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Consortium Links Two Dozen New Loci to Nearsightedness Risk

NEW YORK (GenomeWeb News) – A genome-wide meta-analysis has uncovered 24 new loci linked to myopia risk, the Consortium for Refractive Error and Myopia reported online in Nature Genetics yesterday.

The group, led by Christopher Hammond, a professor at King's College London School of Medicine, discovered 16 new loci linked to nearsightedness in a cohort of European ancestry, eight of which replicated in an Asian ancestry cohort. A further eight loci were found in a combined analysis of cohorts. The loci uncovered were located near genes involved in neurotransmission and eye development, suggesting possible ways in which the gene variants could exert their effects on the eye and sight. Additionally, the consortium calculated that these SNPs could dramatically increase risk of myopia.

"We already knew that myopia — or short-sightedness — tends to run in families, but until now we knew little about the genetic causes," Hammond said in a statement. "This study reveals, for the first time, a group of new genes that are associated with myopia and that carriers of some of these genes have a 10-fold increased risk of developing the condition."

In the first stage of their study, Hammond and the CREAM consortium examined about 2.5 million SNPs in 37,382 people from 27 populations of European ancestry, finding 309 SNPs that reached genome-wide significance. Those SNPs, the researchers noted, clustered in 18 regions across 14 chromosomes.

They next tested the top 18 SNPs found in the European populations in 8,376 people from five cohorts of Asian ancestry to determine whether the SNPs were shared among different ethnic groups — about 80 percent of people of Asian descent are nearsighted, the researchers noted, while about 30 percent of Westerners are. Ten of those top SNPs appeared to also be associated with myopia in Asian populations. In addition, two of the SNPs the consortium identified had previously been linked to refractive error.

Then, combining the cohorts into a mega-population of nearly 45,760 people, the researchers hit upon a further eight loci linked to myopia.

All told, the researchers noted, they found 24 new loci and confirmed two known loci associated with myopia.

Those loci, the researchers calculated, contribute to a range of myopia risk scores. Further, those risk scores are associated with odds ratios from 0.38 to 10.97 for myopia.

By looking at RNA expression levels, the researchers confirmed that most of the candidate genes are expressed in the retina. Further, they noted that many of the risk loci contained histone modification marks, which they said signaled a possible regulatory mechanism.

Further, many of the candidate genes appeared to be linked to a signaling cascade that is thought to be involved in the development of myopia. That cascade begins in the sensory retina, traveling through the retinal pigment epithelium to the sclera. Remodeling of the extracellular matrix there is thought to lead to the elongation of the eye that causes myopia.

For example, LAMA2, which encodes laminin α2, is the nearest gene to the SNP rs12205363 that the consortium linked to myopia. Its proteins combine to form part of the heterotrimer laminins that, in turn, make up the basement membrane that helps anchor cellular structures.

Other SNPs are located near genes involved in eye development. Rs8000973 is near ZIC2, which encodes a C2H2-type zinc finger that has previously been linked to brain development and vision.

The researchers wrote, though, that further study is needed to determine the mechanisms through which these loci affect the eyes and how those effects could be mitigated.

"Currently myopia is corrected with glasses or contact lenses, but now [that] we understand more about the genetic triggers for the condition we can begin to explore other ways to correct it or prevent progression," Hammond added.

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