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Background Joint hypermobility is a common connective tissue variant. Surprisingly, people with this disorder are especially vulnerable to anxiety. Recent imaging studies suggest that non-anxious individuals with hypermobility express structural and functional differences in emotional brain regions. Autonomic dysregulation, typically postural tachycardia, is often found. Our aim was to test the hypothesis that joint hypermobility increases the expression of anxiety through aberrant central autonomic control. Methods The study had a 2×2 factorial design (presence or absence of hypermobility×presence or absence of generalised anxiety disorder). Adults with generalised anxiety disorder and healthy controls were prospectively recruited so that half of each group had hypermobility. Autonomic testing was done before measurement by functional MRI of brain responses to emotional stimuli. Between-group analyses tested for differences in autonomic function and patterns of brain activation. Presence of generalised anxiety disorder was assessed with DSM-IV criteria (MINI, MINI International Neuropsychiatric Interview). Anxiety was quantified with the Beck Anxiety Inventory. All neuroimaging findings are presented at a significance threshold of p(FWE corrected) Findings 70 adults were recruited (32 with generalised anxiety disorder, of whom 16 had hypermobility; 38 controls of whom 19 had hypermobility). An increase in sympathetic reactivity (proportional change in heart rate on active standing) was observed in individuals with hypermobility (n=35) versus those without hypermobility (n=35) (mean change from baseline 22·4% [SE 2·7] vs 14·2 [2·1], p=0·024) and in those with generalised anxiety disorder (n=32) versus those without anxiety (n=38) (24·0 [2·9] vs 13·9 [1·9], p=0·005), correlating with hypermobility ( r =0·34, p=0·024) and anxiety scores ( r =0·38, p=0·004). There was an interaction between the effects of hypermobility and anxiety on sympathetic reactivity (p=0·001). Within the brain, individuals with hypermobility showed increased reactivity to emotional stimuli within brain areas implicated in emotional processing and autonomic control, notably amygdala (p[FWE corrected] Interpretation This study shows that joint hypermobility is associated with the expression of anxiety through autonomic hyper-reactivity linked to aberrant engagement of the amygdala and insula. This study is the first, to our knowledge, to provide a mechanistic understanding of the association between joint hypermobility and anxiety; the findings will enhance recognition across medical disciplines of extra-articular features and vulnerabilities of joint hypermobility, offering possibilities for optimum personalised medicine. Funding Medical Research Council.