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Decode-Led GWAS Uncovers Glaucoma Risk Variant

By Andrea Anderson

NEW YORK (GenomeWeb News) – A Decode Genetics-led research team reported online in Nature Genetics yesterday that it has identified a risk variant linked to the eye condition primary open-angle glaucoma.

"This is shedding a little bit of a light on [glaucoma] pathogenesis — on the way in which one of the most common causes of blindness comes about," senior author Kari Stefansson, executive chairman and president of research at Decode Genetics, told GenomeWeb Daily News.

The international team initially identified the glaucoma-associated variant, which falls near genes coding for membrane proteins known as caveolin 1 and caveolin 2, through a large genome-wide association study involving tens of thousands of individuals with or without the eye disease in Iceland. The team's follow-up studies in individuals from Sweden, the UK, Australia, and China suggest the variant is rarer — but linked to higher glaucoma risk — in Chinese populations than in European populations.

"Discoveries such as today's ... are important because we can fold them directly into tests to target screening and to detect and treat more disease earlier," Stefansson said in a statement. "Moreover, among Chinese this latest SNP alone can define a small fraction of the population that should be very carefully screened."

In 2007, researchers from Decode and elsewhere reported in Science that they had identified a pair of common variants associated with another type of glaucoma, called exfoliation glaucoma, in individuals from Iceland and Sweden.

For the current study, the team turned their attention to primary open-angle glaucoma, a degenerative eye condition in which the optic nerve becomes damaged over time. While treatments such as eye drops or surgery can help ease pressure on the optic nerve, the disease can lead to blindness.

Several primary open-angle glaucoma risk factors — ranging from age to hypertension and diabetes — have been identified. But even though it can run in families and has been linked to about 20 loci affecting a handful of genes, the researchers noted, questions remain about the genetic underpinnings of the heterogeneous condition.

To look for common variants influencing the condition, Stefansson and his co-workers first used the Illumina HumanHap300 or HumanHapCNV370 bead chip arrays to genotype 1,263 Icelandic individuals with primary open-angle glaucoma and 34,877 unaffected controls at more than 300,000 SNPs.

When the team looked for variants associated with primary open-angle glaucoma, they found a pair of chromosome 7 SNPs that reached genome-wide significance. The variants fell in a shared linkage disequilibrium block between the caveolin 1 and 2 genes CAV1 and CAV2.

One of the two SNPs, called rs4236601, remained associated with glaucoma after accounting for linkage disequilibrium — an association the researchers subsequently verified in a replication cohort that included 200 primary open-angle glaucoma cases and 194 controls from Sweden, 871 cases and 865 controls from the UK, and 1,104 cases and 1,001 controls recruited through three different studies in Australia.

But, they noted, the apparent degree of glaucoma risk linked to the SNP varied by population. For instance, in Icelandic and Swedish populations the team estimated that the variant increases primary open-angle glaucoma risk by roughly 33 percent. But glaucoma risk associated with the variant seemed to be slightly lower in populations from the UK and Australia.

Overall, researchers found that between about 20 and 28 percent of those tested in Iceland, Sweden, the UK, and Australia had one copy of the risk allele, while six percent had two copies — a condition that apparently increases primary open-angle glaucoma risk by about 60 percent in individuals from those populations.

On the other hand, when researchers tested 299 cases and 580 controls from Hong Kong and Shantou, a city in China's Guangdong province, they found that just 0.7 percent of individuals tested carried the risk allele.

In the Chinese population, though, the variant corresponded to a much higher glaucoma risk: results from the Hong Kong and Shantou cohorts indicated that individuals carrying the variant were more than five times as likely to have glaucoma as those who do not.

"This is a sequence variant that is relatively common in Europeans, has relatively small effects, but is rather rare and has large effects in the Chinese," Stefansson said.

For his part, Stefansson proposes that this finding not only reflects the importance of both genetic and environmental factors in common diseases, but also offers new clues about human evolution and the influence of geography on such diseases.

"We are beginning, gradually, to gather data that support the notion that the variants in the sequence that affect the risk of common diseases have some geographic specificity," he noted. "What this basically means is that when you're developing diagnostics, you have to be aware of the potential geographic differences. You have to map them out so you can report different results in different populations."

And, he explained, such findings suggest clinical trials in individuals of European descent may not be indicative of drug or treatment response in populations from other parts of the world.

"We should know these differences, we should celebrate them, and we should use the understanding of these differences to make medicine more suitable to the needs of the individual rather than looking at us as one monolithic species," Stefansson said.

The researchers have not yet narrowed in on the functional consequences of the newly detected glaucoma risk variant. Still, because the variant falls near genes coding for caveolin proteins involved in molecular trafficking and signal transduction, they noted, the team suspects it might alter signaling processes previously linked to glaucoma.

Although they found that the CAV1 and CAV2 neighboring SNP did not alter the expression of these genes in blood or adipose tissue, the team has not ruled out the possibility that it may have tissue-specific effects on gene expression. Stefansson noted that the researchers are starting to gather eye autopsy samples to look at how the glaucoma-associated variant affects eye tissue.

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