Much of the speculation about missing heritability from GWAS has focused on the possible contribution of variants of low minor allele frequency (MAF), defined here as roughly 0.5%<MAF <5%, or of rare variants (MAF<0.5%). Such variants are not sufficiently frequent to be captured by current GWA genotyping arrays14,41, nor do they carry sufficiently large effect sizes to be detected by classical linkage analysis in family studies (Fig. 1). Once MAF falls below 0.5%, detection of associations becomes unlikely unless effect sizes are very large, as in monogenic conditions. For modest effect sizes, association testing may require composite tests of overall ‘mutational load’, comparing frequencies of mutations of potentially similar functional effect in cases and controls.
