New Fibromyalgia Genetics Discovery: An Author’s Perspective

New research published in Nature Medicine offers genetic clues about the long-debated origins of fibromyalgia, suggesting that this painful condition is ultimately a central nervous system disorder. A multi-ancestry genome-wide association study meta-analysis across 2,563,755 individuals identified 26 risk loci for fibromyalgia, many associated with genes that regulate brain and neural cells and tissues.Daniel Clauw, MDMedscape Medical News spoke with study co-author Daniel Clauw, MD, professor of anesthesiology, internal medicine (rheumatology), and psychiatry and scientific director for the Chronic Pain and Fatigue Research Center at the University of Michigan Medical School in Ann Arbor, Michigan, to share what makes this study — the largest of its kind — a significant step forward for understanding the causes of fibromyalgia and potentially improving its treatment.Responses have been edited for brevity and clarity.How do the findings of this study bring us closer to understanding the origins of fibromyalgia?There are some ongoing controversies in fibromyalgia where people question whether this is a brain disease or an autoimmune disease or whether there are underlying pathogenic mechanisms. One of the findings that screamed out from this study was that it’s a brain disease. It doesn’t mean there could not be an immune component in a subset of people, but it doesn’t in any way look like an autoimmune disease genetically.Your team identified 26 genetic variants associated with fibromyalgia, many of which were related to genes involved in brain and nerve function. How do these findings strengthen understanding of fibromyalgia as a central nervous system disorder that affects pain processing?It’s another line of evidence. Until this study, the genetic findings came from underpowered studies, and they were a little bit all over the place with respect to whether things were replicated or not. This is, by far, the strongest one in the fibromyalgia space with a really large sample size and multicenter data to suggest that it really looks like this is a neural disease. This is a very real problem that affects a lot of people, and we are beginning to understand fairly well that it is dysregulation of multiple components of the central nervous system.The genetic architecture was nearly identical between men and women. Did this finding surprise you?Not really. It’s not like we don’t see fibromyalgia in men. The older criteria for fibromyalgia that focused on tender points biased the disease toward being such a female-predominant disease. Under the current criteria, fibromyalgia is only about one and a half to two times more common in women than in men. It is no longer a 90% female disease.The genetic variant most strongly linked to fibromyalgia risk was within the gene HTT, the same gene that, with different mutations, causes Huntington disease — a progressive neurodegenerative disease that can cause involuntary movements, dementia, and behavioral changes. Why is this gene so relevant?I don’t know. That was a really surprising finding. It certainly doesn’t seem on its face that fibromyalgia has much in common with Huntington disease, other than it being a nervous system disease. They’re not similar clinically.But another good thing about this study is you can look at the individual genes identified in this paper and see whether there are existing drugs that might work well in someone with these genes. We can also look at individual genes in databases to see what other diagnoses they are associated with. Maybe some genes might cluster with disorders related to multisensory sensitivity. Individuals with fibromyalgia are not just more sensitive to pain. They’re more sensitive to lights, noises, odors, external sensory stimuli, internal sensory stimuli, nausea, palpitations, all sensory information.Other conditions like autism spectrum disorders or variants of attention-deficit/hyperactivity disorder are also associated with multisensory sensitivity. Where might we see overlap between the genes identified in fibromyalgia and some of those other conditions? And what drugs might work in that subset of individuals?The study revealed genetic overlap between fibromyalgia and other chronic pain, psychiatric, and somatic disorders, such as low back pain, posttraumatic stress disorder, and irritable bowel syndrome. Do these findings help explain why so many of these conditions have similar symptoms or appear simultaneously?Yes. Most of the treatments that work in fibromyalgia work in several other chronic overlapping pain conditions, such as irritable bowel syndrome, tension headache, bladder pain syndrome, or temporomandibular disorder.With back pain, probably half of people with low back pain have more nociplastic pain, whereas some have nerve impingement or damage to parts of their spine. When we see that the genetic analyses of fibromyalgia overlap with low back pain, we’re picking up on that half of people with low back pain that really have central nervous system pain and sensory processing abnormalities.How might these findings influence diagnosis and treatment strategies in clinics today and in the future?This study is a natural progression of a lot of different things that have been happening in the broader field. A study like this in a high-impact journal with such strong findings just floats the whole boat higher. For example, one of the treatments that we think is really promising in fibromyalgia-related conditions is low-intensity focused ultrasound, where you can stimulate deeper brain regions we think are more involved in causing conditions like fibromyalgia using magnetic or direct current stimulation.How else can the fibromyalgia field advance?Because I’ve been in the field so long, I’m just happy that almost every physician can actually utter the word fibromyalgia. Almost every physician thinks it’s a real disease even if they’re not comfortable taking care of it. The field is continuing to move forward, although there are still things that need to happen. We need to do a better job of identifying these individuals earlier in their lives before their pain becomes so widespread and they develop severe functional consequences that are hard to reverse. Maybe this genetic study will help us look for people who are enriched for going on to develop something like fibromyalgia.Clauw received funding from the National Institutes of Health. He reported consulting for Tonix, Lilly, Axsome, and Merck.