The impact of genetic variations in the serotonergic system on symptom severity and clinical outcome in functional neurological disorders

Abstract

Objective: We studied gene-environment, as well as gene-gene interaction to elucidate their effects on symptom severity and predict clinical outcomes in functional neurological disorders (FND). Methods: Eighty-five patients with mixed FND were genotyped for ten single-nucleotide polymorphisms (SNP) from seven different stress-related genes. We tested cross-sectionally the association between genotype and the symptomatology of FND (symptom severity assessed with the examiner-based clinical global impression score [CGI] and age of onset). Clinical outcome was assessed in 52 patients who participated in a follow-up clinical visit after eight months (following their individual therapies as usual). We tested longitudinally the association between genotype and clinical outcome in FND. We examined the contribution of each SNP and their interaction between them to FND symptomatology and outcome. Results: We identified a nominal association between tryptophan hydroxylase 1 (TPH1) rs1800532 and symptom severity (CGI1) in FND under a codominant model (T/T: ßT/T = 2.31, seT/T = 0.57; G/T: ßG/T = -0.18, seG/T = 0.29, P = 0.035), with minor allele (T) carriers presenting more severe symptoms. An association was identified between TPH1 and clinical outcome, suggesting that major allele (G) carriers were more likely to have an improved outcome under a codominant model (G/T: ORG/T = 0.18, CIG/T = [0.02-1.34]; T/T: ORT/T = 2.08, CIT/T = [0.30-14.53], P = 0.041). Our analyses suggested a significant gene-gene interaction for TPH2 (rs4570625) and OXTR (rs2254298) on symptom severity, and a significant gene-gene interaction for TPH1, TPH2 and BDNF (rs1491850) on clinical outcome. Conclusion: FND might arise from a complex interplay between individual predisposing risk genes involved in the serotonergic pathway and their gene-gene interactions.