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.

Rodent models of obsessive compulsive disorder: Evaluating validity to interpret emerging neurobiology

“…Interest in the SLITRK (Slit- and Trk-like) gene family initially emerged from a chromosomal translocation and follow-up rare variant association study linking SLITRK1 and Tourette's syndrome (Abelson et al, 2005), with support in some but not all subsequent studies (Keen-Kim et al, 2006, Scharf et al, 2008, Miranda et al, 2009, O'Roak et al, 2010, Karagiannidis et al, 2012, Ozomaro et al, 2013). SLITRKs are single-transmembrane proteins containing two extracellular leucine-rich repeat domains, similar to SLIT proteins, and a carboxy-terminal domain similar to tyrosine kinase receptors (Proenca et al, 2011).…”

Genetics of Obsessive-Compulsive Disorder and Related Disorders

“…36 Of note, preliminary sequencing studies of SLITRK1 in patients with OCD and TTM have suggested that rare variation may also be associated with these two related disorders. 73-75 With the advent of genome and exome sequencing, new appreciation of the high frequency of amino-acid altering variations in the general population now supports the need for follow-up studies in larger case-control samples and/or studies of de novo variation in parent-proband trios to determine the significance of these results. 76 …”

“…It is notable that variations in the related protein, Slitrk1, have been found in cases of human OCD and TS. 64,75 However, the Slitrk5 knockout mouse seems to be a more useful model for studying OCD and related disorders, as the Slitrk1 knockout mouse has been shown to have increased anxiety behaviors but studies have not detected additional behavioral abnormalities consistent with OCD behaviors such as excessive self-grooming. 88 …”

Animal models of tic disorders: A translational perspective

“…In addition, this gene has been implicated in comorbid disorders, such as OCD and trichotillomania (Abelson et al, 2005; Zuchner et al, 2006; Ozomaro et al, 2013). …”