Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 196
Filtrar
1.
Adv Exp Med Biol ; 1162: 129-150, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31332737

RESUMO

Cannabinoid use and dependence are heritable traits controlled in part by genetic factors. Despite a high incidence of use worldwide, genes that contribute to the risk of problematic use and dependence remain enigmatic. Here we review human candidate gene association studies, family-based linkage studies, and genome-wide association studies completed within the last two decades. These studies have expanded the list of candidate genes and intervals. However, there is little overlap between studies and generally low reproducibility in independent samples. Reasons for this lack of coherence vary but may depend on low sample size and statistical power, and the fact that most studies leverage populations ascertained for drug dependence other than cannabis. However, recent well-powered studies on lifetime cannabis use demonstrate that the genetic architecture of cannabis use resembles that of other substance use disorders and psychiatric disease in that many small effect genes contribute in an additive fashion. This finding suggests that increasing sample size and more focused recruitment of individuals based on cannabinoid use and dependence will identify more candidate genes. Follow-up of existing high priority candidates in preclinical model systems will facilitate better understanding of the genetic architecture and genetic risk factors for cannabis use and dependence.


Assuntos
Canabinoides/farmacologia , Abuso de Maconha/genética , Ligação Genética , Estudo de Associação Genômica Ampla , Humanos
2.
Nat Neurosci ; 22(7): 1066-1074, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31209380

RESUMO

Cannabis is the most frequently used illicit psychoactive substance worldwide; around one in ten users become dependent. The risk for cannabis use disorder (CUD) has a strong genetic component, with twin heritability estimates ranging from 51 to 70%. Here we performed a genome-wide association study of CUD in 2,387 cases and 48,985 controls, followed by replication in 5,501 cases and 301,041 controls. We report a genome-wide significant risk locus for CUD (P = 9.31 × 10-12) that replicates in an independent population (Preplication = 3.27 × 10-3, Pmeta-analysis = 9.09 × 10-12). The index variant (rs56372821) is a strong expression quantitative trait locus for cholinergic receptor nicotinic α2 subunit (CHRNA2); analyses of the genetically regulated gene expression identified a significant association of CHRNA2 expression with CUD in brain tissue. At the polygenic level, analyses revealed a significant decrease in the risk of CUD with increased load of variants associated with cognitive performance. The results provide biological insights and inform on the genetic architecture of CUD.


Assuntos
Abuso de Maconha/genética , Proteínas do Tecido Nervoso/fisiologia , Receptores Nicotínicos/fisiologia , Idade de Início , Alelos , Transtorno do Deficit de Atenção com Hiperatividade/genética , Encéfalo/metabolismo , Estudos de Casos e Controles , Cromossomos Humanos Par 8/genética , Cognição/fisiologia , Estudos de Coortes , Fatores de Confusão (Epidemiologia) , Dinamarca , Escolaridade , Feminino , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Islândia , Masculino , Herança Multifatorial , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Receptores Nicotínicos/biossíntese , Receptores Nicotínicos/genética , Esquizofrenia/genética , Fumar/genética , Transcriptoma
3.
Drug Alcohol Depend ; 187: 296-299, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29702338

RESUMO

BACKGROUND: There is high comorbidity between antisocial behaviour (ASB) and substance use, and twin studies have shown that part of the covariation is due to overlapping genetic influences. Here we used measured genetic effects to estimate the genetic correlations of ASB with nicotine, alcohol, and cannabis use. METHODS: We meta-analysed data from two genome-wide association studies for ASB and used existing summary statistics from the largest genome-wide association studies into substance use (ever smoking, cigarettes smoked per day, weekly alcohol consumption, and lifetime cannabis use). We performed cross-trait LD-score regression to estimate genetic correlations between ASB and substance use phenotypes explained by all single nucleotide polymorphisms (SNPs). When significant, we tested whether the signs of the regression coefficients of SNPs from the ASB and substance use phenotypes were in the same direction across multiple p-value thresholds and examined enrichment in overlap of the strongest associated SNPs. RESULTS: We found nominally significant genetic correlations of ASB with lifetime cannabis use (rg = 0.69, p=.016) and cigarettes per day (rg = 0.59, p = 0.036) but not with weekly alcohol consumption or ever smoking. Sign-tests revealed consistent directions of effect of SNPs for ASB and cannabis use for all p-value thresholds except the most stringent one, whereas for ASB with cigarettes per day no consistent evidence was found. We found no evidence of enrichment in overlap of the most associated SNPs across these traits. CONCLUSION: Using measured genetic variants, we found preliminary support for a genetic correlation of ASB with lifetime cannabis use and cigarettes per day.


Assuntos
Consumo de Bebidas Alcoólicas/genética , Transtorno da Personalidade Antissocial/genética , Abuso de Maconha/genética , Fumar/genética , Tabagismo/genética , Adolescente , Adulto , Consumo de Bebidas Alcoólicas/psicologia , Transtorno da Personalidade Antissocial/psicologia , Comorbidade , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Abuso de Maconha/psicologia , Fenótipo , Polimorfismo de Nucleotídeo Único , Fumar/psicologia , Tabagismo/psicologia , Adulto Jovem
4.
Transl Psychiatry ; 8(1): 23, 2018 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-29353877

RESUMO

Genetic and sociodemographic risk factors potentially associated with cannabis use (CU) were investigated in 40 cannabis users and 96 control subjects. DNA methylation analyses were also performed to explore the possibility of epigenetic changes related to CU. We conducted a candidate gene association study that included variants involved in the dopaminergic (ANKK1, NCAM1 genes) and endocannabinoid (CNR1, CNR2 gene) pathways. Sociodemographic data included gender, marital status, level of education, and body mass index. We used MeDIP-qPCR to test whether variations in DNA methylation might be associated with CU. We found a significant association between SNP rs1049353 of CNR1 gene (p = 0.01) and CU. Differences were also observed related to rs2501431 of CNR2 gene (p = 0.058). A higher education level appears to decrease the risk of CU. Interestingly, females were less likely to use cannabis than males. There was a significantly higher level of DNA methylation in cannabis users compared to controls in two of the genes tested: hypermethylation at exon 8 of DRD2 gene (p = 0.034) and at the CpG-rich region in the NCAM1 gene (p = 0.0004). Both genetic variants and educational attainment were also related to CU. The higher rate of DNA methylation, evidenced among cannabis users, may be either a marker of CU or a consequence of long-term exposure to cannabis. The identified genetic variants and the differentially methylated regions may represent biomarkers and/or potential targets for designs of pharmacological therapeutic agents. Our observations also suggest that educational programs may be useful strategies for CU prevention.


Assuntos
Metilação de DNA , Escolaridade , Variação Genética , Abuso de Maconha/genética , Psicoses Induzidas por Substâncias/etiologia , Adolescente , Adulto , Estudos de Casos e Controles , Epigênese Genética , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Psicoses Induzidas por Substâncias/genética , Adulto Jovem
5.
Psychiatry Res ; 262: 357-358, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28917442

RESUMO

ABCB1 polymorphisms are known to modify drug pharmacokinetics but have yet to be studied for their role in generating and maintaining cannabis dependence. The objective of this study is to determine if ABCB1 C3435T (rs1045642) polymorphism may modulate Δ9-Tetrahydrocannabinol (THC) blood levels in a sample of heavy cannabis users. The study sample includes 39 Caucasian individuals, recruited in two French addictology centres, with isolated cannabis dependence and heavy use (defined as ≥ 7 joints per week). Each underwent clinical evaluation, cannabis blood metabolite dosage (THC, 11-OH-THC, and THC-COOH) and genotyping of ABCB1 C3435T polymorphism. In this population (males: 74.4%, average age 29.5 +/- 9), average cannabis use was 21 joints per week (median 12; range 7 - 80). T carriers (TT/CT) had significantly lower plasma THC levels (ng/ml) versus non T carriers (8 vs 15.70, significant), controlling for level of weekly use, 11-OH-THC and THC-COOH levels. Our results show that ABCB1 C3435T polymorphism may modulate serum THC levels in chronic heavy cannabis users. The exact mechanisms and roles that this may play in cannabis dependence genesis and evolution remain to be elucidated. These results should be controlled in a replication study using a larger population.


Assuntos
Alelos , Dronabinol/sangue , Abuso de Maconha/sangue , Abuso de Maconha/genética , Polimorfismo Genético/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adulto , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Triagem de Portadores Genéticos , Genótipo , Humanos , Masculino
6.
Brain Behav ; 7(11): e00850, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29201551

RESUMO

Objective: COMT rs4680 (Val158Met) genotype moderates the effect of cannabis on the age of onset of psychosis (AoP). We investigated the association between rs4680 and AoP, after adjusting for relevant covariates, in a Canadian Caucasian sample. Methods: One hundred and sixty-nine subjects with psychosis were recruited. AoP, defined as age of DSM-IV diagnosis was established using the Structured Clinical Interview for DSM-IV. Cannabis use data were collected using a self-report computerized questionnaire. DNA was extracted from saliva and genotyping of the COMT Val158Met polymorphism was done by SNaPshot and TaqMan assays. Logistic regression and Kaplan-Meier analysis results are reported. Results: In those who had used cannabis before 20 years of age, rs4680 had a trend level effect on AoP (median AoP: Val/Val < Val/Met < Met/Met 19.37, 20.95, 21.24 years, respectively; log-rank test p = .051). Conclusion: Our data are indicative of the need to further investigate the association between the COMT rs4680 variant and AoP in the context of adolescent cannabis use.


Assuntos
Cannabis/efeitos adversos , Catecol O-Metiltransferase/genética , Abuso de Maconha , Psicoses Induzidas por Substâncias , Adolescente , Adulto , Idade de Início , Canadá/epidemiologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Abuso de Maconha/epidemiologia , Abuso de Maconha/genética , Polimorfismo de Nucleotídeo Único , Psicoses Induzidas por Substâncias/epidemiologia , Psicoses Induzidas por Substâncias/genética , Inquéritos e Questionários
7.
J Stud Alcohol Drugs ; 78(5): 686-695, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28930056

RESUMO

OBJECTIVE: Previous studies have found preliminary evidence for associations between common single-nucleotide polymorphisms (SNPs) in the cannabinoid receptor gene CNR1 and cannabis use and dependence. The present study examined a set of eight independent SNPs in or near CNR1 in relation to cannabis use measured longitudinally across emerging adulthood. METHOD: Using latent growth curve modeling of 10 waves of longitudinal data spanning mean ages 18.4-23.8 years in a sample of non-Hispanic White individuals (n = 334), we tested if genotype at each CNR1 SNP was associated with both level and growth of cannabis use over time. Peer group drug use, a known correlate of individual use, was evaluated as a time-varying predictor of cannabis use and as a moderator of the relationship between SNPs and individual use. RESULTS: After correction for multiple comparisons, one SNP, rs806374, was significantly associated with individual differences in level-but not growth-of cannabis use over time, such that C carriers were more likely to use cannabis more frequently at study onset (around age 18). Peer drug use was a predictor of individual cannabis use that grew in terms of effect size with time, but did not significantly moderate the effect of rs806374 genotype. CONCLUSIONS: C carriers at rs806374 may be at specific risk for increased odds of use during the transition out of high school (around age 18). Future studies should investigate potential mechanisms at this developmental stage, including individual differences in subjective response, innate tolerance, reinforcement mechanisms, or general liability for substance misuse.


Assuntos
Genótipo , Abuso de Maconha/genética , Receptor CB1 de Canabinoide/genética , Adolescente , Grupo com Ancestrais do Continente Europeu , Feminino , Humanos , Estudos Longitudinais , Masculino , Polimorfismo de Nucleotídeo Único , Adulto Jovem
8.
Cell Physiol Biochem ; 42(2): 537-550, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28578322

RESUMO

AIMS: Marijuana is a widely used illicit drug and its consumption during pregnancy has been associated with adverse reproductive outcomes. The purpose of this study was to determine the effects of chronic intake of Δ9-tetrahydrocannabinol (THC), the major component of marijuana, on trophoblast function, placental development, and birth outcomes. METHODS: The pathological characteristics and distribution of cannabinoid receptors in placenta were observed by immunohistochemical (IHC) staining. Cell migration in response to THC was measured by transwell assays. The levels of cannabinoid receptors and Signal Transducer and Activator of Transcription 3 (STAT3) were detected by western blot. RESULTS: We found the placenta expressed two main cannabinoid receptors, suggesting that THC induced biological responses in placental cells. Supporting this hypothesis, we observed dramatic alterations of placental morphology in marijuana users. Using THC and inhibitors of cannabinoid receptors, we demonstrated that THC impaired trophoblast cell migration and invasion partly via cannabinoid receptors. Additionally, pregnant mice injected with THC showed adverse reproductive events including reduced number of fetuses, lower maternal and placental weights. Mechanistically, STAT3 signaling pathway was involved in the THC-induced suppression of trophoblast cell motility and pregnancy outcomes. CONCLUSION: Our study indicates that the STAT3 signaling pathway plays a critical role in THC-induced trophoblast dysfunction.


Assuntos
Cannabis/efeitos adversos , Dronabinol/efeitos adversos , Abuso de Maconha/genética , Fator de Transcrição STAT3/genética , Adulto , Animais , Coeficiente de Natalidade , Canabinoides/efeitos adversos , Feminino , Humanos , Abuso de Maconha/patologia , Camundongos , Placenta/efeitos dos fármacos , Placenta/patologia , Gravidez , Receptores de Canabinoides/biossíntese , Receptores de Canabinoides/genética , Fator de Transcrição STAT3/biossíntese , Transdução de Sinais/efeitos dos fármacos , Trofoblastos/efeitos dos fármacos , Trofoblastos/patologia
9.
Behav Genet ; 47(4): 394-404, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28466235

RESUMO

Cannabis use disorder (CUD) co-occurs with major depressive disorder (MDD) more frequently than would be expected by chance. However, studies to date have not produced a clear understanding of the mechanisms underlying this co-morbidity. Genetically informative studies can add valuable insight to this problem, as they allow the evaluation of competing models of co-morbidity. This study uses data from the Australian Twin Registry to compare 13 co-morbidity twin models initially proposed by Neale and Kendler (Am J Hum Genet 57:935-953, 1995). The analysis sample comprised 2410 male and female monozygotic and dizygotic twins (average age 32) who were assessed on CUD and MDD using the SSAGA-OZ interview. Data were analyzed in OpenMx. Of the 13 different co-morbidity models, two fit equally well: CUD causes MDD and Random Multiformity of CUD. Both fit substantially better than the Correlated Liabilities model. Although the current study cannot differentiate between them statistically, these models, in combination, suggest that CUD risk factors may causally influence the risk to develop MDD, but only when risk for CUD is high.


Assuntos
Transtorno Depressivo Maior/genética , Abuso de Maconha/genética , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética , Adulto , Austrália , Cannabis/efeitos adversos , Comorbidade , Depressão/genética , Feminino , Humanos , Entrevista Psicológica/métodos , Masculino , Fumar Maconha , Fatores de Risco , Meio Social , Inquéritos e Questionários , Gêmeos/genética
10.
J Psychiatry Neurosci ; 42(4): 252-261, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28418321

RESUMO

BACKGROUND: We conducted a genome-wide gene × environment interaction analysis to identify genetic variants that interact with cannabis dependence (CaD) in influencing risky sexual behaviours (RSB). METHODS: Our sample included cannabis-exposed and sexually experienced African-American and European-American participants. A DSM-IV CaD diagnosis and RSB were evaluated using the Semi-Structured Assessment for Drug Dependence and Alcoholism. We analyzed RSBs as a score that takes into account experiences of unprotected sex and multiple sexual partners. RESULTS: A total of 3350 people participated in our study; 43% had a CaD diagnosis, 56% were African-American and 33% were women. We identified a genome-wide significant locus in African-American participants (S100A10 rs72993629, p = 2.73 × 10-8) and a potential transpopulation signal in women (CLTC rs12944716, p = 5.27 × 10-8). A resting-state fMRI follow-up analysis of S100A10 rs72993629 conducted in an independent cohort showed 2 significant associations: reduced power of the left paracentral lobule in amplitude of low frequency fluctuations (ALFF) analysis (p = 7.8 × 10-3) and reduced power of the right pallidum in fractional ALFF analysis (p = 4.6 × 10-3). The activity of these brain regions is known to be involved in sexual functions and behaviours. The S100A10 result functionally recapitulated our S100B finding observed in our previous genome-wide association study of CaD. The probability of identifying 2 S100 genes in 2 independent genome-wide investigations by chance is approximately 1 in 1.1 million. LIMITATIONS: We were not able to identify any African-American cohort with appropriate sample size, and phenotypic assessment is available to replicate our findings. CONCLUSION: The S100A10 and S100B genes, which are located on different chromosomes, encode specialized calcium-binding proteins. These data support a role for calcium homeostasis in individuals with CaD and its induced behaviours.


Assuntos
Anexina A2/fisiologia , Interação Gene-Ambiente , Abuso de Maconha/genética , Proteínas S100/fisiologia , Sexo sem Proteção , Adulto , Afro-Americanos/genética , Anexina A2/genética , Cálcio/metabolismo , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Globo Pálido/fisiopatologia , Homeostase , Humanos , Imagem por Ressonância Magnética , Masculino , Abuso de Maconha/fisiopatologia , Lobo Parietal/fisiopatologia , Polimorfismo de Nucleotídeo Único , Proteínas S100/genética , Adulto Jovem
11.
Addict Biol ; 22(4): 1081-1089, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26860734

RESUMO

There is substantial evidence for the assumption that particularly heavy cannabis usett is associated with a variety of psychopathologic conditions. Little is known about the relationship between cannabis and anxiety. Prior studies have concluded that cannabis use alone is not sufficient for the development of long-term anxiety, and it has been suggested that cannabis is simply a risk factor that operates in conjunction with other risk factors. One such risk factor may be an individuals' genetic vulnerability. The present study examines the relationship between cannabis use and symptoms of anxiety by taking a developmental molecular-genetic perspective with a focus on a polymorphism involved in the regulation of serotonin. Specifically, we concentrated on changes in cannabis use and symptoms of anxiety over time and differences herein for individuals with and without the short allele of the 5-HTTLPR genotype. Data were from 1424 adolescents over a period of 5 years. We used different statistical analyses to test co-development of cannabis use and symptoms of anxiety throughout adolescence and the possible role of the 5-HTTLPR genotype in this process. Results from different analyses showed that cannabis use is associated with an increase in symptoms of anxiety, but only in carriers of the short allele of the 5-HTTLPR genotype, not in non-carriers. The findings of the present study show first evidence that the links between cannabis use and symptoms of anxiety are conditional on the individuals' genetic make-up.


Assuntos
Transtornos de Ansiedade/complicações , Transtornos de Ansiedade/genética , Abuso de Maconha/complicações , Abuso de Maconha/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Adolescente , Alelos , Cannabis , Criança , Feminino , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Países Baixos , Polimorfismo Genético/genética , Estudos Prospectivos , Fatores de Risco , Inquéritos e Questionários
12.
Addiction ; 112(1): 113-123, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27517884

RESUMO

BACKGROUND AND AIMS: While the prevalence of major depression is elevated among cannabis users, the role of genetics in this pattern of comorbidity is not clear. This study aimed to estimate the heritability of cannabis use and major depression, quantify the genetic overlap between these two traits and localize regions of the genome that segregate in families with cannabis use and major depression. DESIGN: Family-based univariate and bivariate genetic analysis. SETTING: San Antonio, Texas, USA. PARTICIPANTS: Genetics of Brain Structure and Function study (GOBS) participants: 1284 Mexican Americans from 75 large multi-generation families and an additional 57 genetically unrelated spouses. MEASUREMENTS: Phenotypes of life-time history of cannabis use and major depression, measured using the semistructured MINI-Plus interview. Genotypes measured using ~1 M single nucleotide polymorphisms (SNPs) on Illumina BeadChips. A subselection of these SNPs were used to build multi-point identity-by-descent matrices for linkage analysis. FINDINGS: Both cannabis use [h2  = 0.614, P = 1.00 × 10-6 , standard error (SE) = 0.151] and major depression (h2  = 0.349, P = 1.06 × 10-5 , SE = 0.100) are heritable traits, and there is significant genetic correlation between the two (ρg  = 0.424, P = 0.0364, SE = 0.195). Genome-wide linkage scans identify a significant univariate linkage peak for major depression on chromosome 22 [logarithm of the odds (LOD) = 3.144 at 2 centimorgans (cM)], with a suggestive peak for cannabis use on chromosome 21 (LOD = 2.123 at 37 cM). A significant pleiotropic linkage peak influencing both cannabis use and major depression was identified on chromosome 11 using a bivariate model (LOD = 3.229 at 112 cM). Follow-up of this pleiotropic signal identified a SNP 20 kb upstream of NCAM1 (rs7932341) that shows significant bivariate association (P = 3.10 × 10-5 ). However, this SNP is rare (seven minor allele carriers) and does not drive the linkage signal observed. CONCLUSIONS: There appears to be a significant genetic overlap between cannabis use and major depression among Mexican Americans, a pleiotropy that appears to be localized to a region on chromosome 11q23 that has been linked previously to these phenotypes.


Assuntos
Transtorno Depressivo Maior/epidemiologia , Predisposição Genética para Doença/epidemiologia , Abuso de Maconha/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Transtorno Depressivo Maior/genética , Grupos Étnicos/psicologia , Grupos Étnicos/estatística & dados numéricos , Feminino , Humanos , Masculino , Abuso de Maconha/genética , Pessoa de Meia-Idade , Texas/epidemiologia , Adulto Jovem
13.
Schizophr Bull ; 43(3): 644-653, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-27431873

RESUMO

To investigate contributions of genetic and environmental risk factors and possible direction of causation for the relationship between symptoms of cannabis use disorders (CUD) and psychotic-like experiences (PLEs), a population-based sample of 2793 young adult twins (63.5% female, mean [range] age 28.2 [19-36] y) were assessed for symptoms of CUD and PLEs using the Composite International Diagnostic Interview. Latent risk of having symptoms of CUD or PLEs was modeled using Item Response Theory. Co-twin control analysis was performed to investigate effect of familiar confounding for the association between symptoms of CUD and PLEs. Biometric twin models were fitted to estimate the heritability, genetic and environmental correlations, and direction for the association. Lifetime use of cannabis was reported by 10.4 % of the twins, and prevalence of PLEs ranged from 0.1% to 2.2%. The incidence rate ratio of PLEs due to symptoms of CUD was 6.3 (95% CI, 3.9, 10.2) in the total sample and 3.5 (95% CI, 1.5, 8.2) within twin pairs. Heritability estimates for symptoms of CUD were 88% in men and women, and for PLEs 77% in men and 43% in women. The genetic and environmental correlations between symptoms of CUD and PLEs were 0.55 and 0.52, respectively. The model allowing symptoms of CUD to cause PLEs had a better fit than models specifying opposite or reciprocal directions of causation. The association between symptoms of CUD and PLEs is explained by shared genetic and environmental factors and direct effects from CUD to risk for PLEs.


Assuntos
Abuso de Maconha/epidemiologia , Transtornos Psicóticos/epidemiologia , Adulto , Comorbidade , Doenças em Gêmeos , Feminino , Interação Gene-Ambiente , Humanos , Masculino , Abuso de Maconha/etiologia , Abuso de Maconha/genética , Prevalência , Transtornos Psicóticos/etiologia , Transtornos Psicóticos/genética , Adulto Jovem
14.
Transl Psychiatry ; 6(12): e976, 2016 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-27922636

RESUMO

Epigenetic processes have been implicated in addiction; yet, it remains unclear whether these represent a risk factor and/or a consequence of substance use. Here, we believe we conducted the first genome-wide, longitudinal study to investigate whether DNA methylation patterns in early life prospectively associate with substance use in adolescence. The sample comprised of 244 youth (51% female) from the Avon Longitudinal Study of Parents and Children (ALSPAC), with repeated assessments of DNA methylation (Illumina 450k array; cord blood at birth, whole blood at age 7) and substance use (tobacco, alcohol and cannabis use; age 14-18). We found that, at birth, epigenetic variation across a tightly interconnected genetic network (n=65 loci; q<0.05) associated with greater levels of substance use during adolescence, as well as an earlier age of onset amongst users. Associations were specific to the neonatal period and not observed at age 7. Key annotated genes included PACSIN1, NEUROD4 and NTRK2, implicated in neurodevelopmental processes. Several of the identified loci were associated with known methylation quantitative trait loci, and consequently likely to be under significant genetic control. Collectively, these 65 loci were also found to partially mediate the effect of prenatal maternal tobacco smoking on adolescent substance use. Together, findings lend novel insights into epigenetic correlates of substance use, highlight birth as a potentially sensitive window of biological vulnerability and provide preliminary evidence of an indirect epigenetic pathway linking prenatal tobacco exposure and adolescent substance use.


Assuntos
Consumo de Bebidas Alcoólicas/genética , Metilação de DNA , Epigênese Genética/genética , Genoma Humano/genética , Abuso de Maconha/genética , Fumar/genética , Adolescente , Criança , Pré-Escolar , Feminino , Estudo de Associação Genômica Ampla , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Proteínas do Tecido Nervoso/genética , Gravidez , Estudos Prospectivos , Risco
15.
Curr Pharm Des ; 22(42): 6392-6396, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27587204

RESUMO

Cannabis consumption has radically changed over the last several decades. Tetrahydrcannbidiol concentrations are rising, cannabidiol concentrations falling and cannabis is becoming legalized in several regions of the globe. Concerns have been raised as to the impact of increased cannabis exposure within the general population on public health. One of the more serious concerns is the potential relationship between cannabis consumption and psychosis. Research has shown a relationship between increasing cannabis use and increasing psychosis risk. This risk is moderated by other factors such as stress and a family history of psychosis. Within this context, it is important to determine potential markers for future psychosis risk. Genetic and epigenetic research in cannabis and psychosis is in its early stages. One common denominator between cannabis use disorder and psychosis is dopamine dysfunction. Research has begun to link heightened dopamine reactivity with the psychotomimetic effects of cannabis. Studies in COMT and DRD2 polymorphisms have failed to show greater associations with transition to psychosis. Studies of AKT1 have shown slightly more promising results. Genome-wide association studies have recently been published some indicating novel polymorphisms. These may pave the way to alternate hypotheses to explain the missing links between cannabis use and increased risk of psychosis. Such knowledge may eventually lead to new pharmacotherapies in addition to the means of screening patients for psychosis risk.


Assuntos
Dopamina/metabolismo , Abuso de Maconha , Humanos , Abuso de Maconha/genética , Abuso de Maconha/metabolismo , Abuso de Maconha/psicologia
16.
Acta Psychiatr Scand ; 134(5): 399-409, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27565994

RESUMO

OBJECTIVE: Marijuana (MJ) use is common. Research shows risks for psychiatric illnesses, including major depressive disorder (MDD) and cognitive deficits with MJ use, particularly early-onset use. We investigated cognitive function, functional connectivity, and genetic risk with MDD alone and combined with MJ use, and differences between early-vs. late-onset/non-MJ use in youth. METHOD: A total of 74 youth in four groups were studied: healthy control, MDD, frequent MJ use and current/past MDD plus frequent MJ use. Psychiatric symptoms, cognitive performance and demographics were measured. Default mode network (DMN) brain connectivity was determined. Risk alleles in six genes of interest were evaluated. RESULTS: DMN differences among groups in reward-processing and motor control regions were found; the effects of MJ use and MDD were distinct. Early-onset MJ use was associated with lower IQ and hyperconnectivity within areas of the DMN. Early-onset MJ use was associated with the BDNF risk allele. CONCLUSIONS: Cognitive deficits linked with early-onset MJ use were present within several years after MJ use began and may result from, predispose to, or share a common cause with early-onset MJ use. The DMN was affected by MDD, MJ and their combination, as well as by early-onset MJ use. BDNF carrier state may predispose to early-onset MJ use.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Transtornos Cognitivos/induzido quimicamente , Transtorno Depressivo Maior/fisiopatologia , Abuso de Maconha/fisiopatologia , Adolescente , Idade de Início , Mapeamento Encefálico/métodos , Transtornos Cognitivos/genética , Transtorno Depressivo Maior/genética , Imagem de Difusão por Ressonância Magnética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Abuso de Maconha/genética , Abuso de Maconha/psicologia , Adulto Jovem
17.
J Abnorm Psychol ; 125(7): 946-959, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27537477

RESUMO

Behavioral genetic studies have provided insights into why early substance use initiation is associated with increased risk for disorder. Few genetically informative studies, however, have operationalized initiation as the timing of first use and simultaneously modeled the timing of initiation and problematic use of multiple substances. Such research can help capture the risk associated with early initiation and determine the extent to which genetic and environmental risk generalizes across substances. This study utilized a behavior genetic approach to examine the relation between the age of substance use initiation and symptoms of substance use disorder. Participants were 7,285 monozygotic and dizygotic twins (40% male, mean age at interview = 30.6 years) from the Australian Twin Registry who reported on their ages of tobacco, alcohol, and cannabis initiation and symptoms of Diagnostic and Statistical Manual of Mental Disorders (4th ed., DSM-IV) nicotine dependence, alcohol use disorder, and cannabis use disorder. Biometric modeling was conducted to (a) determine the structure of genetic and environmental influences on initiation and disorder and (b) examine their genetic and environmental overlap. The latent structure of initiation differed across men and women. The familial covariance between initiation and disorder was genetic among men and genetic and environmental among women, suggesting that the relation between first substance use and disorder is partly explained by a shared liability. After accounting for familial overlap, significant unique environmental correlations were observed, indicating that the age of initiation of multiple drugs may directly increase risk for substance-related problems. Results support the utility of conceptualizing initiation in terms of age and of adopting a multivariate approach. (PsycINFO Database Record


Assuntos
Alcoolismo/genética , Interação Gene-Ambiente , Abuso de Maconha/genética , Tabagismo/genética , Adulto , Fatores Etários , Alcoolismo/etiologia , Feminino , Humanos , Masculino , Abuso de Maconha/etiologia , Modelos Psicológicos , Fatores de Risco , Tabagismo/etiologia , Gêmeos Dizigóticos , Gêmeos Monozigóticos
18.
Twin Res Hum Genet ; 19(4): 297-305, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27436053

RESUMO

Our aim was to test the direction of causation between self-report parental monitoring (PM) and the liability to illicit drug initiation (DI) as indicated by cannabis, cocaine, and stimulants. We fitted a multiple indicator model to test causal and non-causal models based on a large, genetically informative cross-sectional sample of male twins. The sample comprised 1,778 males aged 24-62 years from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders. Data came from self-report measures of lifetime cannabis, stimulants, and cocaine initiation, and retrospective assessment of PM between ages 8-17 years. Multivariate modeling showed that familial aggregation in PM and DI were both explained by a combination of additive genetic and shared environmental effects. Moreover, the significant association between PM and DI was best explained by a correlated liability model versus causal models. PM has typically been assumed to be an environmental, causal risk factor for drug use and has been shown to be among the more salient environmental risk factors for illicit DI. Our data were not consistent with this causal hypothesis. Instead, a correlated liability model in which PM and risk of DI share common genetic and environmental risks provided a better fit to the data.


Assuntos
Transtornos Relacionados ao Uso de Cocaína , Abuso de Maconha , Poder Familiar , Adolescente , Adulto , Criança , Transtornos Relacionados ao Uso de Cocaína/genética , Humanos , Masculino , Abuso de Maconha/genética , Metilfenidato , Pessoa de Meia-Idade , Modelos Teóricos , Análise Multivariada , Transtornos Relacionados ao Uso de Substâncias/genética
19.
Drug Alcohol Depend ; 166: 249-53, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27394933

RESUMO

BACKGROUND: Cannabis is a commonly used drug and studies have shown that a significant portion of the variation in cannabis use disorders (CUDs) is heritable. Five genes known to play a role in the endocannabinoid system and CUDs were examined in a community sample of young adult Mexican Americans (MAs): CNR1, MGLL, FAAH, DAGLA, and DAGLB. METHODS: Gene-based tests were run to test for association between each gene and two DSM-5 cannabis phenotypes. Subsequent linear regressions were run in PLINK using an additive model to determine which single nucleotide polymorphisms (SNPs) were driving the association. RESULTS: FAAH was significantly associated with DSM-5 cannabis use disorder group count (DSM-5 CUD) using a gene-based test (p=0.0035). This association survived Bonferroni correction for multiple testing at p<0.004. Post hoc analyses suggested this association was driven by two common (minor allele frequency >5%) SNPs in moderate linkage disequilibrium, rs324420 and rs4141964, at p=0.0014 and p=0.0023, respectively. In both cases the minor allele increased risk for DSM-5 CUD. CONCLUSIONS: Genetic variation in FAAH was associated with DSM-5 CUD in MAs. This association was primarily driven by the missense SNP rs324420. In vitro work has provided evidence that the risk allele generates an enzyme with decreased expression and cellular stability. Although this SNP has been previously associated with substance use in the literature, this is the first association in a young adult MA sample.


Assuntos
Amidoidrolases/genética , Abuso de Maconha/etnologia , Abuso de Maconha/genética , Americanos Mexicanos/genética , Americanos Mexicanos/psicologia , Polimorfismo de Nucleotídeo Único/genética , Adulto , Alelos , Feminino , Frequência do Gene , Predisposição Genética para Doença/genética , Humanos , Desequilíbrio de Ligação/genética , Masculino , Fenótipo , Adulto Jovem
20.
Mutat Res ; 789: 15-25, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27208973

RESUMO

The recent demonstration that massive scale chromosomal shattering or pulverization can occur abruptly due to errors induced by interference with the microtubule machinery of the mitotic spindle followed by haphazard chromosomal annealing, together with sophisticated insights from epigenetics, provide profound mechanistic insights into some of the most perplexing classical observations of addiction medicine, including cancerogenesis, the younger and aggressive onset of addiction-related carcinogenesis, the heritability of addictive neurocircuitry and cancers, and foetal malformations. Tetrahydrocannabinol (THC) and other addictive agents have been shown to inhibit tubulin polymerization which perturbs the formation and function of the microtubules of the mitotic spindle. This disruption of the mitotic machinery perturbs proper chromosomal segregation during anaphase and causes micronucleus formation which is the primary locus and cause of the chromosomal pulverization of chromothripsis and downstream genotoxic events including oncogene induction and tumour suppressor silencing. Moreover the complementation of multiple positive cannabis-cancer epidemiological studies, and replicated dose-response relationships with established mechanisms fulfils causal criteria. This information is also consistent with data showing acceleration of the aging process by drugs of addiction including alcohol, tobacco, cannabis, stimulants and opioids. THC shows a non-linear sigmoidal dose-response relationship in multiple pertinent in vitro and preclinical genotoxicity assays, and in this respect is similar to the serious major human mutagen thalidomide. Rising community exposure, tissue storage of cannabinoids, and increasingly potent phytocannabinoid sources, suggests that the threshold mutagenic dose for cancerogenesis will increasingly be crossed beyond the developing world, and raise transgenerational transmission of teratogenicity as an increasing concern.


Assuntos
Canabinoides/toxicidade , Cromotripsia/efeitos dos fármacos , Anormalidades Congênitas/epidemiologia , Epigênese Genética , Abuso de Maconha/genética , Neoplasias/epidemiologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Anormalidades Congênitas/genética , Relação Dose-Resposta a Droga , Gametogênese/efeitos dos fármacos , Gametogênese/genética , Humanos , Micronúcleos com Defeito Cromossômico/induzido quimicamente , Neoplasias/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA