Rare synaptogenesis-impairing mutations in SLITRK5 are associated with obsessive compulsive disorder

Minseok Song*, Carol A. Mathews, S. Evelyn Stewart, Sergey V. Shmelkov, Jason G. Mezey, Juan L. Rodriguez-Flores, Steven A. Rasmussen, Jennifer C. Britton, Yong Seok Oh, John T. Walkup, Francis S. Lee, Charles E. Glatt

*Corresponding author for this work

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere0169994
JournalPLoS One
Volume12
Issue number1
DOIs
StatePublished - Jan 1 2017

Fingerprint

obsessive-compulsive disorder
Obsessive-Compulsive Disorder
Genes
mutation
Mutation
Serotonin Uptake Inhibitors
Recombinant Proteins
Neurons
Assays
Computer Simulation
Testing
synaptogenesis
Genome
Proteins
Phenotype
Grooming
genome
pathophysiology
recombinant proteins
serotonin

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Song, M., Mathews, C. A., Stewart, S. E., Shmelkov, S. V., Mezey, J. G., Rodriguez-Flores, J. L., ... Glatt, C. E. (2017). Rare synaptogenesis-impairing mutations in SLITRK5 are associated with obsessive compulsive disorder. PLoS One, 12(1), [e0169994]. https://doi.org/10.1371/journal.pone.0169994
Song, Minseok ; Mathews, Carol A. ; Stewart, S. Evelyn ; Shmelkov, Sergey V. ; Mezey, Jason G. ; Rodriguez-Flores, Juan L. ; Rasmussen, Steven A. ; Britton, Jennifer C. ; Oh, Yong Seok ; Walkup, John T. ; Lee, Francis S. ; Glatt, Charles E. / Rare synaptogenesis-impairing mutations in SLITRK5 are associated with obsessive compulsive disorder. In: PLoS One. 2017 ; Vol. 12, No. 1.
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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.",
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Song, M, Mathews, CA, Stewart, SE, Shmelkov, SV, Mezey, JG, Rodriguez-Flores, JL, Rasmussen, SA, Britton, JC, Oh, YS, Walkup, JT, Lee, FS & Glatt, CE 2017, 'Rare synaptogenesis-impairing mutations in SLITRK5 are associated with obsessive compulsive disorder', PLoS One, vol. 12, no. 1, e0169994. https://doi.org/10.1371/journal.pone.0169994

Rare synaptogenesis-impairing mutations in SLITRK5 are associated with obsessive compulsive disorder. / Song, Minseok; Mathews, Carol A.; Stewart, S. Evelyn; Shmelkov, Sergey V.; Mezey, Jason G.; Rodriguez-Flores, Juan L.; Rasmussen, Steven A.; Britton, Jennifer C.; Oh, Yong Seok; Walkup, John T.; Lee, Francis S.; Glatt, Charles E.

In: PLoS One, Vol. 12, No. 1, e0169994, 01.01.2017.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Rare synaptogenesis-impairing mutations in SLITRK5 are associated with obsessive compulsive disorder

AU - Song, Minseok

AU - Mathews, Carol A.

AU - Stewart, S. Evelyn

AU - Shmelkov, Sergey V.

AU - Mezey, Jason G.

AU - Rodriguez-Flores, Juan L.

AU - Rasmussen, Steven A.

AU - Britton, Jennifer C.

AU - Oh, Yong Seok

AU - Walkup, John T.

AU - Lee, Francis S.

AU - Glatt, Charles E.

PY - 2017/1/1

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N2 - 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.

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Song M, Mathews CA, Stewart SE, Shmelkov SV, Mezey JG, Rodriguez-Flores JL et al. Rare synaptogenesis-impairing mutations in SLITRK5 are associated with obsessive compulsive disorder. PLoS One. 2017 Jan 1;12(1). e0169994. https://doi.org/10.1371/journal.pone.0169994