Increased Nigral<i>SLC6A3</i>Activity in Schizophrenia Patients: Findings From the Toronto–McLean Cohorts

Kennedy, James L.; Xiong, Nian; Yu, Jinlong; Zai, Clement C.; Pouget, J; Li, Jie; Liu, Ke-Fu; Qing, Hong; Wang, Tao; Martin, Eden R.; Levy, Deborah L.; Lin, Zhicheng

doi:10.1093/schbul/sbv191

Cited by 10 publications

(12 citation statements)

References 74 publications

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“…Dopaminergic neurons were isolated randomly from the postmortem nigral tissue of 40 subjects (22 males, 18 females, mean age 58 years,), by laser capture microdissection [36]. Briefly, 10-μM sections were immunostained with anti-tyrosine hydroxylase (TH) antibody and labeled neurons were captured via a PixCell II laser capture microdissection instrument (Arcturus, Mountain View, CA, USA).…”

Section: Epigenetic Gene Expression In Human Dopaminergic Neuronsmentioning

confidence: 99%

hVMAT2: A Target of Individualized Medication for Parkinson's Disease

Xiong

Martin

et al. 2016

Neurotherapeutics

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Vesicular monoamine transporter 2 (VMAT2) is responsible for sequestering cytosolically toxic dopamine into intracellular secretory vesicles. Animal genetic studies have suggested that reduced VMAT2 activity contributes to the genetic etiology of Parkinson's disease (PD), but this role has not been established in humans. Based on human genetic association and meta-analysis, we first confirm the human VMAT2 (hVMAT2 or SLC18A2) promoter as a risk factor for PD in both family and unrelated US white people: marker rs363324 at -11.5 kb in the hVMAT2 promoter is reproducibly associated with PD in a cohort of nuclear families (p = 0.04506 in early-onset PD) and 3 unrelated US white people (meta-analysis p = 0.01879). In SH-SY5Y cells, low activity-associated hVMAT2 promoter confers high methylpiperidinopyrazole iodide cytotoxicity, which is likely attributed to functional polymorphisms bound by nuclear proteins. Interestingly, treatments with the dopamine neuron-protecting agent puerarin upregulates the promoter activity in a haplotype- and cell line-dependent manner. These pharmacogenetic findings suggest that hVMAT2 could be a risk factor and imply it as a target of genetic medications for PD.

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Section: Epigenetic Gene Expression In Human Dopaminergic Neuronsmentioning

confidence: 99%

hVMAT2: A Target of Individualized Medication for Parkinson's Disease

Xiong

Martin

et al. 2016

Neurotherapeutics

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“…After genomic quality control, more than 6500 unrelated subjects were used: 6596 unrelated with 53.6% females for SUD datasets; 6572 unrelated with 48.6% females for PD datasets. Imputation was carried for each of these four cleaned datasets as described before [40] , in order to extend genotype coverage. Data manipulation, allelic association, and meta-analysis were carried out using PLINK [41] ; case-control logistic regression analysis of inter-SNP interactions was performed in the CASSI 2.50 software and P values were used to evaluate the presence or strength of interactions [42] .…”

Section: Methodsmentioning

confidence: 99%

Epistatic evidence for gender-dependant slow neurotransmission signalling in substance use disorders: PPP1R12B versus PPP1R1B

et al. 2020

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Background Slow neurotransmission including DARPP-32 signalling is implicated in substance use disorders (SUDs) by experimental systems but not yet in the human aetiology. PPP1R12B , encoding another protein in the DARPP-32 family, hasn't been studied in the brain. Methods Brain-regional gene activity was assessed in three different animal models of SUDs for mRNA level alterations. Genetic associations were assessed by meta-analysis of pre-existing dbGaP GWAS datasets for main effects and epistasis with known genetic risks, followed by cell type-specific pathway delineation. Parkinson's disease (PD) was included as a dopamine-related disease control for SUDs. Findings In animal models of SUDs, environmentally-altered PPP1R12B expression sex-dependently involves motivation-related brain regions. In humans with polysubstance abuse, meta-analysis of pre-existing datasets revealed that PPP1R12B and PPP1R1B , although expressed in dopamine vs. dopamine-recipient neurons, exerted similar interactions with known genetic risks such as ACTR1B and DRD2 in men but with ADH1B, HGFAC and DRD3 in women. These interactions reached genome-wide significances ( P meta <10 −20 ) for SUDs but not for PD (disease selectivity: P = 4.8 × 10 −142 , OR = 6.7 for PPP1R12B; P = 8.0 × 10 −8 , OR = 2.1 for PPP1R1B ). CADM2 was the common risk in the molecular signalling regardless of gender and cell type. Interpretation Gender-dependant slow neurotransmission may convey both genetic and environmental vulnerabilities selectively to SUDs. Funding Grants from National Institute on Drug Abuse (NIDA) and National Institute on Alcohol Abuse and Alcoholism (NIAAA) of U.S.A. and National Natural Science Foundation of China (NSFC).

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“…Datasets were cleaned or quality-controlled extensively by using a published protocol,[86] followed by imputation as described before. [87] Basic manipulations of datasets used PLINK[88].…”

Section: Methodsmentioning

confidence: 99%

Presence of recombination hotspots throughout SLC6A3

et al. 2019

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The human dopamine transporter gene SLC6A3 is involved in substance use disorders (SUDs) among many other common neuropsychiatric illnesses but allelic association results including those with its classic genetic markers 3’VNTR or Int8VNTR remain mixed and unexplainable. To better understand the genetics for reproducible association signals, we report the presence of recombination hotspots based on sequencing of the entire 5’ promoter regions in two small SUDs cohorts, 30 African Americans (AAs) and 30 European Americans (EAs). Recombination rate was the highest near the transcription start site (TSS) in both cohorts. In addition, each cohort carried 57 different promoter haplotypes out of 60 and no haplotypes were shared between the two ethnicities. A quarter of the haplotypes evolved in an ethnicity-specific manner. Finally, analysis of five hundred subjects of European ancestry, from the 1000 Genome Project, confirmed the promoter recombination hotspots and also revealed several additional ones in non-coding regions only. These findings provide an explanation for the mixed results as well as guidance for selection of effective markers to be used in next generation association validation (NGAV), facilitating the delineation of pathogenic variation in this critical neuropsychiatric gene.

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Increased NigralSLC6A3Activity in Schizophrenia Patients: Findings From the Toronto–McLean Cohorts

Cited by 10 publications

References 74 publications

hVMAT2: A Target of Individualized Medication for Parkinson's Disease

hVMAT2: A Target of Individualized Medication for Parkinson's Disease

Epistatic evidence for gender-dependant slow neurotransmission signalling in substance use disorders: PPP1R12B versus PPP1R1B

Presence of recombination hotspots throughout SLC6A3

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