A screen of SLC1A1 for OCD‐related alleles

Wang, Y.; Adamczyk, Abby; Shugart, Yin Yao; Samuels, Jack; Grados, Marco A.; Greenberg, B. D.; Knowles, James A.; McCracken, James T.; Rauch, Scott L.; Murphy, Dennis L.; Rasmussen, Steven A.; Cullen, Bernadette; Pinto, Anthony; Fyer, Abby J.; Piacentini, John; Pauls, David L.; Bienvenu, O. Joseph; Riddle, Mark A.; Liang, Kung‐Yee; Valle, David; Wang, T.; Nestadt, Gerald

doi:10.1002/ajmg.b.31001

Cited by 42 publications

(36 citation statements)

References 15 publications

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“…Identification and characterization of three alternative SLC1A1 /EAAC1 (excitatory amino-acid transporter 1) mRNAs, P2, ex2skip, and ex11skip (Porton et al 2013), gave evidence that all isoforms inhibit glutamate uptake from the full-length EAAC1 transporter (Porton et al 2013). While Wang et al (2010) did find the variant T164A in one family, these authors did not find statistical differences in genotype and allele frequencies of common SNPs in SLC1A1. All in all, however, the results on SLC1A1 in OCD are at discrepancy.…”

Section: Genetic Aspects In Ocd and Adhdmentioning

confidence: 77%

The neurobiological link between OCD and ADHD

Brem

Grünblatt

Drechsler

et al. 2014

ADHD Atten Def Hyp Disord

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Obsessive compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD) are two of the most common neuropsychiatric diseases in paediatric populations. The high comorbidity of ADHD and OCD with each other, especially of ADHD in paediatric OCD, is well described. OCD and ADHD often follow a chronic course with persistent rates of at least 40–50 %. Family studies showed high heritability in ADHD and OCD, and some genetic findings showed similar variants for both disorders of the same pathogenetic mechanisms, whereas other genetic findings may differentiate between ADHD and OCD. Neuropsychological and neuroimaging studies suggest that partly similar executive functions are affected in both disorders. The deficits in the corresponding brain networks may be responsible for the perseverative, compulsive symptoms in OCD but also for the disinhibited and impulsive symptoms characterizing ADHD. This article reviews the current literature of neuroimaging, neurochemical circuitry, neuropsychological and genetic findings considering similarities as well as differences between OCD and ADHD.

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Section: Genetic Aspects In Ocd and Adhdmentioning

confidence: 77%

The neurobiological link between OCD and ADHD

Brem

Grünblatt

Drechsler

et al. 2014

ADHD Atten Def Hyp Disord

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“…A sex-specific association between SLC1A1 and OCD in male, but not in female, patients has been reported, [12][13][14][15][16] although negative results have also been published. 17 Preliminary results also suggest a possible association between OCD and genetic variations of certain ionotropic glutamate receptors, including GRIK2 (glutamate receptor, ionotropic, kainate 2) 18,19 and GRIN2B (ionotropic glutamate receptor, N-methyl-D-aspartate subunit 2B). 20 Arnold and colleagues 20 described a positive association between variants in the 3′ untranslated region (3′ UTR) of the GRIN2B gene -the gene encoding the NR2 subunit of the N-methyl-D-aspartate (NMDA) glutamate receptor -and OCD in 178 affected individuals from 130 families.…”

Section: Introductionmentioning

confidence: 81%

Association between the NMDA glutamate receptor GRIN2B gene and obsessive–compulsive disorder

Alonso

Gratacòs

Segalás

et al. 2012

jpn

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Background: Recent data from neuroimaging, genetic and clinical trials and animal models suggest a role for altered glutamatergic neuro transmission in the pathogenesis of obsessive-compulsive disorder (OCD). The aim of this study was to investigate whether variants in the GRIN2B gene, the gene encoding the NR2 subunit of the N-methyl-D-aspartate (NMDA) glutamate receptor, may contribute to genetic susceptibility to OCD or to different OCD subphenotypes. Methods: Between 2003 and 2008, we performed a case-control association study in which we genotyped 10 tag single-nucleotide polymorphisms (SNPs) in the 3′ untranslated region (3′ UTR) of GRIN2B. We performed SNP association and haplotype analysis considering the OCD diagnosis and different OCD subphenotypes: early-onset OCD, comorbid tic disorders and OCD clinical symptom dimensions. Results: We enrolled 225 patients with OCD and 279 controls recruited from the OCD Clinic at Bellvitge Hospital (Barcelona, Spain). No significant difference in the distribution of alleles or genotypes was detected between patients with OCD and controls. Nonetheless, on analyzing OCD subphenotypes, the rs1805476 SNP in male patients (95% confidence interval [CI] 1.37-4.22, p = 0.002) and a 4-SNP haplotype in the whole sample (rs1805476, rs1805501, rs1805502 and rs1805477; odds ratio 1.92, 95% CI 1.22-3.01; permutation p = 0.023) were significantly associated with the presence of contamination obsessions and cleaning compulsions. Limitations: Study limitations included the risk of population stratification associated with the case-control design, use of psychiatrically unscreened blood donors as the control group, reduced sample size of participants with certain OCD subphenotypes and tested polymorphisms limited to 3′ UTR and exon 13 of GRIN2B. Conclusion: Our results converge with recent data suggesting a possible contribution of glutamatergic variants to the genetic vulnerability to OCD or at least to certain OCD manifestations. The dissection of OCD into more homogeneous subphenotypes may constitute a useful tool to disentangle the complex genetic basis of the disorder.

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“…Slc1a1 nullizygous mice have not yet been thoroughly examined for executive dysfunction phenotypical of OCD. To date, only one rare variant, c.490A > G (p.T164A), in a conserved region of SLC1A1 has been identified in OCD cohorts (40), though this has not been functionally tested. A molecular explanation for a role for SLC1A1 in OCD may yet lie in noncoding regions within or immediately adjacent to the SLC1A1 locus.…”

Section: Discussionmentioning

confidence: 99%

Loss-of-function mutations in the glutamate transporter SLC1A1 cause human dicarboxylic aminoaciduria

Bailey¹,

Ryan²,

Thoeng³

et al. 2011

J. Clin. Invest.

130

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Solute carrier family 1, member 1 (SLC1A1; also known as EAAT3 and EAAC1) is the major epithelial transporter of glutamate and aspartate in the kidneys and intestines of rodents. Within the brain, SLC1A1 serves as the predominant neuronal glutamate transporter and buffers the synaptic release of the excitatory neurotransmitter glutamate within the interneuronal synaptic cleft. Recent studies have also revealed that polymorphisms in SLC1A1 are associated with obsessive-compulsive disorder (OCD) in early-onset patient cohorts. Here we report that SLC1A1 mutations leading to substitution of arginine to tryptophan at position 445 (R445W) and deletion of isoleucine at position 395 (I395del) cause human dicarboxylic aminoaciduria, an autosomal recessive disorder of urinary glutamate and aspartate transport that can be associated with mental retardation. These mutations of conserved residues impeded or abrogated glutamate and cysteine transport by SLC1A1 and led to near-absent surface expression in a canine kidney cell line. These findings provide evidence that SLC1A1 is the major renal transporter of glutamate and aspartate in humans and implicate SLC1A1 in the pathogenesis of some neurological disorders.

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A screen of SLC1A1 for OCD‐related alleles

Cited by 42 publications

References 15 publications

The neurobiological link between OCD and ADHD

The neurobiological link between OCD and ADHD

Association between the NMDA glutamate receptor GRIN2B gene and obsessive–compulsive disorder

Loss-of-function mutations in the glutamate transporter SLC1A1 cause human dicarboxylic aminoaciduria

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