Trio study and meta-analysis support the association of genetic variation at the serotonin transporter with early-onset obsessive–compulsive disorder

Abstract

Despite compelling evidence for major genetic contributions to the etiology of obsessive-compulsive disorder (OCD), few genetic variants have been consistently associated with this debilitating illness. Molecular genetic studies in children and adolescents with OCD are of particular interest, since early onset of the disease has been observed to be associated with increased familiality. We replicate here for the first time in early-onset OCD patients, a previously reported association of OCD with the common gain-of-function LA allele at the serotonin transporter linked polymorphic region known as 5-HTTLPR in a collection of parent-offspring trios. The present meta-analysis of this recently refined serotonin transporter gene variant revealed further support for the LA allele conferring increased genetic susceptibility to OCD. We conclude that the 5-HTTLPR is currently the single best supported risk variant for OCD, in regards of early-onset OCD, albeit of modest effect size and the possibility that the conferred risk might not be specific to OCD.

Imaging genetics in obsessive-compulsive disorder: Linking genetic variations to alterations in neuroimaging

“…In contrast, a recent meta-analysis that subdivided the 5-HTTLPR L allele into the high-functioning L A allele and the low-functioning L G allele (Hu et al, 2006), producing a triallelic form in which the L G allele is pooled with the S allele, reported that being an L A allele carrier was significantly associated with OCD (odds ratio = 1.251, 95% confidence interval = 1.048-1.492, p = 0.001) (Taylor, 2013). Just recently, we could replicate this finding of L A allele association with ealy onset OCD s well as within a meta-Analysis includng early and late onset OCD (Walitza et al, 2014b). However, up to now analysis of these gene variants using genetic imaging techniques in related conditions underscored the effects of the 5-HTTLPR S allele and brain activation.…”

“…This stipulation led to the retrieval of a small collection of manuscripts describing association analyses of genetic variants with neuroimaging techniques in OCD (n = 8). The present study focused on the most significant and nominally significant genes associated with OCD as inclusion criteria by cross-referencing these publications with GWAS and meta-analyzed genetic association (Azzam and Mathews, 2003;Lin, 2007;Pooley et al, 2007;Stewart et al, 2013aStewart et al, , 2013bTaylor, 2013;Walitza et al, 2014b). A publication by Hoexter et al (2009) was not included in the review because it did not include genetic association results in addition to their findings of single-photon emission computed tomography or magnetic resonance imaging in OCD.…”

Early intervention for obsessive compulsive disorder: An expert consensus statement

“…Evidence from studies on convenience samples suggests that early onset OCD is associated with a number of distinguishing features, of relevance for clinical intervention, including comorbidity with neurodevelopmental disorders such as tic disorder and attention deficit hyperactivity disorder (ADHD) and familial clustering suggesting a greater genetic contribution (Walitza et al, 2008, Walitza et al, 2010, Taylor 2011. Indeed, in some studies, early-onset OCD has been associated with specific gene variants of serotonergic, dopaminergic and glutamatergic receptors and synaptic brain related genes, neurotrophic and transcription factors (Walitza et al, 2014, Grünblatt et al, 2017. Symmetry, ordering and sexual or religious symptoms are also associated with early-onset OCD (Labad et al, 2008), possibly linked to comorbidity with tic disorders and tic-specific symptoms.…”

Monoamine abnormalities in the SAPAP3 knockout model of obsessive-compulsive disorder-related behaviour

“…Furthermore, symptom exacerbation generally occurs when targeting receptors that negatively regulate presynaptic serotonin release [20,21], suggesting that deficient serotonin signalling contributes to OCD. In addition, associations of serotonin transporter gene polymorphisms with OCD [22][23][24][25][26][27][28] have led to speculation that OCD is associated with a hyposerotonergic state. However, many inconsistencies have made it difficult to isolate specific abnormalities within the serotonergic system.…”

“…These preclinical data may seem somewhat at odds with some clinical data. For instance, the utility of SRIs in treating OCD symptoms [19,64], decreased serotonin transporter availability [28,31,[65][66][67][68][69], and associations of polymorphisms of the genes encoding serotonin transporter [22][23][24][25][26][27][28] and serotonin 2A receptor [23] proteins with OCD have led to speculation that OCD is associated with a hypo-serotonergic state. However, it is important to note that the serotonin hypothesis has mixed support [1].…”