Hurt, tired and queasy: Specific variants in the ATPase domain of the TRAP1 mitochondrial chaperone are associated with common, chronic “functional” symptomatology including pain, fatigue and gastrointestinal dysmotility

• Functional symptoms are common and often associated with mitochondrial dysfunction.
• TRAP1 encodes a mitochondrial chaperone that is important in antioxidant defense.
• Herein, TRAP1 variants were correlated with chronic pain, fatigue and GI dysmotility.
• These conditions are strongly associated with 3 conserved variants in the TRAP1 gene.
• These variants predispose towards these common functional conditions.

Functional disorders are common conditions with a substantial impact on a patients' wellbeing, and can be diagnostically elusive. There are bidirectional associations between functional disorders and mitochondrial dysfunction. In this study, provided clinical information and the exon sequence of the TRAP1 mitochondrial chaperone were retrospectively reviewed with a focus on the functional categories of chronic pain, fatigue and gastrointestinal dysmotility. Very-highly conserved TRAP1 variants were identified in 73 of 930 unrelated patients. Functional symptomatology is strongly associated with specific variants in the ATPase binding pocket. In particular, the combined presence of all three functional categories is strongly associated with p.Ile253Val (OR 7.5, P = 0.0001) and with two other interacting variants (OR 18, P = 0.0005). Considering a 1–2% combined variant prevalence and high odds ratios, these variants may be an important factor in the etiology of functional symptomatology.