title: Characterization of SLITRK1 variation in obsessive-compulsive disorder.
abstract: Obsessive compulsive disorder (OCD) is a syndrome characterized by recurrent and intrusive thoughts and ritualistic behaviors or mental acts that a person feels compelled to perform. Twin studies, family studies, and segregation analyses provide compelling evidence that OCD has a strong genetic component. The SLITRK1 gene encodes a developmentally regulated stimulator of neurite outgrowth and previous studies have implicated rare variants in this gene in disorders in the OC spectrum, specifically Tourette syndrome (TS) and trichotillomania (TTM). The objective of the current study was to evaluate rare genetic variation in SLITRK1 in risk for OCD and to functionally characterize associated coding variants. We sequenced SLITRK1 coding exons in 381 individuals with OCD as well as in 356 control samples and identified three novel variants in seven individuals. We found that the combined mutation load in OCD relative to controls was significant (p = 0.036). We identified a missense N400I change in an individual with OCD, which was not found in more than 1000 control samples (P<0.05). In addition, we showed the the N400I variant failed to enhance neurite outgrowth in primary neuronal cultures, in contrast to wildtype SLITRK1, which enhanced neurite outgrowth in this assay. These important functional differences in the N400I variant, as compared to the wildtype SLITRK1 sequence, may contribute to OCD and OC spectrum symptoms. A synonymous L63L change identified in an individual with OCD and an additional missense change, T418S, was found in four individuals with OCD and in one individual without an OCD spectrum disorder. Examination of additional samples will help assess the role of rare SLITRK1 variation in OCD and in related psychiatric illness.
authors.affiliation: John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, United States of America ; Department of Neuroscience, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Uzoezi
authors.initials: U
authors.lastname: Ozomaro
authors.forename: Guiqing
authors.initials: G
authors.lastname: Cai
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kajiwara
authors.forename: Seungtai
authors.initials: S
authors.lastname: Yoon
authors.forename: Vladimir
authors.initials: V
authors.lastname: Makarov
authors.forename: Richard
authors.initials: R
authors.lastname: Delorme
authors.forename: Catalina
authors.initials: C
authors.lastname: Betancur
authors.forename: Stephan
authors.initials: S
authors.lastname: Ruhrmann
authors.forename: Peter
authors.initials: P
authors.lastname: Falkai
authors.forename: Hans Jörgen
authors.initials: HJ
authors.lastname: Grabe
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Maier
authors.forename: Michael
authors.initials: M
authors.lastname: Wagner
authors.forename: Leonhard
authors.initials: L
authors.lastname: Lennertz
authors.forename: Rainald
authors.initials: R
authors.lastname: Moessner
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Murphy
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
authors.forename: Stephan
authors.initials: S
authors.lastname: Züchner
authors.forename: Dorothy E
authors.initials: DE
authors.lastname: Grice
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000196:embryology; D016022:Case-Control Studies; D002648:Child; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D001523:Mental Disorders / Q000235:genetics; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics*; D016501:Neurites / Q000378:metabolism; D009771:Obsessive-Compulsive Disorder / Q000235:genetics*; D010641:Phenotype; D017386:Sequence Homology, Amino Acid; D005879:Tourette Syndrome / Q000235:genetics
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C505093:SLITRK1 protein, human; C587905:SLITRK1 protein, mouse