The identification of individuals resilient to genetic diseases

23andMe-Brian-049

Brian Naughton

Perhaps you or someone you know is a genetic superhero and simply doesn’t know it yet.

A new paper by researchers at the Icahn School of Medicine at Mount Sinai’s Department of Genetics and Genomics, found more than a dozen individuals who based on their genetics should have developed one of eight severe childhood diseases but never did. The research, which includes contributions and data from 23andMe and 12 other institutions, could help scientists searching for new treatments and cures for disease.

More than identifying those individuals, the study – dubbed “The Resilience Project” – offers a new model for disease research, one that focuses on studying healthy populations as way to gain new insight into disease. In other words, finding out what keeps some people healthy even though they are genetically predisposed to get sick.

“Usually in scientific studies, we start with a disease and try to figure out the genetics behind it,” said Brian Naughton, a co-author on the paper and the founding scientist at 23andMe.  “This study is very unusual in taking the opposite approach. By finding healthy people with what should be disease-causing mutations, we get a more complete picture of the disease and we may even learn what makes some people resistant.”

A Few Examples Of How Resilient Individuals Have Already Helped Researchers
  • Human Knockout Project – Daniel MacArthur started this project out of his lab at Massachusetts General Hospital and the Broad Institute. He’s looking for healthy individuals with so-called loss function variants, genes that do not code for a protein. Researchers routinuely “knock-out” the function of a gene in mice when studying what a gene does.
  • PCSK9 – The gene regulates the level of LDL cholestrol, but researchers found that certain individuals with loss function variants in the gene were protected against high lipid levels. Since the discovery several pharmacuetical companies have used this discovery to develop new therapies for combating high cholesterol.
  • Alzheimer’s Escapers  – “Escapers” are individuals who have the genetic variants that put them at very high risk for disease, but for whatever reason never develop it. The Washington University School of Medicine is looking at families that are genetically predisposed to Alzheimer’s Disease looking for individuals who have “escaped” getting the disease for insights into new treatments. 23andMe has also found escapers.
  • HIV – By identifying rare mutations in the gene CCR5 that provide resistance to HIV infection, researchers hope to find a vaccine against AIDS.
  • Diabetes – A few years ago researchers discovered that a variant in the gene ZNT8 protects even obese people from diabetes. Since then researchers have been using this as a possible drug target to protect against diabetes.

To find those resistant, or as the research calls them “resilient” individuals, the scientists gathered genetic data from more than half a million people who consented to participate in research. It included genotypic data, exome data and a few thousand whole genome sequences from databanks around the world.

The researchers decided to set strict criteria for their search. The first was that they would only look at severe or fatal “Mendelian” childhood diseases. These are disorders that are clearly inherited and in which the pathogenic mutations are already known. And then they looked at adults with those known mutations, but who never got sick.

In a TED talk given two years ago, Stephen Friend, a co-founder of the Resiliency Project and President of Sage Bionetworks and one of the paper’s co-authors, outlined the project by posing this question:

“Are there a very few of us walking around with a risk that would normally cause a disease but have something in them that is protective?”

The short answer is an emphatic “yes,” but even though the concept for this study seemed simple enough the work proved more difficult. The researchers looked at more than 870 genetic variants known to cause more than 580 severe Mendelian conditions. Initially they identified thousands of candidates but less than 1 percent of those survived the rigorous bioinformatic scrutiny applied by the team, that included filtering out candidates due to errors in variant calls because of low coverage for specific genetic regions or candidates that failed to pass the team’s criteria for clinical presentation for the conditions.

Another issue was that the initial consent documents for this study, and other complications, did not allow for participants to be recontacted, preventing researchers from following up with candidates.In the end 13 individuals were identified with mutations that normally would lead to one of eight different Mendelian conditions including such things as cystic fibrosis and the often fatal campomelic dysplasia.

While all of those conditions typically manifest themselves at infancy or before adulthood, they never did in these 13 people.The researchers say this study provides a “proof of principle” for future targeted large-scale prospective screen to identify “resilient individuals.”

Finding these 13 individuals or others like them, could help researchers in the fight to combat genetic disease in the future.

  • Patty Ritchie

    Intriguing research which should be pursued!

  • Cindy

    I cant wait to get my DNA info back, interesting, I have never had a childhood disease while my siblings did.