Fibromyalgia
Fibromyalgia affects millions of people with widespread chronic pain, exhaustion, sleep problems, brain fog, and a host of other symptoms that can seriously disrupt daily life. For years, it’s been considered the classic “mystery illness” – common, debilitating, but without a clear biological cause.
In our recent large-scale study of more than 2.5 million people, we discovered the first 26 genetic variants linked to fibromyalgia risk. The strongest association was with an in-frame deletion in HTT (huntingtin), the causal gene for Huntington’s disease. The results show that fibromyalgia is primarily driven by changes in how the nervous system processes pain, not by inflammation or immune dysfunction as some had suspected. The genetics point to a centrally mediated pain condition – meaning the problem originates in the brain and spinal cord.
We also found that fibromyalgia shares substantial genetic overlap with other chronic pain conditions, neuropsychiatric conditions, and conditions like irritable bowel syndrome and polycystic ovarian syndrome, but shows surprisingly little connection to autoimmune diseases. Despite large differences in how often fibromyalgia occurs in men versus women, the underlying genetic architecture was nearly identical between the sexes.
The findings also highlight concrete therapeutic opportunities. Among the genes implicated was GPR52, a brain-specific regulator of huntingtin that is already being explored as a drug target for neuropsychiatric diseases. This provides a direct path from genetic discovery to mechanism-based treatments that address the underlying biology of fibromyalgia, rather than just managing symptoms.
Complex regional pain syndrome
Complex regional pain syndrome (CRPS) is a severe chronic pain condition that typically develops after an injury, surgery, or trauma to a limb, though it can also arise spontaneously. Patients experience intense, disproportionate pain along with changes in skin color and temperature, swelling, and abnormal sweating in the affected area. The condition can be profoundly debilitating, and in many cases, the pain persists or worsens long after the initial injury has healed. CRPS is classified into two subtypes: about 90% of patients have CRPS-I (without confirmed nerve injury), while the other 10% have CRPS-II (with confirmed nerve injury).
Despite decades of clinical research, the biological mechanisms underlying CRPS remain poorly understood. Why does a relatively minor injury trigger such severe, persistent pain in some people but not others? What drives the transition from acute to chronic pain? And why do current treatments like physical therapy, sympathetic nerve blocks, ketamine infusions and spinal cord stimulation provide dramatic relief for some patients while having little effect on others?
We’re launching a large-scale genome-wide association study meta-analysis to identify the first genetic risk factors for CRPS. By analyzing genetic data from thousands of CRPS patients and controls across multiple cohorts, we aim to uncover the biological pathways that contribute to CRPS susceptibility and progression. This genetic evidence will help clarify the extent to which CRPS is driven by peripheral mechanisms like inflammation and vascular dysfunction, central nervous system changes in pain processing, or a combination of both. Understanding the genetic architecture of CRPS could point toward new therapeutic targets and help explain the considerable variability in how patients respond to current treatments.
Chronic pelvic pain
Chronic pelvic pain is persistent or recurrent pain in the lower abdomen and pelvic region that lasts for months or years. It affects both women and men, though it’s much more common in women, and the underlying causes often differ by sex. In women, the most common causes include endometriosis, pelvic vein dysfunction, internal scarring from prior surgeries, bladder pain syndrome, and musculoskeletal dysfunction. In men, it’s overwhelmingly linked to chronic prostatitis, which may involve pelvic floor muscle spasms, nerve dysfunction, or inflammation. The pain can range from dull and aching to sharp and debilitating, interfering with work, relationships, and quality of life.
Key questions remain about the biology of chronic pelvic pain. Why do some people with these underlying conditions develop chronic pelvic pain while others do not? Why does pelvic pain often disappear after menopause in women? And what explains the unpredictable response to treatment, where hormonal therapies or surgical interventions work well for some patients but fail in others with seemingly similar presentations?
We are performing a genome-wide association study to identify the genetic variants that increase risk for chronic pelvic pain. Given the distinct anatomical and hormonal contexts in which pelvic pain arises, we’ll analyze genetic risk separately in women and men. In women, we’ll also examine how genetic risk varies by age and/or menopausal status, since the dramatic reduction in symptoms after menopause suggests underlying biological mechanisms that could inform new therapeutic approaches, and consider the influence of duration and severity. By analyzing genetic data from thousands of patients across multiple cohorts, we aim to map the biological pathways driving chronic pelvic pain and identify targets for more effective, personalized treatments.
Rare variants
While common genetic variants help us understand the overall genetic architecture of chronic pain conditions, rare variants – those found in less than 1% of the population – offer a different kind of insight. Because rare variants are often more recent mutations that haven’t been filtered out by natural selection, they tend to have larger effects on disease risk than common variants. We’re conducting rare variant analyses using whole-genome sequencing data from multiple biobank cohorts, with fibromyalgia as our pilot case. By meta-analyzing exome sequences across tens of thousands of individuals, we can identify both single rare variants with large effects and assess the cumulative burden of multiple rare variants within the same gene.
Large-effect variants often point more directly to causal genes and mechanisms, making rare variant discovery particularly valuable for identifying therapeutic targets. Rare variants that protect against disease are especially promising for drug development. If we find that people carrying rare loss-of-function mutations in a particular gene – either through single-variant or burden tests – are protected from chronic pain, that gene becomes an attractive target for therapeutic inhibition. As we extend this work beyond fibromyalgia to other chronic pain conditions, rare variant analyses will complement our genome-wide association studies and help bridge the gap between genetic discovery and mechanism-based treatments.