Healthy adults found unaffected by their disease-inducing genetic mutations

Researchers who screened the genomes of over half a million people found 13 individuals who, according to medical textbooks, should be seriously sick but have somehow escaped disease.
As we delve deeper into our genomes, we may uncover elements that promote health in ways we might never have imagined.

The findings, published in Nature Biotechnology, represent the first steps of the Resilience Project, a large international study led by the Icahn Institute for Genomics at Mount Sinai, New York, NY, and Sage Bionetworks, a non-profit enterprise based in Seattle, WA.

The project aims to discover hidden factors that protect health. Studying resilient individuals could help find new ways to prevent and treat disease, as co-senior author Eric Schadt, a professor in genomics at the Icahn Institute and one of the project founders, notes:

“Most genomic studies focus on finding the cause of a disease, but we see tremendous opportunity in figuring out what keeps people healthy.”

He explains that our bodies harbor mechanisms of protection that have developed over millions of years. We barely understand how these mechanisms work, but he believes that as we delve deeper into our genomes, we will find elements that promote health in ways we might never have imagined.

Individuals healthy despite genetic mutations for severe diseases

For this particular study, Schadt and colleagues analyzed DNA from 589,306 adults. Using a newly developed panel of 874 gene mutations, they screened all the genomes for 584 distinct genetic diseases.

The genetic diseases were mostly metabolic conditions, neurological diseases or developmental disorders that present in childhood with severe symptoms. All the genomes analyzed were from people who had never been diagnosed with any of the diseases.

The comprehensive screening found 13 healthy individuals harboring mutations for eight severe diseases that develop symptoms in childhood. These included cystic fibrosis, a severe skin disorder, an autoimmune disease and other diseases that can cause skeletal deformity and mental retardation.

However, these startling results need to be considered in the light of some of the study’s limitations. For example, the majority of candidates had to be eliminated because of problems with data quality and interpretation.

The researchers also found that since all the data was obtained anonymously, they could not contact the 13 individuals and thus verify that they were truly resistant to the diseases whose mutations were identified in their genomes.

Co-senior author Stephen Friend, president of Sage Bionetworks and professor of genomics at the Icahn School of Medicine, says the study highlights the benefit of getting informed consent from study participants. “If we could contact these 13 people, we might be even closer to finding natural protections against disease,” he explains.

Friend, who co-founded the Resilience Project with Schadt, says they are planning a new study that will include a “more broadly useful consent policy.”

Good example of harnessing ‘big data’

Despite the limitations, however, at least one expert is prepared to award the study a “proof-of-principle” badge, while others welcome the focus on health as opposed to disease, along with the way the study highlights the usefulness of “big data.”

In an accompanying commentary, Daniel MacArthur of the Broad Institute in Cambridge, MA, who is also researching rare genes that protect against disease, is happy to declare the study “important as a proof-of-principle.” He says it also raises the sobering point that the hunt for resilience genes will require the participation of tens of millions of people willing to donate their DNA.

Dr. Eric Topol, director of the Scripps Translational Science Institute, and chief academic officer of Scripps Health, has been pushing for medical research to shift its focus from disease to health. He was not involved in the study, and describes it as a “standout contribution.” He adds:

“While most genomics research in medicine has been disease focused, this important work exemplifies the benefit of studying health and resilience – the converse of disease – to understand the mechanism for protection in individuals with pathogenic sequence variants.”

And Dr. Vik Bajaj, chief scientific officer of Verily, who was not involved in the research but advocates the harnessing big data for improved healthcare, notes:

“This research also points to the need for more effective standardization in the generation and analysis of genetic data, a field in which the authors are pre-eminent practitioners.”

Last year, Medical News Today came across another good example of what can be achieved by harnessing big data. Researchers produced a catalog of 100 new cancer-driving genes that helps explain how the same gene can lead to different patient outcomes.

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