32 genes thought to be key drivers of long COVID-19 identified
by Don Jacobson · UPIDec. 16 (UPI) -- In what is being hailed as a breakthrough in the fight against long COVID-19, an Australian research team says it has identified dozens of genes responsible for causing the pernicious and mysterious malady.
While previous research has identified genes "associated" with long COVID, the authors of a study published this week in PLOS Computational Biology and Critical Reviews in Clinical Laboratory Sciences claim to have documented "causal" relationships between 32 genes and the likelihood of developing long COVID -- including 13 new genes not previous associated with the disease.
In another first, they also say they have identified three distinct "symptom-based subtypes" of long COVID, each with its own symptoms and underlying biology, which may help to explain why the condition has such wide and diverse symptoms.
"This work represents a significant step toward customized management and treatment strategies for long COVID, ultimately improving patient outcomes," say the authors, who are mostly from the University of South Australia.
Long COVID is a complex disease that affects multiple systems after infection by the SARS‑CoV‑2 coronavirus. Its symptoms include fatigue, pulmonary dysfunction, muscle and chest pain, dysautonomia -- a nervous system disorder that disrupts autonomic body processes such blood pressure and heart rate -- and cognitive disturbances such as "brain fog."
These symptoms can last from months to years after the initial onset of the infection.
Estimates of how many COVID-19 patients develop long COVID varies widely, ranging from 10% to 70%, while affecting an estimated 65 million people globally. Long COVID is more common in people who have been hospitalized or treated at the intensive care unit, but it can also occur in those with initially mild COVID-19 symptoms.
Efforts to uncover genetic clues in the search for the causes of long COVID have been ongoing in recent years. For example, researchers in May identified the first genome-wide "significant association" for long COVID with the FOXP4 gene, which is connected to both how the lungs work and how the immune system responds to infections.
But in general, the genetic evidence identifying what's behind long COVID has remained limited.
A co-author of the current study, Sindy Licette Piñero, said the "breakthrough" in identifying the 32 causal genes was made by developing a novel analytical framework.
In it, two types of statistical modeling used in genetics called Mendelian Randomization and Control Theory are combined with large-scale "multi-omics" data, in which patient data from genomic, epigenomic, transcriptomic and proteomic studies are all melded to provide a much more complete genetic picture.
"To our knowledge, this is among the first applications of long COVID that integrate MR and network CT within a single workflow with adjustable weighting and then extend it using multi-omics evidence to prioritize [gene] candidates," she told UPI in emailed comments.
Licette Piñero, a doctoral candidate in bioinformatics at the University of South Australia in Adelaide, said the approach has been used in other diseases, including cancer-related applications, "but the specific MR-plus-CT integration and weighting strategy is what we brought to long COVID."
She said the method addresses the current lack of effective treatments for long COVID in several ways, including its ability to establish "causality" rather than just "associations" with various genes.
"We prioritized 32 candidate genes with evidence consistent with causal roles, including 13 not previously linked -- which is more actionable for therapy development than correlation alone -- while still requiring experimental follow-up," said said.
She added that the discovery of distinct biological subtypes of long COVID "supports the idea that different mechanisms may drive symptoms in different people, and that 'one-size-fits-all' treatments may not work."
The platform has also been made freely available "so other groups can test, extend and validate the findings across cohorts."
Another researcher of the links between genetics and long COVID who is not connected to the Australian study called its results "interesting."
Art Schuermans, a medical student at KU Leuven University in Belgium and an affiliated researcher with the Broad Institute of the Massachusetts Institute of Technology and Harvard University, co-authored an international study published Tuesday that found an association between long COVID and genetic variants related to thromboembolism, a serious condition where a blood clot forms in a blood vessel, blocking blood flow.
"The authors use novel, statistically advanced, methods to help identify causal genes for long COVID," he told UPI. "While their approach is interesting, interpretability is a bit hampered by the complexity and multitude of approaches."
While the study "helps advance the field by prioritizing causal genes that could -- potentially -- someday be targeted therapeutically," he cautioned that it remains undetermined if targeting these specific genes will actually help cure or prevent long COVID.
"Further experimental studies, including animal models and eventually clinical trials, are needed to further delineate the role of the identified genes in long COVID and their clinical actionability," Schuermans said.