A major argument against rare variants as the predominant source of missing heritability comes from the analysis of allele frequency distributions of GWAS data19. Rare allele proponents point out that it is difficult to model the true distribution of rare variants, and that they are under-represented on genotyping arrays, which complicates the interpretation. Nevertheless, considerations of linkage disequilibrium using standard quantitative genetic theory19 place strong constraints on the number of rare variants and their range of effect sizes that would be compatible with them making a major contribution yet remaining undetected in GWAS, as explained in Figure 2. Furthermore, analyses of the distribution of risk allele frequencies across 8 traits argues that if anything minor allele frequencies are skewed to be greater than 0.2, providing strong empirical evidence that rare alleles are not alone responsible53. No-one doubts that some fraction of the total risk for any complex disease is due to rare alleles, but these studies argue that it is not the majority.
