A pilot study exploring the association of morphological changes with 5-HTTLPR polymorphism in OCD patients

Honda, Shinichi; Nakao, Tomohiro; Mitsuyasu, Hiroshi; Okada, Kanzo; Gotoh, Leo; Tomita, Masaru; Sanematsu, Hirokuni; Murayama, Keitaro; Ikari, Keisuke; Kuwano, Masumi; Yamada, Takashi; Kawasaki, Hiroaki; Kanba, Shigenobu

doi:10.1186/s12991-017-0126-6

Cited by 11 publications

(11 citation statements)

References 47 publications

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“…This allows the division of the 5-HTTLPR modulated by rs25531 into a triallelic polymorphism: L A , which is high-expressing and L G and S (from here on referred to as S), which are low-expressing. The association of the triallelic 5-HTTLPR polymorphism with OCD risk has since been investigated in both adult and early-onset samples (Honda et al, 2017;Hu et al, 2006;Kenezloi et al, 2010;Moya et al, 2013;Rocha et al, 2009;Tibrewal et al, 2010;Tükel et al, 2016;Voyiaziakis et al, 2011;Walitza et al, 2014;Wendland et al, 2007), in which a significant association of the L A allele has been confirmed by our group in a small metaanalysis of OCD patients (Walitza et al, 2014). In addition, modulation of 5-HTTLPR functionality by the non-coding SLC6A4 polymorphisms rs25532 and rs16965628 has been demonstrated (Martin et al, 2007;Wendland et al, 2008).…”

Section: A N U S C R I P Tsupporting

confidence: 55%

“…We excluded a study reporting genetic association between 5-HTTLPR+rs25531 and rs25532 of adult Tourette patients comorbid with OCD (Moya et al, 2013), since DSM-5 differentiates between Tourette and OCD. A study of adult OCD and 5-HTTLPR+rs25531 by Honda et al (Honda et al, 2017) was also excluded, as it deviated from all other studies causing an increase in heterogeneity (I 2 ). It also demonstrated low quality scores and was the only Asian ethnicity (see supplementary Table S2).…”

Section: Meta-analysis For Slc6a4 Promoter Polymorphism In Ocdmentioning

confidence: 99%

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Combining genetic and epigenetic parameters of the serotonin transporter gene in obsessive-compulsive disorder

Grünblatt

Marinova

Röth

et al. 2018

Journal of Psychiatric Research

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While genetic variants have been reported to be associated with obsessive-compulsive disorder (OCD), the small effect sizes suggest that epigenetic mechanisms such as DNA methylation may also be relevant. The serotonin transporter (SLC6A4) gene has been extensively investigated in relation to OCD, since serotonin reuptake inhibitors are the pharmacological treatment of choice for the disorder. The current study set three questions: Firstly, whether the high expressing loci of the SLC6A4 polymorphisms, 5-HTTLPR + rs25531, rs25532 and rs16965628 are associated with family-based (n = 164 trios) and case-control OCD (n = 186, 152, respectively). This was also examined by a meta-analysis. Secondly, whether DNA methylation and RNA levels of the SLC6A4 differ in saliva and blood of a subset of samples from pediatric and adult OCD patients and matched controls. And lastly, whether morning awakening cortisol levels correlate with the above. A meta-analysis confirmed the association of the L-allele with OCD (OR = 1.21, p = 0.00018), maintaining significance in the early-onset OCD subgroup (OR = 1.21, p = 0.022). There was no association between rs25532 or rs16965628 and OCD. Our preliminary data showed that SLC6A4 DNA methylation levels in an amplicon located at the beginning of the first intron were significantly higher in the saliva of pediatric OCD patients compared to controls and adult patients with OCD, but no alterations in RNA levels or in polymorphism interactions were observed. Morning awakening salivary cortisol levels positively correlated with methylation levels, and negatively correlated with RNA levels. This study further supports the involvement of the SLC6A4 gene in OCD through both genetic and epigenetic mechanisms. This finding needs to be explored further in an independent large sample.

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Section: A N U S C R I P Tsupporting

confidence: 55%

Section: Meta-analysis For Slc6a4 Promoter Polymorphism In Ocdmentioning

confidence: 99%

Combining genetic and epigenetic parameters of the serotonin transporter gene in obsessive-compulsive disorder

Grünblatt

Marinova

Röth

et al. 2018

Journal of Psychiatric Research

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“…However, unlike in the present study, in this meta-analysis symptom spectra or the interrelation between different symptoms was not taken into account but symptoms were assessed independently for each Y-BOCS checklist symptom dimension. Present findings not only corroborate the clinical relevance of hippocampal volume alterations in OCD as reported before ( Honda et al, 2017 ) but strongly suggest that the interrelation of symptom dimensions should be taken into account in this regard. As also shown in Fig.…”

Section: Discussionsupporting

confidence: 92%

Association between hippocampus volume and symptom profiles in obsessive–compulsive disorder

Reeß

Rus

Gürsel

et al. 2018

NeuroImage: Clinical

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BackgroundThe hippocampus has recently been identified to play a key role in the pathophysiology of adult obsessive-compulsive disorder (OCD). Surprisingly, there is only limited evidence regarding the potential relationships with symptom dimensions. Due to the heterogeneity of symptoms in OCD, we aimed at further examining, whether hippocampal volume differences might be related to symptom profiles instead of single symptom dimensions.MethodsIn order to find out more about the potential association between clinical symptom profiles and alterations in hippocampal volume we categorized a large sample of OCD patients (N = 66) into distinct symptom profile groups using K-means clustering. In addition, hippocampal volumes of the different symptom profile groups were compared with hippocampal volumes in a sample of 66 healthy controls.ResultsWe found significant differences in hippocampal volume between the different symptom profile groups which remained significant after correcting for age, sex, total intracranial volume, OCI-total score, depression, medication, disease duration and scanner. The patient group characterized by overall lower symptom scores and without high symptom severity in any specific domain showed the highest hippocampal volume. Finally, the comparison with healthy controls demonstrated significantly lower hippocampal volumes in those patients whose symptom profile was characterized by a high severity of ordering and checking symptoms.ConclusionsPresent results provide further confirmation for alterations in hippocampus structure in OCD and suggest that symptom profiles which take into account the multi-symptomatic character of the disorder should be given greater attention in this context.

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“…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.…”

Section: (B) Evidence From Clinical Obsessive-compulsive Disorder Stumentioning

confidence: 99%

“…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].…”

Section: (A) Serotonergic Disruptions In Sapap-3 Knockout Micementioning

confidence: 99%

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

Wood

LaPalombara

Ahmari

2018

Phil. Trans. R. Soc. B

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Obsessive-compulsive disorder (OCD) is a leading cause of illness-related disability, but the neural mechanisms underlying OCD symptoms are unclear. One potential mechanism of OCD pathology is monoamine dysregulation. Because of the difficulty of studying monoamine signalling in patients, animal models offer a viable alternative to understanding this aspect of OCD pathophysiology. We used HPLC to characterize post-mortem monoamine levels in lateral orbitofrontal cortex (OFC), medial OFC, medial prefrontal cortex and dorsal and ventral striatum of SAPAP-3 knockout (KO) mice, a well-validated model of compulsive-like behaviours in OCD. As predicted from previous studies, excessive grooming was significantly increased in SAPAP-3 KO mice. Overall levels of the serotonin metabolite 5-hydroxyindoleacetic acid (HIAA) and the ratio of 5HIAA/serotonin (serotonin turnover) were increased in all cortical and striatal regions examined. In addition, dihydroxyphenylacetic acid/dopamine ratio was increased in lateral OFC, and HVA/dopamine ratio was increased in lateral and medial OFC. No baseline differences in serotonin or dopamine tissue content were observed. These data provide evidence of monoaminergic dysregulation in a translational model of OCD symptoms and are consistent with aberrant cortical and striatal serotonin and dopamine release/metabolism in SAPAP-3 KO mice. These results are guiding ongoing experiments using circuit and cell-type specific manipulations of dopamine and serotonin to determine the contributions of these monoaminergic systems to compulsive behaviours, and serve here as a touchstone for an expanded discussion of these techniques for precise circuit dissection.This article is part of the discussion meeting issue 'Of mice and mental health: facilitating dialogue between basic and clinical neuroscientists'.

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A pilot study exploring the association of morphological changes with 5-HTTLPR polymorphism in OCD patients

Cited by 11 publications

References 47 publications

Combining genetic and epigenetic parameters of the serotonin transporter gene in obsessive-compulsive disorder

Combining genetic and epigenetic parameters of the serotonin transporter gene in obsessive-compulsive disorder

Association between hippocampus volume and symptom profiles in obsessive–compulsive disorder

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

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