Complex Genetics and Regulatory Drivers of Hypermobile Ehlers-Danlos Syndrome: Insights from Genome-Wide Association Study Meta-analysis
Abstract
Background. 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. Methods. We conducted a genome wide association study (GWAS) of hEDS across three case controls studies, including 1,815 cases and 5,008 ancestry-matched controls. Fixed effects metaanalysis 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. LDscore genetic correlations were assessed between hEDS and 19 frequently reported comorbid conditions. Results. Two loci reached genome wide significance, including a regulatory region near the atypical chemokine receptor 3 gene (ACKR3) on chromosome 2. Functional annotation supports ACKR3 risk alleles colocalize with eQTLs in tibial nerve, alter enhancer activity, and…
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