@article{e6ff6156cca84587ae2c53c1b6a72656,
title = "A functional substitution in the L-aromatic amino acid decarboxylase enzyme worsens somatic symptoms via a serotonergic pathway",
abstract = "Objective: Heightened somatic symptoms are reported by a wide range of patients with chronic pain and have been associated with emotional distress and physical dysfunction. Despite their clinical significance, molecular mechanisms leading to their manifestation are not understood. Methods: We used an association study design based on a curated list of 3,295 single nucleotide polymorphisms mapped to 358 genes to test somatic symptoms reporting using the Pennebaker Inventory of Limbic Languidness questionnaire from a case–control cohort of orofacial pain (n = 1,607). A replication meta-analysis of 3 independent cohorts (n = 3,189) was followed by functional validation, including in silico molecular dynamics, in vitro enzyme assays, and measures of serotonin (5-HT) plasma concentration. Results: An association with the T allele of rs11575542 coding for an arginine to glutamine substitution in the L-aromatic amino acid decarboxylase (AADC) enzyme was replicated in a meta-analysis of 3 independent cohorts. In a combined meta-analysis of all cohorts, this association reached p = 6.43 × 10−8. In silico studies demonstrated that this substitution dramatically reduces the conformational dynamics of AADC, potentially lowering its binding capacity to a cofactor. in vitro enzymatic assays showed that this substitution reduces the maximum kinetic velocity of AADC, hence lowering 5-HT levels. Finally, plasma samples from 90 subjects showed correlation between low 5-HT levels and heightened somatic symptoms. Interpretation: Using functional genomics approaches, we identified a polymorphism in the AADC enzyme that contributes to somatic symptoms through reduced levels of 5-HT. Our findings suggest a molecular mechanism underlying the pathophysiology of somatic symptoms and opens up new treatment options targeting the serotonergic system. ANN NEUROL 2019;86:168–180.",
author = "Samar Khoury and Piltonen, {Marjo H.} and Ton, {Anh Tien} and Tiffany Cole and Alexander Samoshkin and Smith, {Shad B.} and Inna Belfer and Slade, {Gary D.} and Fillingim, {Roger B.} and Greenspan, {Joel D.} and Richard Ohrbach and William Maixner and Neely, {G. Gregory} and Serohijos, {Adrian W.R.} and Luda Diatchenko",
note = "Funding Information: From the 1Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec, Canada; 2Department of Biochemistry, Robert Cedergren Centre on Bioinformatics and Genomics, University of Montreal, Montreal, Quebec, Canada; 3Dr John and Anne Chong Laboratory for Functional Genomics, Charles Perkins Centre and School of Life and Environmental Sciences, University of Sydney, Sydney, New South Wales, Australia; 4School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom; 5Department of Anesthesia, Center for Translational Pain Medicine, Duke University Medical Center, Durham, NC; 6National Center for Complementary and Integrative Health, National Institutes of Health, Bethesda, MD; 7Department of Dental Ecology, School of Dentistry, University of North Carolina Chapel Hill, Chapel Hill, NC; 8University of Florida Pain Research and Intervention Center of Excellence, College of Dentistry, University of Florida, Gainesville, FL; 9Department of Neural and Pain Sciences, Brotman Facial Pain Clinic, School of Dentistry, University of Maryland, Baltimore, MD; and 10Department of Oral Diagnostic Services, University at Buffalo, Buffalo, NY Funding Information: This work was supported by the Canadian Institutes of Health Research (G237818/CERC09/CIHR to L.D.), Natural Sciences and Engineering Research Council of Canada (to A.S.), and NIH National Institute of Dental and Craniofacial Research grant U01DE017018. A.-T.T. acknowledges a fellowship from the University of Montreal Faculty of Graduate and Postdoctoral Studies. Publisher Copyright: {\textcopyright} 2019 American Neurological Association",
year = "2019",
month = aug,
doi = "10.1002/ana.25521",
language = "English (US)",
volume = "86",
pages = "168--180",
journal = "Annals of Neurology",
issn = "0364-5134",
publisher = "John Wiley and Sons Inc.",
number = "2",
}