. Comparing any two people, most sequence differences are ancient, “common” SNPs (by convention, varying on at least 5% of chromosomes in a population), which Lander argued must confer at least some (not all) of the genetic risk for common diseases. He proposed cataloguing them and studying their association to disease in large samples. SNPs become common because they are neutral or favorable with respect to survival (e.g., evolutionary pressures can rapidly increase frequencies of adaptive SNPs in gene-regulating regions). But some have mildly harmful effects, perhaps depending on environmental conditions (e.g., preserving fat during an ice age but leading to obesity in the fast food era).
