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2.
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
3.
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 Epidemiológicos , 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
4.
Chronobiol Int ; 36(1): 122-134, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30526093

RESUMO

Circadian rhythms have been related to psychiatric diseases and regulation of dopaminergic transmission, especially in substance abusers. The relationship between them remained enigmatic and no data on the role of clock genes on cannabis dependence have been documented. We aimed at exploring the role of clock gene genotypes as potential predisposing factor to cannabis addiction, using a high throughput mass spectrometry methodology that enables the large-scale analysis of the known relevant polymorphisms of the clock genes. We have conducted a case-control study on 177 Caucasians categorizing between cannabis-addicted subjects and casual consumers based on structured interviews recorded socio-demographic data, AUDIT, Fagerström test, MINI, and medical examinations. Alcohol, opiates, and stimulants' consumption was as exclusion criteria. We report an association between several Single Nucleotide Polymorphism (SNP)s in main circadian genes SNPs, especially the gene locus HES7/PER1 on chromosome 17 and cannabis consumption as well as the development of neuropsychiatric and social disorders. This SNP's signature that may represent a meaningful risk factor in the development of cannabis dependence and its severity requires to be deeply explored in a prospective study.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Abuso de Maconha/genética , Fumar Maconha/genética , Proteínas Circadianas Period/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Perfilação da Expressão Gênica/métodos , Predisposição Genética para Doença , Haplótipos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Desequilíbrio de Ligação , Masculino , Abuso de Maconha/etnologia , Fumar Maconha/etnologia , Pessoa de Meia-Idade , Fenótipo , Fatores de Risco , Índice de Gravidade de Doença , Transcriptoma , Adulto Jovem
5.
Epigenetics ; 13(12): 1208-1221, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30521419

RESUMO

Little is known about the reproductive effects of paternal cannabis exposure. We evaluated associations between cannabis or tetrahydrocannabinol (THC) exposure and altered DNA methylation in sperm from humans and rats, respectively. DNA methylation, measured by reduced representation bisulfite sequencing, differed in the sperm of human users from non-users by at least 10% at 3,979 CpG sites. Pathway analyses indicated Hippo Signaling and Pathways in Cancer as enriched with altered genes (Bonferroni p < 0.02). These same two pathways were also enriched with genes having altered methylation in sperm from THC-exposed versus vehicle-exposed rats (p < 0.01). Data validity is supported by significant correlations between THC exposure levels in humans and methylation for 177 genes, and substantial overlap in THC target genes in rat sperm (this study) and genes previously reported as having altered methylation in the brain of rat offspring born to parents both exposed to THC during adolescence. In humans, cannabis use was also associated with significantly lower sperm concentration. Findings point to possible pre-conception paternal reproductive risks associated with cannabis use.


Assuntos
Agonistas de Receptores de Canabinoides/farmacologia , Metilação de DNA , Dronabinol/farmacologia , Abuso de Maconha/genética , Espermatozoides/efeitos dos fármacos , Adolescente , Adulto , Animais , Ilhas de CpG , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Espermatozoides/metabolismo
6.
Drug Alcohol Depend ; 191: 365-373, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30195949

RESUMO

Externalizing disorders have been extensively linked to substance use problems. However, less is known about whether genetic factors underpinning externalizing disorders and environmental features interact to predict substance use disorders (i.e., marijuana abuse and dependence) among urban African Americans. We examined whether polygenic risk scores (PRS) for conduct disorder (CD) and attention-deficit hyperactivity disorder (ADHD) interacted with contextual factors (i.e., parental monitoring, community disadvantage) to influence risk for marijuana use disorders in a sample of African American youth. Participants (N=1,050; 44.2% male) were initially recruited for an elementary school-based universal prevention trial in a Mid-Atlantic city and followed through age 20. Participants reported on their parental monitoring in sixth grade and whether they were diagnosed with marijuana abuse or dependence at age 20. Blood or saliva samples were genotyped using the Affymetrix 6.0 microarrays. The CD and ADHD PRS were created based on genome-wide association studies conducted by Dick et al. (2010) and Demontis et al. (2017), respectively. Community disadvantage was calculated based on census data when participants were in sixth grade. There was an interaction between the CD PRS and community disadvantage such that a higher CD PRS was associated with greater risk for a marijuana use disorder at higher levels of neighborhood disadvantage. This finding should be interpreted with caution owing to the number of significance tests performed. Implications for etiological models and future research directions are presented.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno da Conduta/genética , Estudo de Associação Genômica Ampla , Abuso de Maconha/genética , Herança Multifatorial/genética , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Criança , Comorbidade , Transtorno da Conduta/epidemiologia , Transtorno da Conduta/psicologia , Suscetibilidade a Doenças/epidemiologia , Suscetibilidade a Doenças/psicologia , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Abuso de Maconha/epidemiologia , Abuso de Maconha/psicologia , Uso da Maconha/epidemiologia , Uso da Maconha/genética , Uso da Maconha/psicologia , Adulto Jovem
7.
Nat Neurosci ; 21(9): 1161-1170, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30150663

RESUMO

Cannabis use is a heritable trait that has been associated with adverse mental health outcomes. In the largest genome-wide association study (GWAS) for lifetime cannabis use to date (N = 184,765), we identified eight genome-wide significant independent single nucleotide polymorphisms in six regions. All measured genetic variants combined explained 11% of the variance. Gene-based tests revealed 35 significant genes in 16 regions, and S-PrediXcan analyses showed that 21 genes had different expression levels for cannabis users versus nonusers. The strongest finding across the different analyses was CADM2, which has been associated with substance use and risk-taking. Significant genetic correlations were found with 14 of 25 tested substance use and mental health-related traits, including smoking, alcohol use, schizophrenia and risk-taking. Mendelian randomization analysis showed evidence for a causal positive influence of schizophrenia risk on cannabis use. Overall, our study provides new insights into the etiology of cannabis use and its relation with mental health.


Assuntos
Estudo de Associação Genômica Ampla , Abuso de Maconha/genética , Abuso de Maconha/psicologia , Esquizofrenia/induzido quimicamente , Esquizofrenia/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Moléculas de Adesão Celular/genética , Bases de Dados Genéticas , Feminino , Regulação da Expressão Gênica/genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Análise da Randomização Mendeliana , Saúde Mental , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Assunção de Riscos , Adulto Jovem
8.
Mol Psychiatry ; 23(12): 2277-2286, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29875475

RESUMO

Cannabis use is increasing in the United States, as are its adverse effects. We investigated the genetics of an adverse consequence of cannabis use: cannabis-related aggression (CRA) using a genome-wide association study (GWAS) design. Our GWAS sample included 3269 African Americans (AAs) and 2546 European Americans (EAs). An additional 89 AA subjects from the Grady Trauma Project (GTP) were also examined using a proxy-phenotype replication approach. We identified genome-wide significant risk loci contributing to CRA in AAs at the serotonin receptor 2B receptor gene (HTR2B), and the lead SNP, HTR2B*rs17440378, showed nominal association to aggression in the GTP cohort of cannabis-exposed subjects. A priori evidence linked HTR2B to impulsivity/aggression but not to cannabis response. Human functional data regarding the HTR2B variant further supported our finding. Treating an Htr2b-/- knockout mouse with THC resulted in increased aggressive behavior, whereas wild-type mice following THC administration showed decreased aggression in the resident-intruder paradigm, demonstrating that HTR2B variation moderates the effects of cannabis on aggression. These concordant findings in mice and humans implicate HTR2B as a major locus associated with cannabis-induced aggression.


Assuntos
Fumar Maconha/genética , Receptor 5-HT2B de Serotonina/genética , Receptor 5-HT2B de Serotonina/metabolismo , Adulto , Afro-Americanos/genética , Agressão/efeitos dos fármacos , Alcoolismo/genética , Animais , Cannabis/efeitos adversos , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Abuso de Maconha/genética , Fumar Maconha/efeitos adversos , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Receptor 5-HT2B de Serotonina/fisiologia , Fatores de Risco
10.
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
11.
Addiction ; 113(8): 1488-1498, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29500852

RESUMO

BACKGROUND AND AIMS: Individual differences in DSM-IV personality disorders (PDs) are associated with increased prevalence of substance use disorders. Our aims were to determine which combination of PDs trait scores best predict cannabis use (CU) and cannabis use disorder (CUD), and to estimate the size and significance of genetic and environmental risks in PD traits shared with CU and CUD. DESIGN: Linear mixed-effects models were used to identify PD traits for inclusion in twin analyses to explore the genetic and environmental associations between the traits and cannabis use. SETTING: Cross-sectional data were obtained from Norwegian adult twins in a face-to-face interview in 1999-2004 as part of a population-based study of mental health. PARTICIPANTS: Subjects were 1419 twins (µage  = 28.2 years, range = 19-36) from the Norwegian Institute of Public Health Twin Panel with complete PD and cannabis data. MEASUREMENTS: PD traits were assessed using DSM-IV criteria. Life-time CU and CUD were based on DSM-IV abuse and dependence criteria, including withdrawal and craving. FINDINGS: After adjusting for age and sex, antisocial [ß = 0.23, 95% confidence interval (CI) = 0.19-0.28] and borderline PDs (ß = 0.20, 95% CI = 0.14-0.26) were associated strongly with CU. Antisocial (ß = 0.26, 95% CI = 0.21-0.31) and borderline PDs (ß = 0.12, 95% CI = 0.06-0.18) were also linked strongly to CUD. Genetic risks in antisocial and borderline PD traits explained 32-60% of the total variance in CU and CUD. Dependent and avoidant PDs explained 11 and 16% of the total variance in CU and CUD, respectively. CONCLUSIONS: Individual differences in the liability to cannabis use and cannabis use disorder appear to be linked to genetic risks correlated with antisocial and borderline personality disorder traits.


Assuntos
Transtorno da Personalidade Antissocial/epidemiologia , Transtorno da Personalidade Borderline/epidemiologia , Transtorno da Personalidade Dependente/epidemiologia , Abuso de Maconha/epidemiologia , Uso da Maconha/epidemiologia , Adulto , Transtorno da Personalidade Antissocial/genética , Transtorno da Personalidade Borderline/genética , Transtorno da Personalidade Dependente/genética , Feminino , Humanos , Masculino , Abuso de Maconha/genética , Uso da Maconha/genética , Noruega/epidemiologia , Transtornos da Personalidade/epidemiologia , Transtornos da Personalidade/genética , Adulto Jovem
12.
Psychol Med ; 48(16): 2786-2793, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29530110

RESUMO

BACKGROUND: The genetic component of Cannabis Use Disorder may overlap with influences acting more generally on early stages of cannabis use. This paper aims to determine the extent to which genetic influences on the development of cannabis abuse/dependence are correlated with those acting on the opportunity to use cannabis and frequency of use. METHODS: A cross-sectional study of 3303 Australian twins, measuring age of onset of cannabis use opportunity, lifetime frequency of cannabis use, and lifetime DSM-IV cannabis abuse/dependence. A trivariate Cholesky decomposition estimated additive genetic (A), shared environment (C) and unique environment (E) contributions to the opportunity to use cannabis, the frequency of cannabis use, cannabis abuse/dependence, and the extent of overlap between genetic and environmental factors associated with each phenotype. RESULTS: Variance components estimates were A = 0.64 [95% confidence interval (CI) 0.58-0.70] and E = 0.36 (95% CI 0.29-0.42) for age of opportunity to use cannabis, A = 0.74 (95% CI 0.66-0.80) and E = 0.26 (95% CI 0.20-0.34) for cannabis use frequency, and A = 0.78 (95% CI 0.65-0.88) and E = 0.22 (95% CI 0.12-0.35) for cannabis abuse/dependence. Opportunity shares 45% of genetic influences with the frequency of use, and only 17% of additive genetic influences are unique to abuse/dependence from those acting on opportunity and frequency. CONCLUSIONS: There are significant genetic contributions to lifetime cannabis abuse/dependence, but a large proportion of this overlaps with influences acting on opportunity and frequency of use. Individuals without drug use opportunity are uninformative, and studies of drug use disorders must incorporate individual exposure to accurately identify aetiology.


Assuntos
Predisposição Genética para Doença/genética , Abuso de Maconha/genética , Uso da Maconha/genética , Sistema de Registros/estatística & dados numéricos , Adulto , Austrália/epidemiologia , Estudos Transversais , Feminino , Humanos , Masculino , Abuso de Maconha/epidemiologia , Abuso de Maconha/etiologia , Uso da Maconha/epidemiologia
13.
Psychol Med ; 48(15): 2500-2507, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29455677

RESUMO

BACKGROUND: Using a longitudinal twin design and a latent growth curve/autoregressive approach, this study examined the genetic-environmental architecture of substance use across adolescence. METHODS: Self-reports of substance use (i.e. alcohol, marijuana) were collected at ages 13, 14, 15, and 17 years from 476 twin pairs (475 boys, 477 girls) living in the Province of Quebec, Canada. Substance use increased linearly across the adolescent years. RESULTS: ACE modeling revealed that genetic, as well as shared and non-shared environmental factors explained the overall level of substance use and that these same factors also partly accounted for growth in substance use from age 13 to 17. Additional genetic factors predicted the growth in substance use. Finally, autoregressive effects revealed age-specific non-shared environmental influences and, to a lesser degree, age-specific genetic influences, which together accounted for the stability of substance use across adolescence. CONCLUSIONS: The results support and expand the notion that genetic and environmental influences on substance use during adolescence are both developmentally stable and developmentally dynamic.


Assuntos
Comportamento do Adolescente , Desenvolvimento do Adolescente , Alcoolismo/etiologia , Alcoolismo/genética , Predisposição Genética para Doença , Abuso de Maconha/etiologia , Abuso de Maconha/genética , Sistema de Registros , Meio Social , Adolescente , Feminino , Humanos , Estudos Longitudinais , Masculino , Quebeque
14.
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
15.
Addict Biol ; 23(1): 461-473, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28111843

RESUMO

Recent advances in genome wide sequencing techniques and analytical methods allow for more comprehensive examinations of the genome than microarray-based genome-wide association studies (GWAS). The present report provides the first application of whole genome sequencing (WGS) to identify low frequency variants involved in cannabis dependence across two independent cohorts. The present study used low-coverage whole genome sequence data to conduct set-based association and enrichment analyses of low frequency variation in protein-coding regions as well as regulatory regions in relation to cannabis dependence. Two cohorts were studied: a population-based Native American tribal community consisting of 697 participants nested within large multi-generational pedigrees and a family-based sample of 1832 predominantly European ancestry participants largely nested within nuclear families. Participants in both samples were assessed for Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) lifetime cannabis dependence, with 168 and 241 participants receiving a positive diagnosis in each sample, respectively. Sequence kernel association tests identified one protein-coding region, C1orf110 and one regulatory region in the MEF2B gene that achieved significance in a meta-analysis of both samples. A regulatory region within the PCCB gene, a gene previously associated with schizophrenia, exhibited a suggestive association. Finally, a significant enrichment of regions within or near genes with multiple splice variants or involved in cell adhesion or potassium channel activity were associated with cannabis dependence. This initial study demonstrates the potential utility of low pass whole genome sequencing for identifying genetic variants involved in the etiology of cannabis use disorders.


Assuntos
Grupo com Ancestrais do Continente Europeu/genética , Índios Norte-Americanos/genética , Abuso de Maconha/genética , Adulto , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Fatores de Transcrição MEF2/genética , Masculino , Metilmalonil-CoA Descarboxilase/genética , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Canais de Potássio/genética , Sequenciamento Completo do Genoma
16.
Mol Psychiatry ; 23(5): 1287-1292, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-28115737

RESUMO

Cannabis use is observationally associated with an increased risk of schizophrenia, but whether the relationship is causal is not known. Using a genetic approach, we took 10 independent genetic variants previously identified to associate with cannabis use in 32 330 individuals to determine the nature of the association between cannabis use and risk of schizophrenia. Genetic variants were employed as instruments to recapitulate a randomized controlled trial involving two groups (cannabis users vs nonusers) to estimate the causal effect of cannabis use on risk of schizophrenia in 34 241 cases and 45 604 controls from predominantly European descent. Genetically-derived estimates were compared with a meta-analysis of observational studies reporting ever use of cannabis and risk of schizophrenia or related disorders. Based on the genetic approach, use of cannabis was associated with increased risk of schizophrenia (odds ratio (OR) of schizophrenia for users vs nonusers of cannabis: 1.37; 95% confidence interval (CI), 1.09-1.67; P-value=0.007). The corresponding estimate from observational analysis was 1.43 (95% CI, 1.19-1.67; P-value for heterogeneity =0.76). The genetic markers did not show evidence of pleiotropic effects and accounting for tobacco exposure did not alter the association (OR of schizophrenia for users vs nonusers of cannabis, adjusted for ever vs never smoker: 1.41; 95% CI, 1.09-1.83). This adds to the substantial evidence base that has previously identified cannabis use to associate with increased risk of schizophrenia, by suggesting that the relationship is causal. Such robust evidence may inform public health messages about cannabis use, especially regarding its potential mental health consequences.


Assuntos
Fumar Maconha/genética , Esquizofrenia/etiologia , Esquizofrenia/genética , Adulto , Cannabis/metabolismo , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Variação Genética , Humanos , Masculino , Abuso de Maconha/genética , Abuso de Maconha/psicologia , Fumar Maconha/efeitos adversos , Fumar Maconha/psicologia , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Distribuição Aleatória , Fatores de Risco , Fumantes/psicologia
17.
J Abnorm Psychol ; 127(1): 79-91, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29172598

RESUMO

There is a limited understanding as to how specific genes impact addiction risk. Applying a developmental framework and research domain criteria (RDoC) to identify etiological pathways from genetic markers to addiction may have utility. Prior research has largely focused on externalizing pathways to substance use. Although internalizing mechanisms have received less attention, there is strong support that addiction is a longer term consequence of using substances to cope with internalizing as well as externalizing problems. This study tests whether temperament and depression mediate the association between specific genetic variants and substance use. The sample consisted of 426 adolescents from the Michigan Longitudinal Study (70.9% boys, 84.0% White). Four specific genetic variants were examined: SLC6A4 (5HTTLPR), BDNF (rs6265), NPY (rs3037354), and CRHBP (rs7728378). Childhood resiliency and behavioral control were examined as potential mediators, in addition to early adolescent depression, using a multiple-mediator path model. Resiliency and depression were supported as mediators in the association between genetic risk and later substance use. Important differences emerged across substances of abuse. Indirect effects via depression were not significant with the inclusion of aggression. Early difficulties with emotional coping may represent nonspecific neurobiological underpinnings for an internalizing pathway to addiction. (PsycINFO Database Record


Assuntos
Alcoolismo/genética , Abuso de Maconha/genética , Tabagismo/genética , Adolescente , Alcoolismo/psicologia , Fator Neurotrófico Derivado do Encéfalo/genética , Proteínas de Transporte/genética , Criança , Depressão , Feminino , Genótipo , Humanos , Masculino , Abuso de Maconha/psicologia , Neuropeptídeo Y/genética , Resiliência Psicológica , Fatores de Risco , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Temperamento , Tabagismo/psicologia
18.
Psychiatry Res ; 262: 357-358, 2018 Apr.
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
19.
Mol Psychiatry ; 23(5): 1293-1302, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29112194

RESUMO

Despite moderate heritability, only one study has identified genome-wide significant loci for cannabis-related phenotypes. We conducted meta-analyses of genome-wide association study data on 2080 cannabis-dependent cases and 6435 cannabis-exposed controls of European descent. A cluster of correlated single-nucleotide polymorphisms (SNPs) in a novel region on chromosome 10 was genome-wide significant (lowest P=1.3E-8). Among the SNPs, rs1409568 showed enrichment for H3K4me1 and H3K427ac marks, suggesting its role as an enhancer in addiction-relevant brain regions, such as the dorsolateral prefrontal cortex and the angular and cingulate gyri. This SNP is also predicted to modify binding scores for several transcription factors. We found modest evidence for replication for rs1409568 in an independent cohort of African American (896 cases and 1591 controls; P=0.03) but not European American (EA; 781 cases and 1905 controls) participants. The combined meta-analysis (3757 cases and 9931 controls) indicated trend-level significance for rs1409568 (P=2.85E-7). No genome-wide significant loci emerged for cannabis dependence criterion count (n=8050). There was also evidence that the minor allele of rs1409568 was associated with a 2.1% increase in right hippocampal volume in an independent sample of 430 EA college students (fwe-P=0.008). The identification and characterization of genome-wide significant loci for cannabis dependence is among the first steps toward understanding the biological contributions to the etiology of this psychiatric disorder, which appears to be rising in some developed nations.


Assuntos
Cromossomos Humanos Par 10/genética , Abuso de Maconha/genética , Adulto , Afro-Americanos/genética , Alelos , Cannabis , Estudos de Casos e Controles , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Adulto Jovem
20.
Brain Behav ; 7(11): e00850, 2017 11.
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. 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
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