A screen of SLC1A1 for OCD-related alleles
ABSTRACT SLC1A1, which encodes the neuronal and epithelial glutamate transporter, is a promising candidate gene for obsessive-compulsive disorder (OCD). In this study, we conducted capillary electrophoresis single-strand conformation polymorphism (CE-SSCP) screen for all 12 identified exons, including all coding regions and approximately 50 bp of flanking introns of the human SLC1A1 in 378 OCD-affected individuals. Full sequencing was completed on samples that showed an aberrant SSCP tracing for identification of the underlying sequence variants. Our aim was to determine if there are differences in the frequencies of relatively common alleles, or rare functional alleles, in 378 OCD cases and 281 ethnically matched controls. We identified one nonsynonymous coding SNP (c.490A > G, T164A) and three synonymous coding SNP (c.81G > C, A27A; c.414A > G, T138T; c.1110T > C, T370T) in case samples. We found no statistical differences in genotype and allele frequencies of common cSNPs in SLC1A1 between the OCD cases and controls. The rare variant T164A was found only in one family. Further investigation of this variant is necessary to determine whether and how it is related to OCD. There was no other evidence of significant accumulation of deleterious coding mutations in SLC1A1 in the OCD cases.
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ABSTRACT: Obsessive-compulsive disorder (OCD) is a psychiatric condition characterized by intrusive thoughts and urges and repetitive, intentional behaviors that cause significant distress and impair functioning. The OCD Collaborative Genetics Association Study (OCGAS) is comprised of comprehensively assessed OCD patients with an early age of OCD onset. After application of a stringent quality control protocol, a total of 1065 families (containing 1406 patients with OCD), combined with population-based samples (resulting in a total sample of 5061 individuals), were studied. An integrative analyses pipeline was utilized, involving association testing at single-nucleotide polymorphism (SNP) and gene levels (via a hybrid approach that allowed for combined analyses of the family- and population-based data). The smallest P-value was observed for a marker on chromosome 9 (near PTPRD, P=4.13 × 10(-)(7)). Pre-synaptic PTPRD promotes the differentiation of glutamatergic synapses and interacts with SLITRK3. Together, both proteins selectively regulate the development of inhibitory GABAergic synapses. Although no SNPs were identified as associated with OCD at genome-wide significance level, follow-up analyses of genome-wide association study (GWAS) signals from a previously published OCD study identified significant enrichment (P=0.0176). Secondary analyses of high-confidence interaction partners of DLGAP1 and GRIK2 (both showing evidence for association in our follow-up and the original GWAS study) revealed a trend of association (P=0.075) for a set of genes such as NEUROD6, SV2A, GRIA4, SLC1A2 and PTPRD. Analyses at the gene level revealed association of IQCK and C16orf88 (both P<1 × 10(-)(6), experiment-wide significant), as well as OFCC1 (P=6.29 × 10(-)(5)). The suggestive findings in this study await replication in larger samples.Molecular Psychiatry advance online publication, 13 May 2014; doi:10.1038/mp.2014.43.Molecular Psychiatry 05/2014; 20(3). DOI:10.1038/mp.2014.43 · 15.15 Impact Factor
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ABSTRACT: 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.ADHD Attention Deficit and Hyperactivity Disorders 07/2014; 6(3). DOI:10.1007/s12402-014-0146-x
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ABSTRACT: Evidence-based pharmacological interventions for obsessive compulsive disorder (OCD) are targeted mainly at the serotonergic and dopaminergic pathways, and are not always effective. It is timely to review the growing evidence from animal models and clinical research (e.g., brain imaging, genetics) on the role of the glutamatergic system in OCD. Emerging evidence from both animal models and clinical research (including brain imaging, neurogenetics) supports the glutamatergic system as a potential target for pharmacotherapy in OCD. Although there have been relatively few randomized controlled trials of glutamatergic agents in pediatric or adult OCD to date, there is some work on riluzole, memantine, ketamine, topiramate, lamotrigine, N-acetylcysteine, and D-cycloserine. Given the need for more efficacious treatments in OCD, and given emergent findings on the role of the glutamatergic system in this disorder, there is a need for additional pharmacotherapy trials on glutamatergic agents in OCD. Possible research designs for such trials might include stand-alone approaches, pharmacotherapy augmentation, or psychotherapy augmentation.Current opinion in psychiatry 11/2013; DOI:10.1097/YCO.0000000000000017 · 3.55 Impact Factor