Diabetic retinopathy: Association mapping holds key to understanding mechanism of major diseases

Fort Lauderdale, FL-Association mapping is a new perspective on the use of genomic tools that allows the study of common disorders, such as diabetic retinopathy (DR), and tries to tease apart genes as a way of studying disease pathophysiology. Aravinda Chakravarti, PhD, explained this approach at the annual meeting of the Association for Research in Vision and Ophthalmology.

AMD initiation

Dr. Chakravarti explained how the notion of association mapping developed.

"Complex, that is, non-Mendalian, inheritance essentially arises from the accumulation of common polymorphisms with small to modest allelic effects at multiple genes that accumulate to produce risk in the common disorders of our time," he said.

"The common polymorphism implies that in any group of individuals, not necessarily patients, sequencing the genome at a particular spot will identify risk factors of a disease," Dr. Chakravarti continued. "This would be clearly appropriate for DR, in which initial studies have shown disease heritability of about 25% and a degree of familial aggregation that is typical of most common phenotypes."

Benefit of shared ancestry

Association mapping works for any trait, he said, because when the underlying mutation is common and has one origin, then it can be identified by finding the individual variant by association with neighboring markers.

"This is a remarkable principle because, even if the gene or marker is unknown, because of shared genetic ancestry, all individuals can be used to search a region and then, by location, find the gene," he said.

To meet this need, however, a map of common worldwide variants was needed. Various investigators worldwide sampled DNA from normal individuals and created such a map under the aegis of the International HapMap Project. After the DNA samples were collected, sequencing was done to identify common variants that differed among individuals around the world.

Dr. Chakravarti reported that study of the DNA samples has yielded roughly 4 million markers, more than 2 million of which are common, with frequencies greater than 5% in individuals from Europe, Asia, or Africa.

"This brings into practical use what had been referred to as whole genome association scans," he said, noting that they can be remarkably powerful tools in large sample sizes.