Complex Genetics and Regulatory Drivers of Hypermobile Ehlers-Danlos Syndrome

Hypermobile Ehlers-Danlos syndrome (hEDS) is the most common subtype of EDS, a group of heritable connective tissue disorders. Clinically, hEDS is defined by generalized joint hypermobility and chronic musculoskeletal pain, but its impact extends beyond the musculoskeletal system. Affected individuals frequently experience autonomic, gastrointestinal, immune, and neuropsychiatric involvement, highlighting both the multisystemic nature of the condition and challenges of diagnosis. In contrast to other EDS subtypes with defined genetic causes, the molecular basis of hEDS has remained elusive.

A genome-wide association study (GWAS) of hEDS across three case controls studies, including 1,815 cases and 5,008 ancestry-matched controls was conducted. Fixed-effects meta-analysis of 6.2 million variants was complemented with LDAK gene-based association testing, transcriptome-wide association studies, and integrative annotation across multiple tissues and cell types including eQTLs, enhancer marks and open chromatin accessibility profiles, supported by luciferase assays on one candidate variant. LD-score genetic correlations were assessed between hEDS and 19 frequently reported comorbid conditions.

Two gene loci emerged with significance, including a regulatory region near the atypical chemokine receptor 3 gene (ACKR3) on chromosome 2. Altered enhancer activity and transcription factor regulation implicates neuroimmune and pain signaling pathways. Gene-based and transcriptome-wide analyses identified common variants in a locus containing multiple candidates, including SLC39A13, a zinc transporter critical for connective tissue development previously implicated in a rare form of EDS, and PSMC3, a gene involved in central nervous system development. LD-score regression revealed significant genetic correlations between hEDS and joint hypermobility, myalgic encephalomyelitis/chronic fatigue syndrome, fibromyalgia, depression, anxiety, autism spectrum disorder, migraine, and gastrointestinal diseases.

These results establish the first evidence of common variant contributions to hEDS, supporting a complex, multisystem model involving neuroimmune-stromal dysregulation. These findings add novel indications to hEDS pathogenesis and provide solid foundations for future molecular definition and therapeutic discovery.

So much more research still needs to be done before we could definitively locate genetic markers for hEDS and comorbid conditions. But studies like this one show promising improvement and a path to future scientific discovery.

Read the full study here.