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Effects of TPH2 Gene Variation and Childhood Trauma on the Clinical Movement disorders J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2019-322636 on 23 June 2020. Downloaded from ORIGINAL RESEARCH Effects of TPH2 gene variation and childhood trauma on the clinical and circuit- level phenotype of functional movement disorders Primavera A Spagnolo ,1 Gina Norato,2 Carine W Maurer,3 David Goldman,4 Colin Hodgkinson,4 Silvina Horovitz,1 Mark Hallett 1 ► Additional material is ABSTRact known about the contribution of genetic factors to published online only. To view, Background Functional movement disorders (FMDs), the pathophysiology of FMD. please visit the journal online (http:// dx. doi. org/ 10. 1136/ part of the wide spectrum of functional neurological Several studies have indicated that positive jnnp- 2019- 322636). disorders (conversion disorders), are common and often family history for FMD is associated with increased associated with a poor prognosis. Nevertheless, little morbidity risk among family members.2 3 However, 1 Human Motor Control is known about their neurobiological underpinnings, large- scale genetic epidemiology studies (eg, twin- Section, Medical Neurology particularly with regard to the contribution of genetic based, family- based, adoption- based and other Branch, National Institute on Nuerological Disorders and factors. Because FMD and stress-related disorders share population-based studies), which have provided a Stroke, National Institutes of a common core of biobehavioural manifestations, we necessary first step in establishing heritability and Health, Bethesda, MD, USA investigated whether variants in stress-related genes exploring genetic interactions in several neuropsy- 2 Office of Biostatistics, National also contributed, directly and interactively with childhood chiatric disorders, have not yet been carried out in Institute on Neurological Disorders and Stroke, National trauma, to the clinical and circuit-level phenotypes of patients with FMD. Institutes of Health, Bethesda, FMD. This dearth of data may be related to several Maryland, USA, Bethesda, Methods Sixty- nine patients with a ’clinically factors, including difficulties in case definition Maryland, USA 3 defined’ diagnosis of FMD were genotyped for 18 and ascertainment, absence of a clinical pheno- Department of Neurology, single- nucleotide polymorphisms (SNPs) from 14 Stony Brook University type of FMD rooted in their neurobiology, as well Renaissance School of Medicine, candidate genes. FMD clinical characteristics, psychiatric as the lack of adequate animal models. Further- copyright. Stony Brook, New York, USA comorbidity and symptomatology, and childhood trauma more, the heterogeneous phenotype characterising 4 National Institute of Alcohol exposure were assessed. Resting-state functional patients with FMD suggests that the prevalence Abuse and Alcoholism, National connectivity data were obtained in a subgroup of 38 Institutes of Health, Bethesda, and severity of this disorder unlikely stems from a Maryland, USA patients with FMD and 38 age- matched and sex- single dysfunctional gene but could be modulated matched healthy controls. Amygdala–frontal connectivity by multiple genes of small effect, in interaction Correspondence to was analysed using a whole-br ain seed-based approach. with each other and in conjunction with environ- Dr Primavera A Spagnolo, Results Among the SNPs analysed, a tryptophan mental events. National Institute of hydroxylase 2 (TPH2) gene polymorphism—G703T— Since numerous genetic variants can be impli- Neurological Disorders and significantly predicted clinical and neurocircuitry Stroke, National Institutes of cated in the pathophysiology of FMD, very large Health, Bethesda, Maryland, manifestations of FMD. Relative to GG homozygotes, T samples are needed for gene discovery. Alterna- http://jnnp.bmj.com/ USA; vera. spagnolo@ nih. gov carriers were characterised by earlier FMD age of onset tively, shifting the focus from the entire FMD and decreased connectivity between the right amygdala phenotype to common domains of symptoms Received 14 December 2019 and the middle frontal gyrus. Furthermore, the TPH2 and behaviours shared across FMD and other Revised 19 March 2020 genotype showed a significant interaction with childhood Accepted 6 May 2020 disorders may represent a first, important step trauma in predicting worse symptom severity. to identify genetic contributors. In line with this Conclusions This is, to our knowledge, the first study perspective, increasing evidence has indicated showing that the TPH2 genotype may modulate FMD that stress response dysfunctions are commonly on September 29, 2021 by guest. Protected both directly and interactively with childhood trauma. observed in individuals with FMD, as well as in Because both this polymorphism and early-life stress other functional neurological disorders.4 Patients alter serotonin levels, our findings support a potential with FMD exhibit hyperarousal, increased stress molecular mechanism modulating FMD phenotype. reactivity,5 6 alterations in threat responses and traumatic memory recall, and dysregulation in © Author(s) (or their 7 8 employer(s)) 2020. Re- use neurocircuitry implicated in emotion regulation. permitted under CC BY-­NC. No These manifestations are also commonly observed commercial re- use. See rights INTRODUCTION in stress- related disorders (eg, mood and anxiety and permissions. Published disorders), which are often comorbid with FMD, by BMJ. Functional movement disorders (FMDs) represent one of the more common disorders referred to the suggesting they may share overlapping biological To cite: Spagnolo PA, Norato modern neurology clinic,1 yet they pose unresolved substrates.4 In stress- related disorders, neuro- G, Maurer CW, et al. J Neurol etiological and diagnostic challenges. In the last circuitry and behavioural alterations associated Neurosurg Psychiatry Epub ahead of print: [please two decades, important advances in neuroscience with impaired stress response mechanisms mainly include Day Month Year]. have begun to unravel the neurobiological under- result from interaction between genes, particularly doi:10.1136/jnnp-2019- pinnings of FMD, although several relevant aspects stress- related genes (ie, serotonin (5- HT)- related 322636 still need to be investigated. In particular, little is genes and hypothalamic pituitary adrenal (HPA) Spagnolo PA, et al. J Neurol Neurosurg Psychiatry 2020;0:1–8. doi:10.1136/jnnp-2019-322636 1 Movement disorders J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2019-322636 on 23 June 2020. Downloaded from axis- related genes), and adverse life experiences, particularly signal transduction (5- HTR2A, 5- HTR1A and 5- HTR1B) and early in life (eg, childhood trauma).9 reuptake (5- HT transporter, SLC6A4).18 Furthermore, previous Taken together, these findings lend support to an evolving studies in patients with somatoform disorders seem to indicate a concept of a core phenotype shared across FMD and stress- role for serotonergic pathway genes also in FMD.19 20 related disorders, which is linked to dysregulation of neuro- In addition to these genes, we also selected genes from the biological systems implicated in stress response, and may be HPA axis and endocannabinoid system (CNR1, FAAH, FKBP5, modulated by a common set of genes and gene×environment CRHR1 and NR3C2), given that these systems play a critical role interactions. To begin addressing this set of questions, we inves- in regulating stress response21 and that several of these genes tigated the relationship between single- nucleotide polymor- have been indicated as potential candidate genetic factors for phism (SNPs) previously implicated with stress- related disorders FMD.22 Both HPA axis and endocannabinoid- related genetic and/or associated endophenotypes, childhood trauma, and the variations interact with early-life stress in predicting mood and behavioural and circuit-level phenotypes of FMD. anxiety symptoms, as well as threat- related amygdala function.23 An important exception is represented by a common variant on MatERIALS AND METHODS the FAAH gene (C385A, rs324420), which has been associated with reduced anxiety levels in patients with stress-related disor- Subjects 24 Sixty- nine patients with clinically definite FMD, as diagnosed ders. Finally, polymorphisms on catechol- O- methyltransferase by at least two movement disorder specialists using Fahn and (COMT), brain-derived neurotrophic factor (BDNF) and gluta- Williams criteria,10 were recruited from the Human Motor mate solute carrier family 1 member 3 (SLC1A3) genes were Control Clinic at the NIH between October 2011 and December also included in our analysis, given the large body of literature implicating polymorphisms in these genes with impairment in 2018. Participants partially overlap with those reported in a 25–27 previous article.11 In brief, all patients were enrolled in a 3- day stress response. inpatient study aimed at investigating the clinical and neurobio- Eighteen SNPs from the 14 selected genes (HTR1A, HTR2A, logical correlates of FMD. Exclusion criteria included comorbid HTR1B, TPH1, TPH2, SLC6A4, CNR1, FAAH, FKBP5, CRHR1, neurological disease; psychosis, bipolar disorder or current NR3C1, COMT, BDNF and SLC1A3) were included in our anal- substance abuse; a history of traumatic brain injury; active auto- ysis (table 1). Priority was given to functional SNPs or SNPs immune disorder; current suicidality; disease severity requiring within regulatory regions using online genetic database ensemble
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