Many rare alleles account for common genetic diseases

The last three years have witnessed an explosion of genome-wide association studies. A catalog of results at the National Human Genome Research Institute (www.genome.gov/gwastudies) currently lists 545 publications associating 2,664 single nucleotide polymorphisms with human traits, and top journals in the field (such as Nature Genetics) have devoted themselves almost entirely to the publication of GWAS results. However, as summarized in an excellent review in the current issue of Cell (McClellan and King, "Genetic Heterogeneity in Human Disease"), it appears that "common risk variants fail to explain the vast majority of genetic heritability for any human disease, either individually or collectively (Manolio et al., 2009)." Instead, while "most human variation is ancient and shared," most alleles, including those that cause disease, are recent and rare. "Rare large-effect mutations are now recognized as the causes of many different common medical conditions." This makes sense in that deleterious alleles should be eliminated relatively quickly by selection, but leaves us unsure of how to interpret the available GWAS data. The good news is that genome sequencing will soon be used to discover rare variants in many people. At least for the researchers, "it will be fun to sort out."