Using data from large biobanks, Yale scientists have gained new insight into the genetic architecture of fibromyalgia, a chronic disorder that affects the quality of life of around 3% of the world’s population.
The condition, which mostly affects women, causes widespread pain, muscle stiffness, sleep problems, fatigue, depression, and anxiety. The cause of fibromyalgia is unknown, and doctors usually diagnose it based on a person’s symptoms.
Studies show that fibromyalgia is influenced by genetics, although earlier studies used small sample sizes and revealed little about the exact genes involved in the disorder.
Yale scientists conducted a much larger study, using data from biobanks such as All of Us, the Million Veteran Program, UK Biobank, and Finngen, to investigate the genetic architecture of fibromyalgia in subjects of European, African, and Latin American origins.
The analysis, published July 28 in Nature Communications, included 1.7 million subjects and 85,000 fibromyalgia cases. The scientists used a method called multi-trait analysis of genome-wide association studies (GWAS), which combines information from pain GWAS to strengthen fibromyalgia analyses.
They identified 10 independent genomic risk loci associated with fibromyalgia in European ancestry, one in African ancestry, and 12 cross-ancestry. The analysis revealed 45 independent genomic loci associated with fibromyalgia.
Among the genetic variants they identified, several are linked to genes involved in nerve pathways, diseases, protein production, and mental health, which can help explain the complex genetics behind fibromyalgia.
“With more than 1.7 million participants, including tens of thousands of fibromyalgia cases, this study now enables us to understand the genetic architecture of fibromyalgia better than ever,” says Uri Bright, PhD, postdoctoral associate in psychiatry, and the paper’s first author. “Understanding the genetic architecture of this complex trait can be the first step toward the development of more target-specific medical treatments, and hopefully also prevention of this syndrome.”
Genetic correlation analyses revealed that although fibromyalgia is more prevalent in females (75% of the cases are females), its genetic architecture in both sexes is similar. The strongest genetic correlation the scientists found for fibromyalgia with a different trait was with chronic pain, and they also found a relatively high correlation with migraine.
In a genomic structural equation modeling analysis—a method that models the shared genetic architecture among multiple complex traits—fibromyalgia shared architecture with chronic pain and migraine, as well as with endometriosis, autoimmune response, insomnia, and physical activity, but not with psychiatric traits. This suggests that fibromyalgia may be contextualized more as a pain and autoimmune trait, even though the genetic correlations with psychiatric traits such as depression, suicidality, attention-deficit/hyperactivity disorder, and post-traumatic stress disorder (PTSD) are moderate to high.
The scientists also found moderate genetic links between fibromyalgia and opioid use disorder and cannabis use disorder, which is important because opioids are used to relieve pain and cannabis use has increased in recent years to treat fibromyalgia symptoms.
“Having completed a powerful GWAS analysis, we were able to use those data to explore other genetic and biological characteristics of fibromyalgia,” says senior author Joel Gelernter, MD, Foundations Fund Professor of Psychiatry and professor of genetics and of neuroscience. “One of the most interesting of these outcomes was the demonstration of the close genetic relationship fibromyalgia has with PTSD and depression, a finding that adds to our understanding of how pain relates to psychiatric traits.”
The scientists said their findings allow for a deeper understanding of fibromyalgia genomics, which in turn may help with diagnosis. Genetic correlations between fibromyalgia and physical activity, as well as with traits that are highly associated with nutrition and cardiovascular function, may support the importance of adopting a healthier lifestyle for the treatment and/or prevention of fibromyalgia, they said.
Other Yale contributors include Sarah Beck, MD; Daniel F. Levey, PhD; and Joseph D. Deak, PhD.