A Meta-analysis of the Association Between SLC6A3 Gene Polymorphisms and Schizophrenia

Xu, Feng‐ling; Ding, Mei; Wu, Xue; Liu, Yongping; Xia, Xi; Yao, Jun; Wang, Baojie

doi:10.1007/s12031-019-01399-5

Cited by 9 publications

(7 citation statements)

References 77 publications

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“…Impaired dopamine clearance due to DAT deficiency results in prolonged dopamine surge with consequent loss of informational value from dopamine signals. Mutations or polymorphisms in the DAT gene SLC6A3 contribute to ADHD [ 11 ], OCD [ 12 ], bipolar disorder [ 13 ] and schizophrenia [ 14 ]. Therefore, systematic investigations of DAT dysfunction provide a transdiagnostic approach towards better understanding of the common underlying mechanistic pathways across disorders.…”

Section: Introductionmentioning

confidence: 99%

Dopamine transporter silencing in the rat: systems-level alterations in striato-cerebellar and prefrontal-midbrain circuits

et al. 2022

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Silencing of dopamine transporter (DAT), a main controlling factor of dopaminergic signaling, results in biochemical and behavioral features characteristic for neuropsychiatric diseases with presumed hyperdopaminergia including schizophrenia, attention deficit hyperactivity disorder (ADHD), bipolar disorder, and obsessive-compulsive disorder (OCD). Investigation of DAT silencing thus provides a transdiagnostic approach towards a systems-level understanding of common underlying pathways. Using a high-field multimodal imaging approach and a highly sensitive cryogenic coil, we integrated structural, functional and metabolic investigations in tandem with behavioral assessments on a newly developed preclinical rat model, comparing DAT homozygous knockout (DAT-KO, N = 14), heterozygous knockout (N = 8) and wild-type male rats (N = 14). We identified spatially distributed structural and functional brain alterations encompassing motor, limbic and associative loops that demonstrated strong behavioral relevance and were highly consistent across imaging modalities. DAT-KO rats manifested pronounced volume loss in the dorsal striatum, negatively correlating with cerebellar volume increase. These alterations were associated with hyperlocomotion, repetitive behavior and loss of efficient functional small-world organization. Further, prefrontal and midbrain regions manifested opposite changes in functional connectivity and local network topology. These prefrontal disturbances were corroborated by elevated myo-inositol levels and increased volume. To conclude, our imaging genetics approach provides multimodal evidence for prefrontal-midbrain decoupling and striato-cerebellar neuroplastic compensation as two key features of constitutive DAT blockade, proposing them as transdiagnostic mechanisms of hyperdopaminergia. Thus, our study connects developmental DAT blockade to systems-level brain changes, underlying impaired action inhibition control and resulting in motor hyperactivity and compulsive-like features relevant for ADHD, schizophrenia and OCD.

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Section: Introductionmentioning

confidence: 99%

Dopamine transporter silencing in the rat: systems-level alterations in striato-cerebellar and prefrontal-midbrain circuits

et al. 2022

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“…Studies employing meta-analyses have implicated this gene in posttraumatic stress disorder (PTSD) (3’VNTR9r OR = 1.62) [ 78 ], MDD (pooled OR = 1.26) [ 79 , 80 ], schizophrenia (SCZ) (pooled OR = 3.2) [ 81 ], sleep duration (rs464049 G allele, beta [standard error, SE] = − 0.96 [0.18] minutes/allele; P = 5.71 × 10 −10 as a genome-wide significance) [ 82 ] and PD [ 83 ]. An early Dutch study examined 16 SNPs plus 3’VNTR in 720 patients and uncovered selective rs393795 A/A protection against delirium in PD [ 84 ].…”

Section: Resultsmentioning

confidence: 99%

The dopamine transporter gene SLC6A3: multidisease risks

et al. 2021

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The human dopamine transporter gene SLC6A3 has been consistently implicated in several neuropsychiatric diseases but the disease mechanism remains elusive. In this risk synthesis, we have concluded that SLC6A3 represents an increasingly recognized risk with a growing number of familial mutants associated with neuropsychiatric and neurological disorders. At least five loci were related to common and severe diseases including alcohol use disorder (high activity variant), attention-deficit/hyperactivity disorder (low activity variant), autism (familial proteins with mutated networking) and movement disorders (both regulatory variants and familial mutations). Association signals depended on genetic markers used as well as ethnicity examined. Strong haplotype selection and gene-wide epistases support multimarker assessment of functional variations and phenotype associations. Inclusion of its promoter region’s functional markers such as DNPi (rs67175440) and 5’VNTR (rs70957367) may help delineate condensate-based risk action, testing a locus-pathway-phenotype hypothesis for one gene-multidisease etiology.

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“…The SLC6A3 gene encodes the dopamine transporter and can be determinative in the regulation of dopamine in the synaptic cleft. It has been well indicated that its polymorphisms are risk factors for SCZ [ 74 ]. Also, the manifestation of OCD symptoms can be associated with SLC6A3 [ 75 ].…”

Section: Discussionmentioning

confidence: 99%

Disclosing common biological signatures and predicting new therapeutic targets in schizophrenia and obsessive–compulsive disorder by integrated bioinformatics analysis

et al. 2023

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Schizophrenia (SCZ) is a severe mental illness mainly characterized by a number of psychiatric symptoms. Obsessive–compulsive disorder (OCD) is a long-lasting and devastating mental disorder. SCZ has high co-occurrence with OCD resulting in the emergence of a concept entitled “schizo-obsessive disorder” as a new specific clinical entity with more severe psychiatric symptoms. Many studies have been done on SCZ and OCD, but the common pathogenesis between them is not clear yet. Therefore, this study aimed to identify shared genetic basis, potential biomarkers and therapeutic targets between these two disorders. Gene sets were extracted from the Geneweaver and Harmonizome databases for each disorder. Interestingly, the combination of both sets revealed 89 common genes between SCZ and OCD, the most important of which were BDNF, SLC6A4, GAD1, HTR2A, GRIN2B, DRD2, SLC6A3, COMT, TH and DLG4. Then, we conducted a comprehensive bioinformatics analysis of the common genes. Receptor activity as the molecular functions, neuron projection and synapse as the cellular components as well as serotonergic synapse, dopaminergic synapse and alcoholism as the pathways were the most significant commonalities in enrichment analyses. In addition, transcription factor (TFs) analysis predicted significant TFs such as HMGA1, MAPK14, HINFP and TEAD2. Hsa-miR-3121-3p and hsa-miR-495-3p were the most important microRNAs (miRNAs) associated with both disorders. Finally, our study predicted 19 existing drugs (importantly, Haloperidol, Fluoxetine and Melatonin) that may have a potential influence on this co-occurrence. To summarize, this study may help us to better understand and handle the co-occurrence of SCZ and OCD by identifying potential biomarkers and therapeutic targets.

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A Meta-analysis of the Association Between SLC6A3 Gene Polymorphisms and Schizophrenia

Cited by 9 publications

References 77 publications

Dopamine transporter silencing in the rat: systems-level alterations in striato-cerebellar and prefrontal-midbrain circuits

Dopamine transporter silencing in the rat: systems-level alterations in striato-cerebellar and prefrontal-midbrain circuits

The dopamine transporter gene SLC6A3: multidisease risks

Disclosing common biological signatures and predicting new therapeutic targets in schizophrenia and obsessive–compulsive disorder by integrated bioinformatics analysis

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