After a GWAS finds SNPs linked to a disease, researchers then perform a "fine-mapping" study by additional genotyping--sequencing of the gene regions near the SNP signal, to uncover an altered gene that harbors a mutation responsible for the disease. Most of the results, said Hakonarson, have been unimpressive, yielding causal variants with very small effects. "These efforts have not identified 'smoking gun' mutations that cause a disease," he added.

The current study uses different assumptions. Instead of inferring the presence of a nearby common disease-causing gene linked to a given SNP, the researchers propose that numerous rare causal variants may separately "hitchhike" on the same tag SNP, often from locations further away than those scrutinized in conventional fine-mapping approaches. Those more distant genetic factors are typically overlooked in the conventional GWAS approach. By missing these actual causative gene variants, the conventional technique underestimates the strength of their effect on the disease.

By applying their methods to real DNA samples from patients with genetic hearing loss, the researchers' approach helped them to select from GWAS data a subset of cases for sequencing analysis that were most likely to carry causative mutations. Sequencing the DNA in this subset, the study team found that the majority of those patients carried an actual mutation known to cause hearing loss. "Our technique suggests that when we do our resequencing follow-up studies, we can identify people who are much more likely to carry a causative gene," said Kai Wang, who analyzed the dataset. Hakonarson added, "We present a more efficient approach for mining GWAS data to find the actual causative gene variants that will have future utility in designing therapies."

Source: Children's Hospital of Philadelphia