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Serotonin system gene variants and regional brain volume differences in pediatric OCD

  • Vanessa M. Sinopoli
  • Lauren Erdman
  • Christie L. Burton
  • Phillip Easter
  • Rageen Rajendram
  • Gregory Baldwin
  • Kelli Peterman
  • Julie Coste
  • S-M Shaheen
  • Gregory L. Hanna
  • David R. Rosenberg
  • Paul D. ArnoldEmail author
ORIGINAL RESEARCH
  • 16 Downloads

Abstract

Obsessive-compulsive disorder (OCD) is phenotypically heterogeneous and genetically complex. This study aimed to reduce heterogeneity using structural brain imaging to study putative intermediate phenotypes for OCD. We hypothesized that select serotonin gene variants would differ in their relationship with brain volume in specific regions of the cortico-striato-thalamo-cortical (CSTC) circuits between OCD patients and controls. In a total of 200 pediatric subjects, we genotyped candidate serotonin genes (SLC6A4, HTR2A, HTR1B, and HTR2C) and conducted structural magnetic resonance imaging (sMRI) to measure regional brain volumes within CSTC circuits. In males and females separately, we first tested the association between serotonin gene variants and OCD and the effect of serotonin gene variants on brain volume irrespective of diagnosis. We then carried out a series of analyses to assess the effect of genotype-diagnosis interaction on brain volume. In females, but not in males, we identified a statistically significant genotype-diagnosis interaction for two single nucleotide polymorphisms (SNPs) in HTR2C, rs12860460 (interaction term estimate of 5.45 cc and interaction P value of 9.70e-8) and rs12854485 (interaction term estimate of 4.28 cc and interaction P value of 2.07e-6). The tested allele in each SNP was associated with decreased anterior cingulate cortex (ACC) volume in controls and with increased ACC volume in OCD patients. Our findings suggest that, in females, sequence variation in HTR2C influences ACC volume in pediatric OCD. The variants may contribute to differences in ACC volume and to OCD in a sex-specific manner when acting together with other genetic, biological, and/or environmental factors.

Keywords

Obsessive-compulsive disorder OCD Serotonin system genes Neuroimaging Intermediate phenotype 

Notes

Funding

This work was supported by the National Institutes of Health (NIH) grants R01-MH101493, R01-MH085300, R01-MH085321, and R01-MH59299. Dr. Arnold receives support from the Alberta Innovates Health Solutions (AIHS) Translational Research Chair in Child and Youth Mental Health. Dr. Rosenberg receives support from the Lycaki-Young Fund, State of Michigan, Miriam L. Hamburger Endowed Chair of Child Psychiatry, Paul and Anita Strauss Endowment, Children’s Hospital of Michigan Foundation, and Donald and Mary Kosch Foundation. Vanessa Sinopoli received funding from the Canadian Institutes of Health Research (CIHR) Master’s Award: Frederick Banting and Charles Best Canada Graduate Scholarships, Ontario Graduate Scholarship (OGS), and the Hospital for Sick Children Restracomp Studentship.

Compliance with ethical standards

Conflict of interest

The authors have no conflicts of interest to disclose.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Written and informed consent and assent was obtained for all participants. Each site received study approval from its Human Investigation Committee prior to recruitment of participants.

References

  1. Alvarenga, P. G., Cesar, R. C., Leckman, J. F., Moriyama, T. S., Torres, A. R., Bloch, M. H., Coughlin, C. G., Hoexter, M. Q., Manfro, G. G., Polanczyk, G. V., Miguel, E. C., & do Rosario, M. C. (2015). Obsessive-compulsive symptom dimensions in a population-based, cross-sectional sample of school-aged children. Journal of Psychiatric Research, 62, 108–114.CrossRefGoogle Scholar
  2. American Psychiatric Association. (2000). Diagnostic and statistical manual of mental disorders (4th ed., text rev.). Washington, DC.Google Scholar
  3. American Psychiatric Association (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA.Google Scholar
  4. Arnold, P., & Richter, M. A. (2007). Genetics of obsessive-compulsive disorder: Evidence from pediatric and adult studies. In E. A. Storch & G. R. Greffken (Eds.), Handbook of child and adolescent obsessive-compulsive disorder. New Jersey: Lawrence Erlbaum Associates Inc..Google Scholar
  5. Arnold, P. D., MacMaster, F. P., Hanna, G. L., Richter, M. A., Sicard, T., Burroughs, E., Mirza, Y., Easter, P. C., Rose, M., Kennedy, J. L., & Rosenberg, D. R. (2009). Glutamate system genes associated with ventral prefrontal and thalamic volume in pediatric obsessive-compulsive disorder. Brain Imaging and Behavior, 3(1), 64–76.CrossRefGoogle Scholar
  6. Atmaca, M., Onalan, E., Yildirim, H., Yuce, H., Koc, M., Korkmaz, S., & Mermi, O. (2011). Serotonin transporter gene polymorphism implicates reduced orbito-frontal cortex in obsessive-compulsive disorder. Journal of Anxiety Disorders, 25(5), 680–685.CrossRefGoogle Scholar
  7. Bloch, M. H., Landeros-Weisenberger, A., Rosario, M. C., Pittenger, C., & Leckman, J. F. (2008). Meta-analysis of the symptom structure of obsessive-compulsive disorder. The American Journal of Psychiatry, 165(12), 1532–1542.CrossRefGoogle Scholar
  8. Boedhoe, P. S., Schmaal, L., Abe, Y., Ameis, S. H., Arnold, P. D., Batistuzzo, M. C., Benedetti, F., Beucke, J. C., Bollettini, I., Bose, A., Brem, S., Calvo, A., Cheng, Y., Cho, K. I., Dallaspezia, S., Denys, D., Fitzgerald, K. D., Fouche, J. P., Giménez, M., Gruner, P., Hanna, G. L., Hibar, D. P., Hoexter, M. Q., Hu, H., Huyser, C., Ikari, K., Jahanshad, N., Kathmann, N., Kaufmann, C., Koch, K., Kwon, J. S., Lazaro, L., Liu, Y., Lochner, C., Marsh, R., Martínez-Zalacaín, I., Mataix-Cols, D., Menchón, J. M., Minuzzi, L., Nakamae, T., Nakao, T., Narayanaswamy, J. C., Piras, F., Piras, F., Pittenger, C., Reddy, Y. C., Sato, J. R., Simpson, H. B., Soreni, N., Soriano-Mas, C., Spalletta, G., Stevens, M. C., Szeszko, P. R., Tolin, D. F., Venkatasubramanian, G., Walitza, S., Wang, Z., van Wingen, G. A., Xu, J., Xu, X., Yun, J. Y., Zhao, Q., ENIGMA OCD Working Group, Thompson, P. M., Stein, D. J., & van den Heuvel, O. A. (2017). Distinct subcortical volume alterations in pediatric and adult OCD: A worldwide Meta- and mega-analysis. American Journal of Psychiatry, 174(1), 60–69.CrossRefGoogle Scholar
  9. Brem, S., Hauser, T. U., Iannaccone, R., Brandeis, D., Drechsler, R., & Walitza, S. (2012). Neuroimaging of cognitive brain function in paediatric obsessive compulsive disorder: A review of literature and preliminary meta-analysis. Journal of Neural Transmission (Vienna), 119(11), 1425–1448.CrossRefGoogle Scholar
  10. Carter, C. S., Bearden, C. E., Bullmore, E. T., Geschwind, D. H., Glahn, D. C., Gur, R. E., Meyer-Lindenberg, A., & Weinberger, D. R. (2017). Enhancing the informativeness and replicability of imaging genomics studies. Biological Psychiatry, 82(3), 157–164.CrossRefGoogle Scholar
  11. Davis, L. K., Yu, D., Keenan, C. L., Gamazon, E. R., Konkashbaev, A. I., Derks, E. M., Neale, B. M., Yang, J., Lee, S. H., Evans, P., Barr, C. L., Bellodi, L., Benarroch, F., Berrio, G. B., Bienvenu, O. J., Bloch, M. H., Blom, R. M., Bruun, R. D., Budman, C. L., Camarena, B., Campbell, D., Cappi, C., Cardona, Silgado, J. C., Cath, D. C., Cavallini, M. C., Chavira, D. A., Chouinard, S., Conti, D. V., Cook, E. H., Coric, V., Cullen, B. A., Deforce, D., Delorme, R., Dion, Y., Edlund, C. K., Egberts, K., Falkai, P., Fernandez, T. V., Gallagher, P. J., Garrido, H., Geller, D., Girard, S. L., Grabe, H. J., Grados, M. A., Greenberg, B. D., Gross-Tsur, V., Haddad, S., Heiman, G. A., Hemmings, S. M., Hounie, A. G., Illmann, C., Jankovic, J., Jenike, M. A., Kennedy, J. L., King, R. A., Kremeyer, B., Kurlan, R., Lanzagorta, N., Leboyer, M., Leckman, J. F., Lennertz, L., Liu, C., Lochner, C., Lowe, T. L., Macciardi, F., McCracken, J. T., McGrath, L. M., Mesa Restrepo, S. C., Moessner, R., Morgan, J., Muller, H., Murphy, D. L., Naarden, A. L., Ochoa, W. C., Ophoff, R. A., Osiecki, L., Pakstis, A. J., Pato, M. T., Pato, C. N., Piacentini, J., Pittenger, C., Pollak, Y., Rauch, S. L., Renner, T. J., Reus, V. I., Richter, M. A., Riddle, M. A., Robertson, M. M., Romero, R., Rosàrio, M. C., Rosenberg, D., Rouleau, G. A., Ruhrmann, S., Ruiz-Linares, A., Sampaio, A. S., Samuels, J., Sandor, P., Sheppard, B., Singer, H. S., Smit, J. H., Stein, D. J., Strengman, E., Tischfield, J. A., Valencia Duarte, A. V., Vallada, H., Van Nieuwerburgh, F., Veenstra-Vanderweele, J., Walitza, S., Wang, Y., Wendland, J. R., Westenberg, H. G., Shugart, Y. Y., Miguel, E. C., McMahon, W., Wagner, M., Nicolini, H., Posthuma, D., Hanna, G. L., Heutink, P., Denys, D., Arnold, P. D., Oostra, B. A., Nestadt, G., Freimer, N. B., Pauls, D. L., Wray, N. R., Stewart, S. E., Mathews, C. A., Knowles, J. A., Cox, N. J., & Scharf, J. M. (2013). Partitioning the heritability of Tourette syndrome and obsessive compulsive disorder reveals differences in genetic architecture. PLoS Genetics, 9(10), e1003864.CrossRefGoogle Scholar
  12. Delaneau, O., Marchini, J., & 1000 Genomes Project Consortium. (2014). Integrating sequence and array data to create an improved 1000 genomes project haplotype reference panel. Nature Communications, 5, 3934.Google Scholar
  13. Di Narzo, A. F., Kozlenkov, A., Roussos, P., Hao, K., Hurd, Y., Lewis, D. A., Sibille, E., Siever, L. J., Koonin, E., & Dracheva, S. (2014). A unique gene expression signature associated with serotonin 2C receptor RNA editing in the prefrontal cortex and altered in suicide. Human Molecular Genetics, 23(18), 4801–4813.CrossRefGoogle Scholar
  14. Dracheva, S., Patel, N., Woo, D. A., Marcus, S. M., Siever, L. J., & Haroutunian, V. (2008). Increased serotonin 2C receptor mRNA editing: A possible risk factor for suicide. Molecular Psychiatry, 13(11), 1001–1010.CrossRefGoogle Scholar
  15. Fagerberg, L., Hallstrom, B. M., Oksvold, P., Kampf, C., Djureinovic, D., Odeberg, J., Habuka, M., Tahmasebpoor, S., Danielsson, A., Edlund, K., Asplund, A., Sjöstedt, E., Lundberg, E., Szigyarto, C. A., Skogs, M., Takanen, J. O., Berling, H., Tegel, H., Mulder, J., Nilsson, P., Schwenk, J. M., Lindskog, C., Danielsson, F., Mardinoglu, A., Sivertsson, A., von Feilitzen, K., Forsberg, M., Zwahlen, M., Olsson, I., Navani, S., Huss, M., Nielsen, J., Ponten, F., & Uhlen, M. (2014). Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Molecular & Cellular Proteomics : MCP, 13(2), 397–406.CrossRefGoogle Scholar
  16. Gelernter, J., Kranzler, H., & Cubells, J. F. (1997). Serotonin transporter protein (SLC6A4) allele and haplotype frequencies and linkage disequilibria in african- and european-american and japanese populations and in alcohol-dependent subjects. Human Genetics, 101(2), 243–246.CrossRefGoogle Scholar
  17. Grados, M. A. (2010). The genetics of obsessive-compulsive disorder and tourette syndrome: An epidemiological and pathway-based approach for gene discovery. Journal of the American Academy of Child and Adolescent Psychiatry, 49(8), 810-9, 819.e1-2.Google Scholar
  18. Gurevich, I., Tamir, H., Arango, V., Dwork, A. J., Mann, J. J., & Schmauss, C. (2002). Altered editing of serotonin 2C receptor pre-mRNA in the prefrontal cortex of depressed suicide victims. Neuron, 34(3), 349–356.CrossRefGoogle Scholar
  19. Hanna, G. L. (2010). Schedule for obsessive-compulsive and other behavioral syndromes (SOCOBS). Ann Arbor, MI: University of Michigan.Google Scholar
  20. Heils, A., Teufel, A., Petri, S., Stober, G., Riederer, P., Bengel, D., & Lesch, K. P. (1996). Allelic variation of human serotonin transporter gene expression. Journal of Neurochemistry, 66(6), 2621–2624.CrossRefGoogle Scholar
  21. Hesse, S., Stengler, K., Regenthal, R., Patt, M., Becker, G. A., Franke, A., Knüpfer, H., Meyer, P. M., Luthardt, J., Jahn, I., Lobsien, D., Heinke, W., Brust, P., Hegerl, U., & Sabri, O. (2011). The serotonin transporter availability in untreated early-onset and late-onset patients with obsessive-compulsive disorder. The International Journal of Neuropsychopharmacology / Official Scientific Journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), 14(5), 606–617.CrossRefGoogle Scholar
  22. Honda, S., Nakao, T., Mitsuyasu, H., Okada, K., Gotoh, L., Tomita, M., Sanematsu, H., Murayama, K., Ikari, K., Kuwano, M., Yoshiura, T., Kawasaki, H., & Kanba, S. (2017). A pilot study exploring the association of morphological changes with 5-HTTLPR polymorphism in OCD patients. Annals of General Psychiatry, 16, 2-017-0126-6. eCollection 2017.Google Scholar
  23. Howie, B. N., Donnelly, P., & Marchini, J. (2009). A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genetics, 5(6), e1000529.CrossRefGoogle Scholar
  24. Hu, X. Z., Lipsky, R. H., Zhu, G., Akhtar, L. A., Taubman, J., Greenberg, B. D., Xu, K., Arnold, P. D., Richter, M. A., Kennedy, J. L., Murphy, D. L., & Goldman, D. (2006). Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder. American Journal of Human Genetics, 78(5), 815–826.CrossRefGoogle Scholar
  25. Iwamoto, K., & Kato, T. (2003). RNA editing of serotonin 2C receptor in human postmortem brains of major mental disorders. Neuroscience Letters, 346(3), 169–172.CrossRefGoogle Scholar
  26. Kaufman, J., Birmaher, B., Brent, D., Rao, U., Flynn, C., Moreci, P., Williamson, D., & Ryan, N. (1997). Schedule for affective disorders and schizophrenia for school-age children-present and lifetime version (K-SADS-PL): Initial reliability and validity data. Journal of the American Academy of Child and Adolescent Psychiatry, 36(7), 980–988.CrossRefGoogle Scholar
  27. Leckman, J. F., Denys, D., Simpson, H. B., Mataix-Cols, D., Hollander, E., Saxena, S., Miguel, E. C., Rauch, S. L., Goodman, W. K., Phillips, K. A., & Stein, D. J. (2010). Obsessive-compulsive disorder: A review of the diagnostic criteria and possible subtypes and dimensional specifiers for DSM-V. Depression and Anxiety, 27(6), 507–527.CrossRefGoogle Scholar
  28. Leite, J., Hespanhol, R., & Buchpiguel, C. A. (2015). Molecular imaging in genetics. Neuroimaging Clinics of North America, 25(1), 17–29.CrossRefGoogle Scholar
  29. Lesch, K. P., Bengel, D., Heils, A., Sabol, S. Z., Greenberg, B. D., Petri, S., Benjamin, J., Müller, C. R., Hamer, D. H., & Murphy, D. L. (1996). Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science (New York, N.Y.), 274(5292), 1527–1531.CrossRefGoogle Scholar
  30. Lestrade, L., & Weber, M. J. (2006). snoRNA-LBME-db, a comprehensive database of human H/ACA and C/D box snoRNAs. Nucleic Acids Research, 34(Database issue), D158–D162.CrossRefGoogle Scholar
  31. Li, M. X., Yeung, J. M., Cherny, S. S., & Sham, P. C. (2012). Evaluating the effective numbers of independent tests and significant p-value thresholds in commercial genotyping arrays and public imputation reference datasets. Human Genetics, 131(5), 747–756.CrossRefGoogle Scholar
  32. Lu, Z. X., Jiang, P., & Xing, Y. (2012). Genetic variation of pre-mRNA alternative splicing in human populations. Wiley Interdisciplinary Reviews RNA, 3(4), 581–592.CrossRefGoogle Scholar
  33. Lyddon, R., Dwork, A. J., Keddache, M., Siever, L. J., & Dracheva, S. (2013). Serotonin 2c receptor RNA editing in major depression and suicide. The World Journal of Biological Psychiatry : The Official Journal of the World Federation of Societies of Biological Psychiatry, 14(8), 590–601.CrossRefGoogle Scholar
  34. MacMaster, F. P. (2010). Translational neuroimaging research in pediatric obsessive-compulsive disorder. Dialogues in Clinical Neuroscience, 12(2), 165–174.Google Scholar
  35. Magnotta, V. A., Harris, G., Andreasen, N. C., O'Leary, D. S., Yuh, W. T., & Heckel, D. (2002). Structural MR image processing using the BRAINS2 toolbox. Computerized Medical Imaging and Graphics : The Official Journal of the Computerized Medical Imaging Society, 26(4), 251–264.CrossRefGoogle Scholar
  36. Mak, L., Streiner, D. L., & Steiner, M. (2015). Is serotonin transporter polymorphism (5-HTTLPR) allele status a predictor for obsessive-compulsive disorder? A meta-analysis. Archives of Women's Mental Health, 18(3), 435–445.CrossRefGoogle Scholar
  37. Mattina, G. F., & Steiner, M. (2016). The need for inclusion of sex and age of onset variables in genetic association studies of obsessive-compulsive disorder: Overview. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 67, 107–116.CrossRefGoogle Scholar
  38. Meyer-Lindenberg, A., & Weinberger, D. R. (2006). Intermediate phenotypes and genetic mechanisms of psychiatric disorders. Nature Reviews. Neuroscience, 7(10), 818–827.Google Scholar
  39. Molineaux, S. M., Jessell, T. M., Axel, R., & Julius, D. (1989). 5-HT1c receptor is a prominent serotonin receptor subtype in the central nervous system. Proceedings of the National Academy of Sciences of the United States of America, 86(17), 6793–6797.CrossRefGoogle Scholar
  40. National Institutes of Health. (2008). Novel interventions for neurodevelopmental disorders (R21/R33). Retrieved from http://grants.nih.gov/grants/guide/rfa-files/RFA-MH-09-021.html
  41. Niswender, C. M., Herrick-Davis, K., Dilley, G. E., Meltzer, H. Y., Overholser, J. C., Stockmeier, C. A., Emeson, R. B., & Sanders-Bush, E. (2001). RNA editing of the human serotonin 5-HT2C receptor. Alterations in suicide and implications for serotonergic pharmacotherapy. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology, 24(5), 478–491.CrossRefGoogle Scholar
  42. Pauls, D. L., Abramovitch, A., Rauch, S. L., & Geller, D. A. (2014). Obsessive-compulsive disorder: An integrative genetic and neurobiological perspective. Nature Reviews. Neuroscience, 15(6), 410–424.CrossRefGoogle Scholar
  43. Petersen, A. C., Crockett, L., Richards, M., & Boxer, A. (1988). A self-report measure of pubertal status: Reliability, validity and initial norms. Journal of Youth and Adolescence, 7(2), 117–133.CrossRefGoogle Scholar
  44. Price, A. L., Patterson, N. J., Plenge, R. M., Weinblatt, M. E., Shadick, N. A., & Reich, D. (2006). Principal components analysis corrects for stratification in genome-wide association studies. Nature Genetics, 38(8), 904–909.CrossRefGoogle Scholar
  45. Rosenberg, D. R., & Keshavan, M. S. (1998). A.E. Bennett research award. Toward a neurodevelopmental model of obsessive-compulsive disorder. Biological Psychiatry, 43(9), 623–640.CrossRefGoogle Scholar
  46. Rutter, M., Bailey, A., Berument, S. K., Lord, C., & Pickles, A. (2003). Social communication questionnaire. Los Angeles, CA: Western Psychological Services.Google Scholar
  47. Scahill, L., Riddle, M. A., McSwiggin-Hardin, M., Ort, S. I., King, R. A., Goodman, W. K., Cicchetti, D., & Leckman, J. F. (1997). Children's Yale-Brown obsessive compulsive scale: Reliability and validity. Journal of the American Academy of Child and Adolescent Psychiatry, 36(6), 844–852.CrossRefGoogle Scholar
  48. Sinopoli, V. M., Erdman, L., Burton, C. L., Park, L. S., Dupuis, A., Shan, J., Goodale, T., Li, B., Shaheen, S-M, Crosbie, J., Schachar, R. J., Arnold, P. D. (under review). Serotonin system genes and obsessive-compulsive trait dimensions in a population-based, pediatric sample: A genetic association study. Journal of Child Psychology and Psychiatry.Google Scholar
  49. Sinopoli, V. M., Burton, C. L., Kronenberg, S., & Arnold, P. D. (2017). A review of the role of serotonin system genes in obsessive-compulsive disorder. Neuroscience and Biobehavioral Reviews, 80, 372–381.CrossRefGoogle Scholar
  50. Szeszko, P. R., MacMillan, S., McMeniman, M., Chen, S., Baribault, K., Lim, K. O., Ivey, J., Rose, M., Banerjee, S. P., Bhandari, R., Moore, G. J., & Rosenberg, D. R. (2004). Brain structural abnormalities in psychotropic drug-naive pediatric patients with obsessive-compulsive disorder. The American Journal of Psychiatry, 161(6), 1049–1056.CrossRefGoogle Scholar
  51. Taylor, S. (2013). Molecular genetics of obsessive-compulsive disorder: A comprehensive meta-analysis of genetic association studies. Molecular Psychiatry, 18(7), 799–805.CrossRefGoogle Scholar
  52. Taylor, S. (2016). Disorder-specific genetic factors in obsessive-compulsive disorder: A comprehensive meta-analysis. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics : The Official Publication of the International Society of Psychiatric Genetics, 171B(3), 325–332.CrossRefGoogle Scholar
  53. Voyiaziakis, E., Evgrafov, O., Li, D., Yoon, H. J., Tabares, P., Samuels, J., Wang, Y., Riddle, M. A., Grados, M. A., Bienvenu, O. J., Shugart, Y. Y., Liang, K. Y., Greenberg, B. D., Rasmussen, S. A., Murphy, D. L., Wendland, J. R., McCracken, J. T., Piacentini, J., Rauch, S. L., Pauls, D. L., Nestadt, G., Fyer, A. J., & Knowles, J. A. (2011). Association of SLC6A4 variants with obsessive-compulsive disorder in a large multicenter US family study. Molecular Psychiatry, 16(1), 108–120.CrossRefGoogle Scholar
  54. Walitza, S., Marinova, Z., Grunblatt, E., Lazic, S. E., Remschmidt, H., Vloet, T. D., & Wendland, J. R. (2014). Trio study and meta-analysis support the association of genetic variation at the serotonin transporter with early-onset obsessive-compulsive disorder. Neuroscience Letters, 580, 100–103.CrossRefGoogle Scholar
  55. Wang, Y., Liu, J., Huang, B. O., Xu, Y. M., Li, J., Huang, L. F., Lin, J., Zhang, J., Min, Q. H., Yang, W. M., & Wang, X. Z. (2015). Mechanism of alternative splicing and its regulation. Biomedical Reports, 3(2), 152–158.CrossRefGoogle Scholar
  56. Weissmann, D., van der Laan, S., Underwood, M. D., Salvetat, N., Cavarec, L., Vincent, L., Molina, F., Mann, J. J., Arango, V., & Pujol, J. F. (2016). Region-specific alterations of A-to-I RNA editing of serotonin 2c receptor in the cortex of suicides with major depression. Translational Psychiatry, 6(8), e878.CrossRefGoogle Scholar
  57. Wendland, J. R., Martin, B. J., Kruse, M. R., Lesch, K. P., & Murphy, D. L. (2006). Simultaneous genotyping of four functional loci of human SLC6A4, with a reappraisal of 5-HTTLPR and rs25531. Molecular Psychiatry, 11(3), 224–226.CrossRefGoogle Scholar
  58. Werry, T. D., Loiacono, R., Sexton, P. M., & Christopoulos, A. (2008). RNA editing of the serotonin 5HT2C receptor and its effects on cell signalling, pharmacology and brain function. Pharmacology & Therapeutics, 119(1), 7–23.CrossRefGoogle Scholar
  59. Wierenga, L. M., Bos, M. G. N., Schreuders, E., Kamp, F.v., Peper, J. S., Tamnes, C. K., & Crone, E. A. (2018). Unraveling age, puberty and testosterone effects on subcortical brain development across adolescence. Psychoneuroendocrinology, 91, 105–114.Google Scholar
  60. Williams, M. T., Mugno, B., Franklin, M., & Faber, S. (2013). Symptom dimensions in obsessive-compulsive disorder: Phenomenology and treatment outcomes with exposure and ritual prevention. Psychopathology, 46(6), 365–376.CrossRefGoogle Scholar
  61. Wu, K., Hanna, G. L., Easter, P., Kennedy, J. L., Rosenberg, D. R., & Arnold, P. D. (2013). Glutamate system genes and brain volume alterations in pediatric obsessive-compulsive disorder: A preliminary study. Psychiatry Research, 211(3), 214–220.CrossRefGoogle Scholar
  62. Yücel, M., Wood, S. J., Wellard, R. M., Harrison, B. J., Fornito, A., Pujol, J., Velakoulis, D., & Pantelis, C. (2008). Anterior cingulate glutamate-glutamine levels predict symptom severity in women with obsessive-compulsive disorder. The Australian and New Zealand Journal of Psychiatry, 42(6), 467–477.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Vanessa M. Sinopoli
    • 1
    • 2
  • Lauren Erdman
    • 2
    • 3
  • Christie L. Burton
    • 2
    • 4
  • Phillip Easter
    • 5
  • Rageen Rajendram
    • 6
  • Gregory Baldwin
    • 5
  • Kelli Peterman
    • 5
  • Julie Coste
    • 2
  • S-M Shaheen
    • 2
    • 7
  • Gregory L. Hanna
    • 8
  • David R. Rosenberg
    • 5
  • Paul D. Arnold
    • 2
    • 7
    • 9
    Email author
  1. 1.Institute of Medical ScienceUniversity of TorontoTorontoCanada
  2. 2.Program in Genetics & Genome BiologyThe Hospital for Sick ChildrenTorontoCanada
  3. 3.Department of Computer ScienceUniversity of TorontoTorontoCanada
  4. 4.Program in Neurosciences and Mental HealthThe Hospital for Sick ChildrenTorontoCanada
  5. 5.Department of PsychiatryWayne State University School of MedicineDetroitUSA
  6. 6.Faculty of MedicineUniversity of TorontoTorontoCanada
  7. 7.Mathison Centre for Mental Health Research & Education, Hotchkiss Brain InstituteUniversity of CalgaryCalgaryCanada
  8. 8.Department of PsychiatryUniversity of MichiganAnn ArborUSA
  9. 9.Departments of Psychiatry and Medical Genetics, Cumming School of MedicineUniversity of CalgaryCalgaryCanada

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