A team of University researchers was instrumental in the discovery of 16 new genetic variations for Age-related Macular Degeneration.

The discovery came during one of that largest experiments of its kind, conducted over the course of a three-year experiment of the exome chip, or small portion of the genome that if mutates causes disease, through the International AMD Genomics Consortium.

AMD, also known as old-age blindness, is one of the leading causes of vision loss in elderly populations. It manifests in two forms: the dry type, where there is occasional death of certain regions in the retina, and the wet type, where retina hemorrhage occurs due to the formation of defective blood vessels in the eye. Currently affecting 30-50 million seniors worldwide, the prevalence of AMD is expected to rise as lifespans lengthen and populations age.

Mohammad Othman, Kellogg Eye Center Research scientist involved in the project, said AMD is a complex disease caused by multiple genetic and environmental factors.

“AMD is a very complex disease; there is no particular gene that accounts for the whole disease,” Othman said. “It is caused by a contribution of several genes that might be altered because of variants that are present in the genes.”

Also involved in the project was Kari Branham, assistant research scientist and genetic counselor at the Inherited Retinal Dystrophy Clinic, said the research would help combat the disease more effectively.

“If you know what you are fighting against — what is it that causes people to get infected, and if you can understand more about the genetic causes and background, then that information can be used for the development of more effective medications and preventions for individuals,” she said.

The genome consortium collaborated with 26 research institutions for the experiment. The University’s role stemmed from a grant secured by Biostatistics Prof. Goncalo Abecasis to conduct genotyping of 43,000 individuals from the National Eye Institute.

The consortium aimed to learn more about disease development and pathology, according to Lars Fritsche, research investigator at the Department of Biostatistics.

“The aim of the experiment was to better characterize the genetics of known AMD risk loci and to find new risk loci,” he said.

Risk loci are regions of the human genome that may affect the risk of disease.

“In this experiment, we jointly analyzed millions of genetic variants in over 16,000 individuals with AMD and compared them with almost 18,000 control individuals. We were able to use a special genotyping platform that allowed us to analyze common as well as very rare genetic variants in our case control study.”

Researchers said the unprecedented size of the study allowed them to identify these rare variants that typically occur at low frequencies.

The University’s multidisciplinary team was comprised of faculty members, graduate and doctoral students from the Kellogg Eye Center and Department of Biostatistics. The eye center specialized primarily in sample collection, while the biostatisticians analyze the data.  

Although the experiment only began in 2012, the collaborative working relationship between the two departments is more than a decade old. 

Othman said the partnership between the biostatistics and ophthalmology departments was important in the collection of samples for the experiment.

“Our work in this integrated department involves clinical and basic research that goes on at the same time,” he said. “We have over the years collected and recruited almost 1500 individuals who have AMD for controls.”

In addition to contributing samples, the team also played a major role in the consortium’s data analyses. 

“We generated several terabytes of raw data and their analyses took many months, in some cases, up to 10 CPU years,” Frtsche said. “Consequently most of the presented analyses were only doable by analysis teams with sufficient computational resources and expertise, in this case, the University of Michigan and the University of Regensburg (Germany).”

The team said their success stemmed from institutional support, the willingness on the part of patients and controls to participate in the experiment and, most importantly, the effectiveness of the international consortium. 

Branham lauded the discovery as a feat of collaboration between the 26 participating institutions.

“It is a major accomplishment to have so many scientific institutions, each used to leading, working together to put differences aside and make this happen,” she said.

For those involved, collaboration is also key in moving forward with the research. University researchers are currently involved in a follow-up genome sequencing study involving the National Eye Institute and University of Pennsylvania. Given that only 6,000 out of 43,000 individual samples in this discovery were of non-European background, there are also ongoing efforts to expand sample collection globally, Othman said.

He added that he is optimistic that the amount of research underway will lead to improved treatments and solutions.

“The consortium is a reflection of the desire and drive to study AMD,” he said. “In the past, the issue of treatment wasn’t even addressed. Now we can see that there is hope, real hope for individuals with this condition. They know that there is something going on.”

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