As part of a global collaboration, scientists from the Icahn School of Medicine at Mount Sinai and Sage Bionetworks conducted the largest genome study to date and reported the first systematic search across hundreds of Mendelian disorders in hundreds of thousands of individuals apparently not afflicted with any of these disorders to identify those carrying disease protective factors. This retrospective study of more than 589,000 genomes was a first step for the Resilience Project and was performed with researchers from 23andMe, BGI, the Ontario Institute for Cancer Research, and other institutions.
The Resilience Project launched in 2014 with a unique vision by Stephen Friend and Eric Schadt that by studying massive numbers of healthy adults, scientists might find rare individuals who are unaffected by genetic variants that should induce disease. Genome analysis of these resilient people could uncover naturally occurring, protective mechanisms that would serve as novel treatments for people affected by these diseases.
“Most genomic studies focus on finding the cause of a disease, but we see tremendous opportunity in figuring out what keeps people healthy,” said Eric Schadt, PhD, the Jean C. and James W. Crystal Professor of Genomics at the Icahn School of Medicine at Mount Sinai, and Founding Director of the Icahn Institute for Genomics and Multiscale Biology. “Millions of years of evolution have produced far more protective mechanisms than we currently understand. Characterizing the intricacies of our genomes will ultimately reveal elements that could promote health in ways we haven’t even imagined.”
In this study, researchers analyzed DNA from 12 previously collected data sets, using a newly developed targeted sequencing panel to screen 874 genes for 584 distinct genetic diseases. The diseases, which were mostly metabolic conditions, neurological diseases, or developmental disorders, present in childhood with severe symptoms. All genomes analyzed were from adults who had never been diagnosed with any of these diseases. A sophisticated, in-depth analysis process identified 13 healthy people with genetic variants associated with eight diseases.
“This study demonstrates the power of using big data to ask new biological questions,” said Anne Wojcicki, co-founder and CEO of 23andMe, which participated in the project. “More than 400,000 23andMe customers contributed to this effort, showing that engaged consumers can make a real impact on scientific research.”
In narrowing the pool of potentially resilient people from an original list of nearly 16,000 candidates, the researchers encountered two significant challenges. First, more than 75% of the candidates were eliminated due to inaccurate or low-confidence variant calls in the existing data, highlighting the need for better protocols and standards for interpreting genetic data. Second, none of the 13 final candidates could be contacted with follow-up questions due to limitations in the original studies’ informed consent policies. It will be impossible to determine whether these people are truly resistant to disease without additional information.
“There’s an important lesson here for genome scientists around the world: the value of any project becomes exponentially greater when informed consent policies allow other scientists to reach out to the original study participants,” said Stephen Friend, President of Sage Bionetworks, Professor of Genomics at the Icahn School of Medicine, and co-founder of the Resilience Project. “If we could contact these 13 people, we might be even closer to finding natural protections against disease. We anticipate launching a prospective study in the future that will include a more broadly useful consent policy.”
"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,” said Eric Topol, MD, Director of the Scripps Translational Science Institute, and Chief Academic Officer of Scripps Health, who was not involved in this study but has been a champion of shifting the research focus to include healthy individuals. “This makes for a standout contribution from the Icahn Institute, Sage Bionetworks, and their extensive network of collaborators.”
“This work demonstrates the power of scale in analyzing root genetic causes of human disease, but more importantly human health. Its focus on studying healthy individuals to understand the things that keep them healthy sounds obvious but actually lies at the vanguard of a movement which puts the engaged study participant at the center of scientific research,” said Vik Bajaj, PhD, Chief Scientific Officer of Verily, who was not involved in this study but has advocated for harnessing big data for improved healthcare. “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.”