They then tested their approach on two large sample sets for well-characterized disorders, sickle cell disease and genetic hearing loss, in which causative genes were already known. They found a similar pattern of synthetic associations between rare and common gene variants. "Under conventional interpretations, GWAS found only modest contributions for associations with the gene that we know causes hearing loss," said Hakonarson. "Our study shows that conventional interpretation may undervalue the contribution of such gene variants in hearing loss, and we suggest that similar underrepresentation of effect sizes by common variants may occur in many other genetic disorders."

The usual assumption in GWAS is that disease-causing variants are located relatively close to the common variants that capture them (referred to as tagging SNPs). Researchers usually seek out causative variants that travel together with the common variant along the genome; in technical terms, the nucleotides are in relatively strong linkage disequilibrium. "Our study found the causative genes may be two to four times farther away than researchers tend to search, so their effect sizes are poorly captured," said Hakonarson.

Hakonarson and Wang are conducting follow-up studies, some in collaboration with Goldstein, to expand and refine the gene-hunting model using resequencing techniques. The immediate implications of this model, said Hakonarson, affect researchers more than clinicians. But eventually, he adds, this work may improve diagnostic evaluation for patients, furthering the goal of personalized medicine tailored to a patient's genetic profile. At the same time, technological advances in automated gene sequencing will enable researchers to work faster as well as smarter.

Source: Children's Hospital of Philadelphia