Low frequency variants could have substantial effect sizes (increasing disease risk two- to threefold) without demonstrating clear Mendelian segregation, and could contribute substantially to missing heritability42. For example, 20 variants with risk allele frequency of 1% and allelic odds ratio (or probability of an event occurring divided by the probability of it not occurring, compared in people with versus without the risk allele) of three would account for most familial aggregation of type 2 diabetes. There are relatively few examples of such variants contributing to complex traits, possibly owing to insufficiently large sample sizes or insufficiently comprehensive arrays.
