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5 results on '"USE INITIATION"'

1. Genome-wide association meta-analysis of age at first cannabis use

Subjects
GENE ONTOLOGY, substance use, Age at first use, ILLICIT DRUG-USE, ALCOHOL, ATP2C2, heritability, MARIJUANA USE, CONDUCT PROBLEMS, ENVIRONMENTAL-INFLUENCES, genome-wide association, LATER SUBSTANCE USE, cannabis initiation, USE INITIATION, OF-ONSET, MENTAL-HEALTH
Abstract

BACKGROUND AND AIMS: Cannabis is one of the most commonly used substances among adolescents and young adults. Earlier age at cannabis initiation is linked to adverse life outcomes including multi-substance use and dependence. This study estimated the heritability of age at first cannabis use and identify associations with genetic variants.METHODS: A twin-based heritability analysis using 8,055 twins from three cohorts was performed. We then carried-out a genome wide survival meta-analysis of age at first cannabis use in a discovery sample of 24,953 individuals from nine European, North American, and Australian cohorts, and a replication sample of 3,735 individuals.RESULTS: The twin-based heritability for age at first cannabis use was 38% (95% confidence interval [CI] 19-60%). Shared and unique environmental factors explained 39% (95% CI 20-56%) and 22% (95% CI 16-29%). The genome wide survival meta-analysis identified five SNPs on chromosome 16 within the Calcium-transporting ATPase gene (ATP2C2) at P < 5E-08. All five SNPs are in high LD (r2 >0.8) with the strongest association at the intronic variant rs1574587 (P=4.09E-09). Gene-based tests of association identified the ATP2C2 gene on 16q24.1 (P=1.33e-06). Although the five SNPs and ATP2C2 did not replicate, ATP2C2 has been associated with cocaine dependence in a previous study. ATP2B2, which is a member of the same calcium signalling pathway, has been previously associated with opioid dependence. SNP-based heritability for age at first cannabis use was non-significant.CONCLUSION: Age at cannabis initiation appears to be moderately heritable in Western countries, and individual differences in onset can be explained by separate but correlated genetic liabilities. The significant association between age of initiation and ATP2C2 is consistent with the role of calcium signalling mechanisms in substance use disorders.

Published
2018

2. Genome-wide association study implicates CHRNA2 in cannabis use disorder

Author

Kalle Leppälä, Ditte Demontis, Ole Mors, Thorarinn Tyrfingsson, Laura M. Huckins, Anders D. Børglum, Kari Stefansson, Mark J. Daly, David M. Hougaard, Carsten Hjorthøj, Daniel F. Gudbjartsson, Gunnar W Reginsson, Thomas Werge, Jane H. Christensen, Per Qvist, Eli A. Stahl, Hreinn Stefansson, Allan Timmermann, Valgerdur Runarsdottir, Thorgeir E. Thorgeirsson, Jonatan Pallesen, Esben Agerbo, Jonas Bybjerg-Grauholm, Merete Nordentoft, Jakob Grove, Preben Bo Mortensen, Marie Bækvad-Hansen, Mette Nyegaard, Veera M. Rajagopal, and Thomas Damm Als

Subjects
Male, 0301 basic medicine, Marijuana Abuse, Multifactorial Inheritance, Denmark, LOCI, Iceland, Genome-wide association study, Receptors, Nicotinic, ACTIVATION, Cohort Studies, Cognition, 0302 clinical medicine, SCHIZOPHRENIA, POLYGENIC RISK, Age of Onset, Genetics, education.field_of_study, HERITABILITY, Research Support, Non-U.S. Gov't, General Neuroscience, PSYCHIATRIC-DISORDERS, Smoking, Brain, Confounding Factors, Epidemiologic, 3. Good health, Educational Status, Female, Chromosomes, Human, Pair 8, Quantitative Trait Loci, Population, Nerve Tissue Proteins, Locus (genetics), Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, Article, MARIJUANA USE, 03 medical and health sciences, Research Support, N.I.H., Extramural, NICOTINE, Journal Article, Humans, Genetic Predisposition to Disease, Allele, USE INITIATION, education, METAANALYSIS, Alleles, Gene Expression Profiling, biology.organism_classification, Genetic architecture, 030104 developmental biology, Attention Deficit Disorder with Hyperactivity, Case-Control Studies, Expression quantitative trait loci, Schizophrenia, Cannabis, Transcriptome, Neuroscience, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

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. The study reports a genome-wide significant locus for cannabis use disorder, replicating in an independent cohort, and implicates CHRNA2, which encodes an acetylcholine receptor subunit, in the disorder by analyses of genetically regulated gene expression.

Published
2019
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3. Genome-wide association meta-analysis of age at first cannabis use

Author

Minică, Camelia C., Verweij, Karin J.H., van der Most, Peter J., Mbarek, Hamdi, Bernard, Manon, van Eijk, Kristel R., Lind, Penelope A., Liu, Meng Zhen, Maciejewski, Dominique F., Palviainen, Teemu, Sánchez-Mora, Cristina, Sherva, Richard, Taylor, Michelle, Walters, Raymond K., Abdellaoui, Abdel, Bigdeli, Timothy B., Branje, Susan J.T., Brown, Sandra A., Casas, Miguel, Corley, Robin P., Davey-Smith, George, Davies, Gareth E., Ehli, Erik A., Farrer, Lindsay, Fedko, Iryna O., Garcia-Martínez, Iris, Gordon, Scott D., Hartman, Catharina A., Heath, Andrew C., Hickie, Ian B., Hickman, Matthew, Hopfer, Christian J., Hottenga, Jouke Jan, Kahn, René S., Kaprio, Jaakko, Korhonen, Tellervo, Kranzler, Henry R., Krauter, Ken, van Lier, Pol A.C., Madden, Pamela A.F., Medland, Sarah E., Neale, Michael C., Meeus, Wim H.J., Montgomery, Grant W., Nolte, Ilja M., Oldehinkel, Albertine J., Pausova, Zdenka, Ramos-Quiroga, Josep A., Richarte, Vanesa, Rose, Richard J., Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Psychiatry, and APH - Mental Health

Subjects
GENE ONTOLOGY, substance use, Age at first use, ILLICIT DRUG-USE, ALCOHOL, ATP2C2, heritability, MARIJUANA USE, CONDUCT PROBLEMS, ENVIRONMENTAL-INFLUENCES, genome-wide association, LATER SUBSTANCE USE, cannabis initiation, USE INITIATION, OF-ONSET, MENTAL-HEALTH
Abstract

Background and aims: Cannabis is one of the most commonly used substances among adolescents and young adults. Earlier age at cannabis initiation is linked to adverse life outcomes, including multi-substance use and dependence. This study estimated the heritability of age at first cannabis use and identified associations with genetic variants. Methods: A twin-based heritability analysis using 8055 twins from three cohorts was performed. We then carried out a genome-wide association meta-analysis of age at first cannabis use in a discovery sample of 24 953 individuals from nine European, North American and Australian cohorts, and a replication sample of 3735 individuals. Results: The twin-based heritability for age at first cannabis use was 38% [95% confidence interval (CI) = 19–60%]. Shared and unique environmental factors explained 39% (95% CI = 20–56%) and 22% (95% CI = 16–29%). The genome-wide association meta-analysis identified five single nucleotide polymorphisms (SNPs) on chromosome 16 within the calcium-transporting ATPase gene (ATP2C2) at P 2 > 0.8), with the strongest association at the intronic variant rs1574587 (P = 4.09E-09). Gene-based tests of association identified the ATP2C2 gene on 16q24.1 (P = 1.33e-06). Although the five SNPs and ATP2C2 did not replicate, ATP2C2 has been associated with cocaine dependence in a previous study. ATP2B2, which is a member of the same calcium signalling pathway, has been associated previously with opioid dependence. SNP-based heritability for age at first cannabis use was non-significant. Conclusion: Age at cannabis initiation appears to be moderately heritable in western countries, and individual differences in onset can be explained by separate but correlated genetic liabilities. The significant association between age of initiation and ATP2C2 is consistent with the role of calcium signalling mechanisms in substance use disorders.

Published
2018

4. GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophrenia

Author

23andMe Res Team, Subst Use Disorders Working Grp Ps, Int Cannabis Consortium, Institute for Molecular Medicine Finland, Jaakko Kaprio / Principal Investigator, Helsinki Institute of Life Science HiLIFE, and Genetic Epidemiology

Subjects
MENDELIAN RANDOMIZATION, 3112 Neurosciences, CELL-ADHESION MOLECULES, ALCOHOL, GENOME-WIDE ASSOCIATION, VARIANTS, USE INITIATION, SUBSTANCE USE, NICOTINE DEPENDENCE, METAANALYSIS, NCAM1
Abstract

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 sub-stance 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.

Published
2018

5. Genome-wide association study of lifetime cannabis use based on a large meta-analytic sample of 32330 subjects from the International Cannabis Consortium

Author

University of Helsinki, Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Clinicum, Stringer, S., Minica, C. C., Verweij, K. J. H., Mbarek, H., Bernard, M., Derringer, J., van Eijk, K. R., Isen, J. D., Loukola, A., Maciejewski, D. F., Mihailov, E., van der Most, P. J., Sanchez-Mora, C., Roos, L., Sherva, R., Walters, R., Ware, J. J., Abdellaoui, A., Bigdeli, T. B., Branje, S. J. T., Brown, S. A., Bruinenberg, M., Casas, M., Esko, T., Garcia-Martinez, I., Gordon, S. D., Harris, J. M., Hartman, C. A., Henders, A. K., Heath, A. C., Hickie, I. B., Hickman, M., Hopfer, C. J., Hottenga, J. J., Huizink, A. C., Irons, D. E., Kahn, R. S., Korhonen, T., Kranzler, H. R., Krauter, K., van Lier, P. A. C., Lubke, G. H., Madden, P. A. F., Magi, R., McGue, M. K., Medland, S. E., Meeus, W. H. J., Miller, M. B., Montgomery, G. W., Nivard, M. G., Nolte, I. M., Oldehinkel, A. J., Pausova, Z., Qaiser, B., Quaye, L., Ramos-Quiroga, J. A., Richarte, V., Rose, R. J., Shin, J., Stallings, M. C., Stiby, A. I., Wall, T. L., Wright, M. J., Koot, H. M., Paus, T., Hewitt, J. K., Ribases, M., Kaprio, J., Boks, M. P., Snieder, H., Spector, T., Munafo, M. R., Metspalu, A., Gelernter, J., Boomsma, D. I., Iacono, W. G., Martin, N. G., Gillespie, N. A., Derks, E. M., Vink, J. M., University of Helsinki, Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Clinicum, Stringer, S., Minica, C. C., Verweij, K. J. H., Mbarek, H., Bernard, M., Derringer, J., van Eijk, K. R., Isen, J. D., Loukola, A., Maciejewski, D. F., Mihailov, E., van der Most, P. J., Sanchez-Mora, C., Roos, L., Sherva, R., Walters, R., Ware, J. J., Abdellaoui, A., Bigdeli, T. B., Branje, S. J. T., Brown, S. A., Bruinenberg, M., Casas, M., Esko, T., Garcia-Martinez, I., Gordon, S. D., Harris, J. M., Hartman, C. A., Henders, A. K., Heath, A. C., Hickie, I. B., Hickman, M., Hopfer, C. J., Hottenga, J. J., Huizink, A. C., Irons, D. E., Kahn, R. S., Korhonen, T., Kranzler, H. R., Krauter, K., van Lier, P. A. C., Lubke, G. H., Madden, P. A. F., Magi, R., McGue, M. K., Medland, S. E., Meeus, W. H. J., Miller, M. B., Montgomery, G. W., Nivard, M. G., Nolte, I. M., Oldehinkel, A. J., Pausova, Z., Qaiser, B., Quaye, L., Ramos-Quiroga, J. A., Richarte, V., Rose, R. J., Shin, J., Stallings, M. C., Stiby, A. I., Wall, T. L., Wright, M. J., Koot, H. M., Paus, T., Hewitt, J. K., Ribases, M., Kaprio, J., Boks, M. P., Snieder, H., Spector, T., Munafo, M. R., Metspalu, A., Gelernter, J., Boomsma, D. I., Iacono, W. G., Martin, N. G., Gillespie, N. A., Derks, E. M., and Vink, J. M.

Abstract

Cannabis is the most widely produced and consumed illicit psychoactive substance worldwide. Occasional cannabis use can progress to frequent use, abuse and dependence with all known adverse physical, psychological and social consequences. Individual differences in cannabis initiation are heritable (40-48%). The International Cannabis Consortium was established with the aim to identify genetic risk variants of cannabis use. We conducted a meta-analysis of genome-wide association data of 13 cohorts (N = 32 330) and four replication samples (N = 5627). In addition, we performed a gene-based test of association, estimated single-nucleotide polymorphism (SNP)-based heritability and explored the genetic correlation between lifetime cannabis use and cigarette use using LD score regression. No individual SNPs reached genome-wide significance. Nonetheless, gene-based tests identified four genes significantly associated with lifetime cannabis use: NCAM1, CADM2, SCOC and KCNT2. Previous studies reported associations of NCAM1 with cigarette smoking and other substance use, and those of CADM2 with body mass index, processing speed and autism disorders, which are phenotypes previously reported to be associated with cannabis use.

Published
2016

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