title: Rare Synaptogenesis-Impairing Mutations in SLITRK5 Are Associated with Obsessive Compulsive Disorder.
abstract: Obsessive compulsive disorder (OCD) is substantially heritable, but few molecular genetic risk factors have been identified. Knockout mice lacking SLIT and NTRK-Like Family, Member 5 (SLITRK5) display OCD-like phenotypes including serotonin reuptake inhibitor-sensitive pathologic grooming, and corticostriatal dysfunction. Thus, mutations that impair SLITRK5 function may contribute to the genetic risk for OCD. We re-sequenced the protein-coding sequence of the human SLITRK5 gene (SLITRK5) in three hundred and seventy seven OCD subjects and compared rare non-synonymous mutations (RNMs) in that sample with similar mutations in the 1000 Genomes database. We also performed in silico assessments and in vitro functional synaptogenesis assays on the Slitrk5 mutations identified. We identified four RNM's among these OCD subjects. There were no significant differences in the prevalence or in silico effects of rare non-synonymous mutations in the OCD sample versus controls. Direct functional testing of recombinant SLITRK5 proteins found that all mutations identified in OCD subjects impaired synaptogenic activity whereas none of the pseudo-matched mutations identified in 1000 Genomes controls had significant effects on SLITRK5 function (Fisher's exact test P = 0.028). These results demonstrate that rare functional mutations in SLITRK5 contribute to the genetic risk for OCD in human populations. They also highlight the importance of biological characterization of allelic effects in understanding genotype-phenotype relationships as there were no statistical differences in overall prevalence or bioinformatically predicted effects of OCD case versus control mutations. Finally, these results converge with others to highlight the role of aberrant synaptic function in corticostriatal neurons in the pathophysiology of OCD.
authors.affiliation: Synaptic Circuit Plasticity Laboratory, Department of Structure & Function of Neural Network, Korea Brain Research Institute, 61 Cheomdan-ro, Dong-gu, Daegu, Korea.
authors.forename: Minseok
authors.identifier: http://orcid.org/0000-0001-9561-8505
authors.initials: M
authors.lastname: Song
authors.affiliation: Department of Psychiatry, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Mathews
authors.affiliation: Department of Psychiatry, Faculty of Medicine, University of British Columbia, Vancouver, Canada.
authors.forename: S Evelyn
authors.initials: SE
authors.lastname: Stewart
authors.affiliation: Department of Neuroscience and Physiology, New York University School of Medicine, New York, NY, United States of America.|Department of Psychiatry, New York University School of Medicine, New York, NY, United States of America.
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Shmelkov
authors.affiliation: Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, NY United States of America.|Department of Genetic Medicine, Weill Cornell Medical College, NY, NY United States of America.
authors.forename: Jason G
authors.initials: JG
authors.lastname: Mezey
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, NY, NY United States of America.
authors.forename: Juan L
authors.initials: JL
authors.lastname: Rodriguez-Flores
authors.affiliation: Department of Psychiatry and Human Behavior, Alpert Medical School, Brown University, Providence, RI, United States of America.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rasmussen
authors.affiliation: Department of Psychology, University of Miami, Miami, FL, United States of America.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Britton
authors.affiliation: Department of Brain-Cognitive Science, Daegu-Gyeongbuk Institute of Science and Technology (DGIST), Hyeonpung-myeon, Dalseong-gun, Daegu, Republic of Korea.
authors.forename: Yong-Seok
authors.initials: YS
authors.lastname: Oh
authors.affiliation: Department of Psychiatry, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: John T
authors.initials: JT
authors.lastname: Walkup
authors.affiliation: Department of Psychiatry, Weill Cornell Medical College, New York, New York, United States of America.|Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Francis S
authors.initials: FS
authors.lastname: Lee
authors.affiliation: Department of Psychiatry, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Glatt
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D005260:Female; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009771:Obsessive-Compulsive Disorder / Q000235:genetics* / Q000473:pathology*; D017386:Sequence Homology, Amino Acid; D013569:Synapses / Q000473:pathology*; D009435:Synaptic Transmission / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C550141:Slitrk5 protein, mouse