Pilot study on HTR 2 A promoter polymorphism ,-1438 G / A ( rs 6311 ) and a nearby copy number variation showed association with onset and severity in early onset obsessive-compulsive disorder

A previous study showed that a single nucleotide polymorphism (SNP), -1438G/A (rs6311), found in the transcriptional control region of the gene that encodes the serotonin-receptor 2A (HTR2A) was associated with obsessive-compulsive disorder (OCD) in a sample of children and adolescents. In this study, we reanalyzed the association of this SNP with OCD in an enlarged population of 136 cases (55 previous + 81 new cases) and compared them to 106 newly recruited, healthy, age-matched controls. We also investigated whether this SNP or its copy number variations (CNV) was associated with OCD severity and age of onset. The CNV was analyzed in a DNA region located near rs6311. The results confirmed the association between the A-allele and early onset OCD in children and adolescents, with an odds ratio (OR) of 1.69 [95% CI (1.17, 2.46); p = 0.005]. Strikingly, we found that carriers of one copy (deletion) of the CNV were associated with a very early onset OCD (2.5 years earlier than the typical onset), and they had increased CY-BOCS scores (8.7 points higher compared to ”normal” CNV and duplications); which is related to increased severity of OCD symptoms (p = 0.031; p = 0.004, respectively). Compared to the normal CNV and duplications, the association between the deletion and OCD showed an OR of 7.56 [95% CI (1.32, 142.84); p = 0.020]. These results pointed to the functional importance of this promoter region of HTR2A; it influenced the occurrence, the onset, and the severity of OCD. DOI: https://doi.org/10.1007/s00702-011-0699-1 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-49842 Accepted Version Originally published at: Walitza, Susanne; Bové, Daniel Sabanes; Romanos, Marcel; Renner, Tobias; Held, Leonhard; Simons, Michael; Wewetzer, Christoph; Fleischhaker, Christian; Remschmidt, Helmut; Warnke, Andreas; Grünblatt, Edna (2012). Pilot study on HTR2A promoter polymorphism, -1438G/A (rs6311) and a nearby copy number variation showed association with onset and severity in early onset obsessive-compulsive disorder. Journal of Neural Transmission, 119(4):507-515. DOI: https://doi.org/10.1007/s00702-011-0699-1 PNAS Research report-Biological Sciences Walitza et al. 2011 1 HTR2A –1438G/A is associated with early-onset obsessive-compulsive disorder and copy number variation affects onset and severity Susanne Walitza, Daniel Sabanés Bové, Marcel Romanos, Tobias Renner, Leonhard Held, Michael Simons, Christoph Wewetze, Christian Fleischhaker, Helmut Remschmidt, Andreas Warnke, Edna Grünblatt 1 Hospital of Child and Adolescent Psychiatry, University of Zurich, Neumuensterallee 9, CH-8032 Zurich, Switzerland 2 Clinical Neurochemistry Laboratory, Clinic & Policlinic for Psychiatry, Psychosomatic and Psychotherapy, University of Wuerzburg, D-97080 Wuerzburg, Germany 3 Institute for Social and Preventive Medicine Division of Biostatistics, University of Zurich, Hirschengraben 84, CH-8001 Zurich, Switzerland 4 Department of Child and Adolescent Psychiatry, University of Wuerzburg, D-97080 Wuerzburg, Germany 5 Department of Child and Adolescent Psychiatry, University of Munich, D-80336 Munich, Germany 6 Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of the RWTH Aachen, Neuenhofer Weg 21, D-52074 Aachen, Germany 7 Municipal Hospitals of Cologne, Clinic for Child and Adolescent Psychiatry and Psychotherapy, FlorentineEichler-Str. 1, D-51067 Köln, Germany 8 Department of Child and Adolescent Psychiatry, University Freiburg, D-79104 Freiburg, Germany 9 Department of Child and Adolescent Psychiatry, Philipps-University Marburg, D-35039 Marburg, Germany Running title: HTR2A polymorphism and CNV in early-onset OCD Page No.: 21 Figures: 1 Tables: 2 Supplementary material: 0 References: 59 Abstract word count: 235 Introduction word count: 684 Total word count: 3271 Corresponding author: Prof. Susanne Walitza / Hospilat of Child and Adolescent Psychiatry; University of Zurich; Zurich/ Switzerland. E.Mail: Susanne.walitza@kjpdzh.ch PNAS Research report-Biological Sciences Walitza et al. 2011 2 Abstract A previous study showed that a single nucleotide polymorphism (SNP), –1438G/A (rs6311), found in the transcriptional control region of the gene that encodes the serotonin-receptor 2A (HTR2A) was associated with obsessive-compulsive disorder (OCD) in a sample of children and adolescents. In this study, we reanalyzed the association of this SNP with OCD in an enlarged population of 136 cases (55 previous + 81 new cases) and compared them to 106 newly recruited, healthy, age-matched controls. We also investigated whether this SNP or its copy number variations (CNV) was associated with OCD severity and age of onset. The CNV was analyzed in a DNA region located near rs6311. The results confirmed the association between the A-allele and early-onset OCD in children and adolescents, with an Odds Ratio (OR) of 1.69 (95% CI: [1.17, 2.46]; p=0.005). Strikingly, we found that carriers of one copy (deletion) of the CNV were associated with a very early-onset OCD (2.5 years earlier than the typical onset), and they had increased Y-BOCS scores (8.7 points higher compared to “normal” CNV and duplications); which is related to increased severity of OCD symptoms (p=0.031; p=0.004, respectively). Compared to the normal CNV and duplications, the association between the deletion and OCD showed an OR of 7.56 (95% CI: [1.32, 142.84]; p=0.020). These results pointed to the functional importance of this promoter region of HTR2A; it influenced the occurrence, the onset, and the severity of OCD.