VMAT2 gene (SLC18A2) variants associated with a greater risk for developing opioid dependence.
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ABSTRACT:
SUBMITTER: Randesi M
PROVIDER: S-EPMC6566135 | biostudies-literature | 2019 Apr
REPOSITORIES: biostudies-literature
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VMAT2 gene (<i>SLC18A2</i>) variants associated with a greater risk for developing opioid dependence.
Randesi Matthew M van den Brink Wim W Levran Orna O Blanken Peter P van Ree Jan M JM Ott Jurg J Kreek Mary Jeanne MJ
Pharmacogenomics 20190415 5
<b>Aim:</b> To determine if selected serotonergic and noradrenergic gene variants are associated with heroin addiction. <b>Subjects & methods:</b> A total of 126 variants in 19 genes in subjects with Dutch European ancestry from The Netherlands. Subjects included 281 opioid-dependent volunteers in methadone maintenance or heroin-assisted treatment, 163 opioid-exposed but not opioid-dependent volunteers who have been using illicit opioids but never became opioid-dependent and 153 healthy controls ...[more]
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Project description:BackgroundHeroin addiction is a chronic, relapsing brain disease. Genetic factors are involved in the development of drug addiction. The aim of this study was to determine whether specific variants in genes of the opioid system are associated with non-dependent opioid use and heroin dependence.MethodsGenetic information from four subject groups was collected: non-dependent opioid users (NOD) [n=163]; opioid-dependent (OD) patients in methadone maintenance treatment (MMT) [n=143]; opioid-dependent MMT-resistant patients in heroin-assisted treatment (HAT) [n=138]; and healthy controls with no history of opioid use (HC) [n=153]. Eighty-two variants in eight opioid system genes were studied. To establish the role of these genes in (a) non-dependent opioid use, and (b) heroin dependence, the following groups were compared: HC vs. NOD; HC vs. OD (MMT+HAT); and NOD vs. OD (MMT+HAT).ResultsFive unique SNPs in four genes showed nominally significant associations with non-dependent opioid use and heroin dependence. The association of the delta opioid receptor (OPRD1) intronic SNP rs2236861 with non-dependent opioid use (HC vs. NOD) remained significant after correction for multiple testing (OR=0.032; pcorrected=0.015). This SNP exhibited a significant gene-gene interaction with prepronociceptin (PNOC) SNP rs2722897 (OR=5.24; pcorrected=0.041) (HC vs. NOD).ConclusionsThis study identifies several new and some previously reported associations of variants with heroin dependence and with non-dependent opioid use, an important and difficult to obtain group not extensively studied previously. Further studies are warranted to confirm and elucidate the potential roles of these variants in the vulnerability to illicit drug use and drug addiction.
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Project description:ObjectiveTo investigate the association between gene polymorphism of vesicular monoamine transporter type 2(VMAT2) and schizophrenia in Han Chinese population.Methods430 patients with schizophrenia and 470 age-sex matched controls were recruited from four mental health centers. All patients were diagnosed by two psychiatrists based on the Structured Clinical Interview for DSM Disorders (SCID). The ligase detection reactions (LDR) method was used to assess the polymorphism of the two SNPs (rs363371 and rs363324) of VMAT2.ResultsNo associations of two SNPs with schizophrenia was found. When we stratified males and females for the analysis, we found that that in the recessive model of rs363371, there was an obvious significant association between rs363371 and schizophrenia in males (OR=0.564, 95% CI=0.357-0.892, p=0.014) but not females. For the association between rs363324 and schizophrenia, no association was found in either males or females. No association was found when stratifying early-onset schizophrenia and late-onset schizophrenia.ConclusionOur findings indicate that both rs363371 and rs363324 were not associated with schizophrenia, while it seemed that the AA genotype of rs363371 plays a protective effect in male Chinese in developing schizophrenia.
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Project description:Vesicular monoamine transporter 2 (VMAT2) is an essential transporter that regulates brain monoamine transmission and is important for mood, cognition, motor activity, and stress regulation. However, VMAT2 remains underexplored as a pharmacological target. In this study, we report that tricyclic and tetracyclic antidepressants acutely inhibit, but persistently upregulate VMAT2 activity by promoting VMAT2 protein maturation. Importantly, the VMAT2 upregulation effect was greater in BE(2)-M17 cells that endogenously express VMAT2 as compared to a heterologous expression system (HEK293). The net sustained effect of tricyclics and tetracyclics is an upregulation of VMAT2 activity, despite their acute inhibitory effect. Furthermore, imipramine and mianserin, two representative compounds, also demonstrated rescue of nine VMAT2 variants that cause Brain Monoamine Vesicular Transport Disease (BMVTD). VMAT2 upregulation could be beneficial for disorders associated with reduced monoamine transmission, including mood disorders and BMVTD, a rare but often fatal condition caused by a lack of functional VMAT2. Our findings provide the first evidence that small molecules can upregulate VMAT2 and have potential therapeutic benefit for various neuropsychiatric conditions.
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Project description:ImportanceAlcohol dependence (AD) and major depression (MD) are leading causes of disability that often co-occur. Genetic epidemiologic data have shown that AD and MD share a common possible genetic cause. The molecular nature of this shared genetic basis is poorly understood.ObjectivesTo detect genetic risk variants for comorbid AD and MD and to determine whether polygenic risk alleles are shared with neuropsychiatric traits or subcortical brain volumes.Design, setting, and participantsThis genome-wide association study analyzed criterion counts of comorbid AD and MD in African American and European American data sets collected as part of the Yale-Penn study of the genetics of drug and alcohol dependence from February 14, 1999, to January 13, 2015. After excluding participants never exposed to alcohol or with missing information for any diagnostic criterion, genome-wide association studies were performed on 2 samples (the Yale-Penn 1 and Yale-Penn 2 samples) totaling 4653 African American participants and 3169 European American participants (analyzed separately). Tests were performed to determine whether polygenic risk scores derived from potentially related traits in European American participants could be used to estimate comorbid AD and MD.Main outcomes and measuresComorbid criterion counts (ranging from 0 to 14) for AD (7 criteria) and MD (9 criteria, scaled to 7) as defined by the DSM-IV.ResultsOf the 7822 participants (3342 women and 4480 men; mean [SD] age, 40.1 [10.7] years), the median comorbid criterion count was 6.2 (interquartile range, 2.3-10.9). Under the linear regression model, rs139438618 at the semaphorin 3A (SEMA3A [OMIM 603961]) locus was significantly associated with AD and MD comorbidity in African American participants in the Yale-Penn 1 sample (β = 0.89; 95% CI, 0.57-1.20; P = 2.76 × 10-8). In the independent Yale-Penn 2 sample, the association was also significant (β = 0.83; 95% CI, 0.39-1.28; P = 2.06 × 10-4). Meta-analysis of the 2 samples yielded a more robust association (β = 0.87; 95% CI, 0.61-1.12; P = 2.41 × 10-11). There was no significant association identified in European American participants. Analyses of polygenic risk scores showed that individuals with a higher risk of neuroticism (β = 1.01; 95% CI, 0.50-1.52) or depressive symptoms (β = 0.87; 95% CI, 0.32-1.42) and a lower level of subjective well-being (β = -0.94; 95% CI, -1.46 to -0.42) and educational attainment (β = -1.00, 95% CI, -1.57 to -0.44) had a higher level of AD and MD comorbidity, while larger intracranial (β = 1.07; 95% CI, 0.50 to 1.64) and smaller putamen volumes (β = -1.16; 95% CI, -1.86 to -0.46) were associated with higher risks of AD and MD comorbidity.Conclusions and relevanceSEMA3A variation is significantly and replicably associated with comorbid AD and MD in African American participants. Analyses of polygenic risk scores identified pleiotropy with neuropsychiatric traits and brain volumes. Further studies are warranted to understand the biological and genetic mechanisms of this comorbidity, which could facilitate development of medications and other treatments for comorbid AD and MD.
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