Largest-ever genetic study of fibromyalgia points to a neurological origin of the disorder

A study co-led by Toronto researchers breaks new ground in understanding fibromyalgia and developing targeted treatments for chronic pain.

In a landmark study published in Nature Medicine, an international team of researchers identified new genetic risk factors associated with fibromyalgia syndrome.

The syndrome is characterized by widespread pain and tenderness, fatigue, and problems with sleep, memory and mood. Despite affecting about two per cent of the global population, its existence has been debated, largely because its biological causes have remained unclear. The results of this study are an important step towards resolving that uncertainty.

The team analyzed genetic data from more than 2.5 million adults, of which 55-thousand were fibromyalgia patients. They identified DNA sequence variants in 26 regions of the genome that affect the risk of developing fibromyalgia. Many of the genes implicated in these regions are involved in brain and nerve function.

The results provide the strongest evidence yet that fibromyalgia is primarily a nervous system disorder rather than an autoimmune disease, as has long been debated.

“This work changes how we think about fibromyalgia at a fundamental level,” said co-senior author Michael Wainberg, an investigator at Sinai Health’s Lunenfeld-Tanenbaum Research Institute and psychiatry professor at the University of Toronto’s Temerty Faculty of Medicine. “For decades, patients have been dismissed or told their pain is simply psychological. Our findings confirm the condition has a clear biological basis.”

Bringing together data from 11 health research studies from the US, UK, Finland, Estonia, Denmark, and Iceland and 53 researchers across 7 countries, the study was jointly led by Wainberg, who is also a member of the Institute of Medical Science at Temerty Medicine, Nasa Sinnott-Armstrong at Fred Hutch Cancer Center and University of Washington in Seattle, and Hanna Ollila at the University of Helsinki in Finland and Massachusetts General Hospital in Boston.

A surprising link to Huntington’s disease

Of the 26 genetic variants identified, the one most strongly linked to fibromyalgia risk was within the gene HTT. Other mutations in this gene cause Huntington’s disease, a severe, progressive and fatal neurodegenerative disorder. Another variant pointed to a receptor called GPR52 that regulates HTT levels. This receptor is already being investigated as a possible drug target in Huntington’s disease.

By integrating their findings with a massive dataset of 20 million cells from various tissues, the researchers found further evidence for a neurological origin of fibromyalgia. Genes near fibromyalgia genetic risk factors were more active in nervous system cells than in other types of cells, which sets fibromyalgia apart from classical autoimmune conditions.

The study also revealed substantial genetic overlap between fibromyalgia and a range of other conditions, including low back pain, irritable bowel syndrome, and post-traumatic stress disorder. The researchers think that shared biological mechanisms within the nervous system may make people susceptible to several of these conditions, explaining why they often appear together. “We know that chronic pain syndromes cluster together in individuals and families and are genetically similar,” said Frances Williams, a rheumatologist at TwinsUK, King’s College London and co-author on the study. “Targeting the shared mechanisms underlying them could potentially benefit a whole cluster of disorders.”

Even so, the study found that genetics is not the main determinant of whether someone develops fibromyalgia. The authors suspect that even people carrying many fibromyalgia genetic variants likely require another risk factor, such as a painful arthritic condition, to trigger fibromyalgia syndrome. “Understanding how genes, environmental exposures, and life events jointly contribute to risk of fibromyalgia syndrome is critical,” said Sinnott-Armstrong. “Further research into triggers of fibromyalgia and corresponding changes to neural tissues will help understand what drives fibromyalgia and how to treat it.”

Despite fibromyalgia being diagnosed roughly three times more often in women than in men, the researchers did not find any genetic differences in risk between the sexes. This suggests that the higher prevalence in women could be driven by non-genetic factors, such as hormonal or environmental, or differences in pain sensitivity and diagnostic patterns.

The findings do not mean that fibromyalgia can now be diagnosed with a genetic test, nor do they immediately lead to a new treatment. However, they provide important new starting points for understanding the biology of fibromyalgia that will help guide future research into better diagnosis and treatment.

The study’s researchers founded the Chronic Pain Genomics Consortium to investigate other chronic pain syndromes, starting with pelvic pain. The consortium sees fibromyalgia as only the beginning of a broader exploration of the landscape of chronic pain conditions.