Association between genetic variants related to glutamatergic, dopaminergic and neurodevelopment pathways and white matter microstructure in child and adolescent patients with obsessive–compulsive disorder

Gassó, Patricia; Ortiz, Ana G.; Mas, Sergi; Morer, Àstrid; Calvo, Anna; Bargalló, Núria; Lafuente, Amàlia; Lázaro, Luisa

doi:10.1016/j.jad.2015.07.035

Cited by 43 publications

(34 citation statements)

References 64 publications

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“…While the study found no linkage disequilibrium, two later studies (one by the same group) published findings showing a correlation between OCD and SLC1A1 (Arnold et al, 2006, Dickel et al, 2006). Since then, several genetic variations in, or in proximity to SLC1A1 have been found to correlate with OCD, either by single marker or haplotype analysis of the SNPs (Stewart et al, 2007, Liang et al, 2008, Shugart et al, 2009, Samuels et al, 2011, Wu et al, 2013a, Wu et al, 2013b, Gasso et al, 2015). …”

Section: Eaat3 In Diseasementioning

confidence: 99%

The importance of the excitatory amino acid transporter 3 (EAAT3)

Bjørn‐Yoshimoto

Underhill

2016

Neurochemistry International

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The neuronal excitatory amino acid transporter 3 (EAAT3) is fairly ubiquitously expressed in the brain, though it does not necessarily maintain the same function everywhere. It is important in maintaining low local concentrations of glutamate, where its predominant post-synaptic localization can buffer nearby glutamate receptors and modulate excitatory neurotransmission and synaptic plasticity. It is also the main neuronal cysteine uptake system acting as the rate-limiting factor for the synthesis of glutathione, a potent antioxidant, in EAAT3 expressing neurons, while on GABAergic neurons, it is important in supplying glutamate as a precursor for GABA synthesis. Several diseases implicate EAAT3, and modulation of this transporter could prove a useful therapeutic approach. Regulation of EAAT3 could be targeted at several points for functional modulation, including the level of transcription, trafficking and direct pharmacological modulation, and indeed, compounds and experimental treatments have been identified that regulate EAAT3 function at different stages, which together with observations of EAAT3 regulation in patients is giving us insight into the endogenous function of this transporter, as well as the consequences of altered function. This review summarizes work done on elucidating the role and regulation of EAAT3.

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Section: Eaat3 In Diseasementioning

confidence: 99%

The importance of the excitatory amino acid transporter 3 (EAAT3)

Bjørn‐Yoshimoto

Underhill

2016

Neurochemistry International

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“…Although the mechanisms of altered WM microstructure in OCD are far from clear, a number of lines of research 35,36 and prior genetic association studies have described specific genes related to myelination 37 , while there is evidence that genetic variants related to glutamatergic, dopaminergic, and neurodevelopmental pathways determine WM microstructure in children and adolescents with OCD 38 . Although no genes related to myelination have yet reached genome wide-significance, given preliminary findings from small samples, it is possible that such significance will be reached with better powered GWASs.…”

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confidence: 99%

White Matter Microstructure and its Relation to Clinical Features of Obsessive-Compulsive Disorder: Findings from the ENIGMA OCD Working Group

Piras¹,

Piras²,

Abe

et al. 2019

Preprint

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KEY POINTSQuestion: Do patients with Obsessive-Compulsive Disorder (OCD) show white matter microstructural alterations, and are these alterations related to clinical features?Findings: Data from 19 sites of the ENIGMA-OCD Consortium were included, involving 700 adult patients and 645 adult controls, 174 pediatric patients and 144 pediatric controls. Diffusion tensor imaging data were meta-analyzed using a harmonized data processing and analysis protocol. Adult, but not pediatric, 6 patients showed alterations in the sagittal stratum and posterior thalamic radiation; sagittal stratum differences were associated with clinical features.Meaning: Microstructural abnormalities found in adult but not in the pediatric cohort, are related to illness duration and medication status. 7 ABSTRACT Importance: Microstructural alterations in cortico-subcortical connections are thought to be present in Obsessive-Compulsive Disorder (OCD). However, prior studies have yielded inconsistent findings, perhaps because small sample sizes provided insufficient power to detect subtle abnormalities. Objective: To investigate microstructural white matter alterations and their relation to clinical features in the largest dataset of adult and pediatric OCD to date. Design, Setting, and Participants: In this cross-sectional case-control magnetic resonance study, we investigated diffusion tensor imaging metrics from 700 adult patients and 645 adult controls, as well as 174 pediatric patients and 144 pediatric controls across 19 sites participating in the ENIGMA-OCD Working Group. Main Outcomes and Measures:We extracted measures of fractional anisotropy (FA) as main outcome, and mean diffusivity, radial diffusivity, and axial diffusivity as secondary outcomes for 25 white matter regions. We meta-analyzed patient-control group differences (Cohen's d) across sites, after adjusting for age and sex, and investigated associations with clinical characteristics.Results: Adult OCD patients showed significant FA reduction in the sagittal stratum (d=-0.21, z=-3.21, p=0.001) and posterior thalamic radiation (d=-0.26, z=-4.57, p<0.0001). In the sagittal stratum only, lower FA was associated with a younger age of onset (z=2.71, p=0.006), longer duration of illness (z=-2.086, p=0.036) and a higher percentage of medicated patients in the cohorts studied (z=-1.98, p=0.047). No significant association with

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“…Some findings showed that rs3780412 and rs301443 were associated with OCD, and its familial form . Gasso et al, reported strong association of SLC1A1 rs3087879 polymorphism with mean diffusivity measures in child and adolescent OCD patients. Two other SLC1A1 polymorphisms, rs301434 and rs301435, and their haplotype were reported to be significantly associated with OCD .…”

Section: Resultsmentioning

confidence: 99%

Genetic and pharmacogenetic study of glutamate transporter (SLC1A1) in Iranian patients with obsessive-compulsive disorder

et al. 2018

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Summary What is known and objective Obsessive‐compulsive disorder (OCD) is a chronic neuropsychiatric disorder. Selective serotonin reuptake inhibitors (SSRIs) are the first line of medication for OCD treatment; however, 40%‐60% of patients with OCD do not respond to SSRIs adequately. There are growing pieces of evidence which suggest a significant role for the glutamatergic system in the genesis of OCD and its consequent treatment. In the present study, we aimed to assess the association of SLC1A1 polymorphisms (rs301430, rs2228622 and rs3780413) with OCD and its clinical characteristics, as well as the importance of these SNPs in the response of OCD patients to SSRI pharmacotherapy. Methods Sample study consisted of 243 OCD cases and 221 control subjects. Patients were treated 12 weeks with fluvoxamine (daily dose: 150‐300 mg). Based on the reduction in obsessive and compulsive severity scores using Y‐BOCS severity scale, patients were classified as responders, non‐responders and refractory. A total of 239, 228 and 215 patients were genotyped for rs301430, rs2228622 and rs3780413, respectively, by the means of PCR‐RFLP. Results and discussion No association was detected between SLC1A1 SNPs and OCD, except an association between the familial form of the disease in males with rs2228622 (P = 0.033). The results of pharmacogenetic studies revealed the associations of two SLC1A1 SNPs, rs2228622 (P = 0.031) and rs3780413 (P = 0.008), with treatment response. What is new and conclusion Results of the current study suggest a role for the glutamate transporter in OCD treatment response with SSRIs which should encourage researchers to further investigate the importance of glutamate transporter in OCD pharmacogenetics.

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Association between genetic variants related to glutamatergic, dopaminergic and neurodevelopment pathways and white matter microstructure in child and adolescent patients with obsessive–compulsive disorder

Cited by 43 publications

References 64 publications

The importance of the excitatory amino acid transporter 3 (EAAT3)

The importance of the excitatory amino acid transporter 3 (EAAT3)

White Matter Microstructure and its Relation to Clinical Features of Obsessive-Compulsive Disorder: Findings from the ENIGMA OCD Working Group

Genetic and pharmacogenetic study of glutamate transporter (SLC1A1) in Iranian patients with obsessive-compulsive disorder

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