The need for inclusion of sex and age of onset variables in genetic association studies of obsessive–compulsive disorder: Overview

Mattina, Gabriella Francesca; Steiner, Meir

doi:10.1016/j.pnpbp.2016.01.012

Cited by 25 publications

(17 citation statements)

References 104 publications

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“…These inconsistencies are most likely to have arisen from some studies only analyzing the 5-HTTLPR polymorphism without the modification of the rs25531 or in combination with the refined 5-HTTLPR+rs25531 polymorphism. Indeed, as discussed previously, age of onset and gender seem to play a role in genetic association in OCD (Mattina et al, 2016), as our stratified analysis of 5-HTTLPR+rs25531 demonstrated a significant association with early-onset OCD. For the two additional SNPs, since heterogeneity was rather large, a larger and more homogenous sample would be required to prove or reject the association.…”

Section: Discussionsupporting

confidence: 76%

“…We further stratified the meta-analysis by age of onset, as this was thought to be an important variable in association studies (Mattina & Steiner, 2016), only running the analysis for earlyonset pediatric OCD publications. This analysis demonstrated a significant association between the L A allele with early-onset OCD (total n=2944, cases n= 1086, OR = 1.207, 95% CI 1.027-1.418, p-value = 0.022, Fig.…”

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: Discussionsupporting

confidence: 76%

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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“…4,38 Genetic studies have also shown the involvement of genes related to GABA or glutamate in OCD pathogenesis. [43][44][45] The imbalance of GABAergic and glutamatergic receptor-mediated neurotransmission in CSTC circuitry may contribute to the regional hyperactivity and lack of response inhibition seen in OCD, leading to obsessive-compulsive symptoms.…”

Section: Discussionmentioning

confidence: 99%

Changes of motor cortical excitability and response inhibition in patients with obsessive–compulsive disorder

Kang

Kim

Lee

et al. 2019

jpn

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Background: Deficits in cortical inhibitory processes have been suggested as underlying pathophysiological mechanisms of obsessivecompulsive disorder (OCD). We examined whether patients with OCD have altered cortical excitability using paired-pulse transcranial magnetic stimulation (TMS). We also tested associations between TMS indices and OCD-related characteristics, including age of onset and response inhibition in the go/no-go paradigm, to examine whether altered cortical excitability contributes to symptom formation and behavioural inhibition deficit in patients with OCD. Methods: We assessed motor cortex excitability using paired-pulse TMS in 51 patients with OCD and 39 age-matched healthy controls. We also assessed clinical symptoms and response inhibition in the go/nogo task. All patients were undergoing treatment with serotonin reuptake inhibitors. We performed repeated-measures multivariate analy sis of covariance to compare TMS indices between patients with OCD and controls. Results: Compared to controls, patients with OCD showed a shorter cortical silent period and decreased intracortical facilitation. However, we found no significant difference between groups for resting motor threshold or short-interval intracortical inhibition. In the OCD group, the shortened cortical silent period was associated with a prompt reaction time in the go/no-go task and with early onset of OCD. Limitations: We could not exclude the influence of medications on motor cortex excitability. Conclusion: These findings suggest abnormal cortical excitability in patients with OCD. The associations between cortical silent period and response inhibition and age of onset further indicate that altered cortical excitability may play an important role in the development of OCD.

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“…Genetic variations in the receptor and enzyme components of the serotonergic, dopaminergic, and glutamatergic neurotransmitter systems, as well genetic variations in growth and transcription factors have been associated with OCD [3] . These gene variations may increase susceptibility of individuals to OCD at various life events.…”

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confidence: 99%

Effect of Gonadal Hormones on Neurotransmitters Implicated in the Pathophysiology of Obsessive-Compulsive Disorder: A Critical Review

Karpinski

Mattina

Steiner³

2016

Neuroendocrinology

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Obsessive-compulsive disorder (OCD) is a relatively common neuropsychiatric disorder affecting between 1.6 and 3.2% of the population. A number of studies have previously reported increased incidence of OCD, or exacerbation of preexisting symptoms in females during reproductive events. Since these periods are known to involve fluctuating levels of gonadal hormones, these steroids have been suggested to be involved in modulating the course of the disorder. However, to date, only a few studies have measured hormone levels and obsessive-compulsive (OC) symptoms concurrently; thus, direct evidence for this relationship is limited. In turn, investigations into neurotransmission in OC individuals have been more extensive, and have implicated the serotonergic, dopaminergic, and glutamatergic neurotransmitter systems in OCD pathology. There is evidence suggesting that reproductive hormones estrogens and progesterone can modulate neurotransmission in the aforementioned signaling pathways by regulating the expression of receptors and channels, as well as the synthesis and release of the neurotransmitter itself. Overall, estrogen and progesterone appear to enhance serotonin signaling, which has been associated with improved OC symptoms. The effect of the gonadal hormones in dopaminergic and glutamatergic signaling is much more variable, highlighting the need for further research in this field. The existing evidence shows that gonadal hormones can have profound impacts on neurotransmission in the brain, leading to the conclusion that the hormonal fluctuations during reproductive events are a plausible factor contributing to the change in OCD course during these times.

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The need for inclusion of sex and age of onset variables in genetic association studies of obsessive–compulsive disorder: Overview

Cited by 25 publications

References 104 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

Changes of motor cortical excitability and response inhibition in patients with obsessive–compulsive disorder

Effect of Gonadal Hormones on Neurotransmitters Implicated in the Pathophysiology of Obsessive-Compulsive Disorder: A Critical Review

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