AMD-Risk Genes: Global Collaborative Finds 7 New Sites

Linda Roach

March 19, 2013

An international research collaborative has identified 7 new genetic loci associated with an increased risk of developing age-related macular degeneration (AMD), bringing the total number of known AMD-susceptibility loci in the human genome to 19.

The AMD Gene Consortium reports the results in an article published online March 3 in Nature Genetics. Scientists from 18 research groups in 14 countries formed the consortium in the spring of 2010 with the goal of speeding up the search for AMD susceptibility genes.

The report on their first collaborative effort describes a series of interrelated analyses that identified the 7 new AMD-associated loci, confirmed 12 other previously identified loci, and suggested where researchers should look next for genetic clues to AMD.

Lead authors of the study include Gonçalo R. Abecasis, DPhil, University of Michigan, Ann Arbor; Lindsay A. Farrer, PhD, Boston University, Massachusetts; Iris Heid, PhD, University of Regensburg, Germany; and Jonathan L. Haines, PhD, Vanderbilt University, Nashville, Tennessee. 

The study began with consortium members contributing their existing data from previous genome-wide association studies to a single genetic database on more than 7600 people with advanced AMD (dry type, neovascular, or both) and more than 50,000 controls. Genome-wide  association studies look for differences in the frequency of single nucleotide polymorphisms (SNPs) in a disease-affected cohort compared with controls.

A meta-analysis of the pooled data identified 32 candidate loci for closer examination. Then, in a targeted association study, the researchers looked at those 32 loci for allelic variants in an additional cohort of more than 17,000 people (more than 9500 with advanced AMD and more than 8200 controls). This targeted analysis, combined with the analysis of the original genome-wide association data, allowed the scientists to hone in on the 19 AMD susceptibility loci (P < 5 × 10-8 for each locus), they report.

At each step in this series, 1 or more statistical verification techniques were used to test the outcomes for statistical significance. The researchers ruled out confounding factors by repeating the original analysis for each of the 19 SNPs, adding in adjustments for age, sex, ethnicity, and AMD subtype of participants. In addition, results of meta-analyses were validated by 4 independent teams.

'Explosion' in Genomics

The broad scope of the consortium's study would not have been possible for any single AMD research group, a US group leader in the consortium, Anand Swaroop, PhD, told Medscape Medical News.

"They would not have enough [statistical] power to do this, but it was so easy for us by joining hands to find out what was going on," explained Dr. Swaroop, who is chief of the National Eye Institute's Laboratory of Neurobiology and Neurodegeneration and Repair, Bethesda, Maryland.

Mark E. Kleinman, MD, assistant professor of ophthalmology at the University of Kentucky, Louisville, agreed in an interview with Medscape Medical News. "This paper really brings to fruition the power of international collaboration on genomics. It signifies the explosion that is going on in the genomics field. In 2005 we finally had 1 polymorphism associated with AMD. Since then we've had new ones year after year, maybe 1, 2, or 3 per study. This is by far the largest one that's ever come out."

Currently, the AMD Gene Consortium is continuing its search for AMD-associated genes by looking for the 19 SNPs in the exomes (protein-coding regions of the DNA) of more than 40,000 AMD cases and controls, Dr. Swaroop said. Other researchers will do targeted DNA resequencing, in the regions around the 19 identified loci, in more than 3000 cases and controls, he said.

The research was funded by grants from foundations and/or government-related agencies in Australia, the European Union, France, Germany, India, Japan, the Netherlands, Republic of Korea, Singapore, the United Kingdom, and the United States. Dr. Swaroop has patent interests related to genetic discoveries in AMD. The online version of the paper has a full list of financial interests for other consortium scientists. Dr. Kleinman has disclosed no relevant financial relationships.

Nat Genet. Published online March 3, 2013. Abstract