Gene analysis: IOP related to plasma membrane adhesion

Using a new analytic approach to dig deeper into data from genome-wide association studies, researchers have found several common mechanisms underlying IOP.

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Using a new analytic approach to dig deeper into data from genome-wide association studies, researchers have found several common mechanisms underlying IOP.


By Nancy Groves; Reviewed by Cristina Venturini, PhD candidate

London-A gene discovery analysis has found evidence that IOP is related to plasma membrane adhesion. Groups of genes involved in biological and cell adhesion-located in the plasma membrane or cellular junction, and involved in calcium ion binding-were significantly overrepresented in genetic association profiles for IOP among large cohorts of Caucasians and Asians in the general population.

These findings could guide the work of researchers investigating the complex role of genetic factors in IOP variation, according to Cristina Venturini, a PhD candidate at the Institute of Ophthalmology, University College London, who presented the findings on behalf of the  International Glaucoma Genetics Consortium (IGGC).

She explained that while genetic factors play a role in IOP variation, the genes identified in genome-wide association studies (GWAS) are responsible for only a fraction of heritability.

“These studies have a conservative design, and we might lose some of the genes that are important,” Venturini said, because they fall below formal significance threshold due to low effect sizes and other factors. She added that it also would be difficult to analyze all of the functions of the genes so far associated with IOP and glaucoma.


Analysis of the IGGC study

The IGGC undertook a study to identify true signals that might be hidden among the random noise, seeking those that ranked higher in GWAS results and shared functional commonalities, and therefore might be part of the same pathways and affect the same biological mechanisms.

Researchers from the consortium conducted two meta-analyses, using GWAS data for IOP from 12 European (Caucasian) cohorts (n = 25,847) and four Asian cohorts (n = 7,761). The analyses were separate because of the possibility that the mechanisms mediating IOP might vary in different populations.

All genes with a p-value ≤0.001 were included. By focusing on the gene ontology categories of biological processes, cellular component, and molecular function, they found several entries that were enriched in all categories, Venturini said.

“We found several terms that are related to adhesion,” she added.

In the biological processes category, biological adhesion and cell adhesion were significantly enriched in the European cohorts (p = 1.91 x 10-20 and p = 1.43 x 10-19, respectively). The results were replicated in the Asian cohorts (p = 1.39 x 10-04 and p = 1.47 x 10-04, respectively). Cell-cell adhesion was significant only in the European cohorts  (p = 1.03 x 10-11).      



Results from the analysis of cellular components showed that plasma membrane and plasma membrane part were significantly overrepresented in relation to IOP in both the European and Asian cohorts.

The analysis of molecular function revealed that calcium ion binding was significant in both cohorts (p = 6.56 x 10-20, European, and p = 1.23 x 10-04, Asian).

“We found that these results were quite interesting because we know that biological and cellular adhesion in the plasma membrane and cell junction affect the regulation of vascular permeability, and vascular permeability affects blood pressure,” Venturini said. “The mechanisms that affect vascular permeability might be very similar to the mechanisms that affect IOP.”

Also, since the calcium channel affects many biological mechanisms, including blood pressure, the findings for calcium ion binding suggest that it, too, may play a role in IOP.

Venturini also noted that results of the analyses confirmed earlier findings that several genes are consistently associated with IOP and glaucoma, such as CAV1 and CAV2. The protein encoded by these genes is found in the plasma membrane and is involved in focal adhesion, and it may also be a component of cardiovascular function and endothelial barrier function.


The results were encouraging, and the approach used in the meta-analyses could be helpful in interpreting the results of genome-wide studies, Venturini said. In addition, this methodology could provide new insights for potential biological mechanisms involved in the disease and phenotype. The analytic technique could be applied to other glaucoma phenotypes such as optic disc measurement.


Cristina Venturini, PhD candidate


This article is adapted from Venturini’s presentation at the 2014 meeting of the Association for Research in Vision and Ophthalmology. She does not have any commercial relationships.