variants, defined here to have a minor allele frequency (MAF) of less than 1%, each of modest effect, but residing within the same functional unit, for example, a gene. Joint analysis of rare variants within a gene, searching for accumulations of minor alleles within the same individual, may thus provide signals of association with complex phenotypes that could not have been identified through traditional association analysis of single nucleotide polymorphisms (SNPs), typically defined to have MAF of at least 1%. For example, minor alleles at multiple rare variants in ABCA1, APOA1 and LCAT have been demonstrated to contribute collectively to low plasma levels of high-density lipoprotein cholesterol [Cohen et al., 2004].
