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Panic disorder is associated with the serotonin transporter gene (SLC6A4) but not the promoter region (5-HTTLPR)

Molecular Psychiatry volume 15, pages 166–176 (2010)Cite this article

Abstract

Panic disorder (PD) and social anxiety disorder (SAD) are moderately heritable anxiety disorders. We analyzed five genes, derived from pharmacological or translational mouse models, in a new case–control study of PD and SAD in European Americans: (1) the serotonin transporter (SLC6A4), (2) the serotonin receptor 1A, (3) catechol-O-methyltransferase, (4) a regulator of g-protein signaling and (5) the gastrin-releasing peptide receptor. Cases were interviewed using the schedule for affective disorders and schizophrenia and were required to have a probable or definite lifetime diagnosis of PD (N=179), SAD (161) or both (140), with first onset by age 31 and a family history of anxiety. Final diagnoses were determined using the best estimate procedure, blind to genotyping data. Controls were obtained from the National Institute of Mental Health Human Genetics Initiative; only subjects above 25 years of age who screened negative for all psychiatric symptoms were included (N=470). A total of 45 single nucleotide polymorphisms were successfully genotyped over the five selected genes using Applied Biosystems SNPlex protocol. SLC6A4 provided strong and consistent evidence of association with the PD and PD+SAD groups, with the most significant association in both groups being at rs140701 (χ2=10.72, P=0.001 with PD and χ2=8.59, P=0.003 in the PD+SAD group). This association remained significant after multiple test correction. Those carrying at least one copy of the haplotype A-A-G constructed from rs3794808, rs140701 and rs4583306 have 1.7 times the odds of PD than those without the haplotype (95% confidence interval: 1.2–2.3). The SAD only group did not provide evidence of association, suggesting a PD-driven association. The findings remained after adjustment for age and sex, and there was no evidence that the association was due to population stratification. The promoter region of the gene, 5-HTTLPR, did not provide any evidence of association, regardless of whether analyzed as a triallelic or biallelic locus, nor did any of the other four candidate genes tested. Our findings suggest that the serotonin transporter gene may play a role in PD; however, the findings require replication. Future studies should attend to the entire genetic region rather than the promoter.

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Acknowledgements

This research was supported by a clinical studies project (Myrna M Weissman, PI) of NIMH Program Project NIMH PO1 MH60970-04 (Rene Hen, PI). We acknowledge the support of MH-48858 (Susan E Hodge, PI) and HG004314 (Lisa J Strug, PI). The NIMH sample was collected by ‘Molecular Genetics of Schizophrenia II’ collaboration, and included the following investigators: ENH/Northwestern University, Evanston, IL, MH059571—Pablo V Gejman, MD (Collaboration coordinator; PI), Alan R Sanders, MD; Emory University School of Medicine, Atlanta, GA, MH59587—Farooq Amin, MD (PI); Louisiana State University Health Sciences Center; New Orleans, LA, MH067257—Nancy Buccola APRN, BC, MSN (PI); University of California-Irvine, Irvine, CA, MH60870—William Byerley, MD (PI); Washington University, St Louis, MO, U01, MH060879—C Robert Cloninger, MD (PI); University of Iowa, Iowa, IA, MH59566—Raymond Crowe, MD (PI), Donald Black, MD; University of Colorado, Denver, CO, MH059565—Robert Freedman, MD (PI); University of Pennsylvania, Philadelphia, PA, MH061675—Douglas Levinson, MD (PI); University of Queensland, QLD, Australia, MH059588—Bryan Mowry, MD (PI); Mt Sinai School of Medicine, New York, NY, MH59586—Jeremy Silverman, PhD (PI).

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Authors and Affiliations

  1. Child Health Evaluative Sciences, The Hospital For Sick Children, Toronto, Canada

    L J Strug & W Li

  2. The Dalla Lana School of Public Health, University of Toronto, Toronto, Canada

    L J Strug

  3. Department of Genetics and Development, Columbia University, New York, NY, USA

    R Suresh

  4. Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, USA

    A J Fyer, S E Hodge & M M Weissman

  5. Clinical Therapeutics, New York State Psychiatric Institute, New York, NY, USA

    A J Fyer

  6. Division of Statistical Genetics, Department of Biostatistics, Columbia University, New York, NY, USA

    A Talati, P B Adams & S E Hodge

  7. Division of Epidemiology, New York State Psychiatric Institute, New York, NY, USA

    A Talati, P B Adams, S E Hodge & M M Weissman

  8. Department of Human Genetics, The University of Chicago, Chicago, IL, USA

    T C Gilliam

  9. Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA

    M M Weissman

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Strug, L., Suresh, R., Fyer, A. et al. Panic disorder is associated with the serotonin transporter gene (SLC6A4) but not the promoter region (5-HTTLPR). Mol Psychiatry 15, 166–176 (2010). https://doi.org/10.1038/mp.2008.79

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