Genome-wide association study of lifetime cannabis use based on a large meta-analytic sample of 32 330 subjects from the International Cannabis Consortium.
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- Stringer, S; MinicΔ, 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; SΓ‘nchez-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; MΓ€gi, 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; RibasΓ©s, M; Kaprio, J; Boks, M P; Snieder, H; Spector, T; MunafΓ², M R; Metspalu, A; Gelernter, J; Boomsma, D I; Iacono, W G; Martin, N G; Gillespie, N A; Derks, E M; Vink, J M
- Year
- 2016
- Journal
- Translational psychiatry
- PMID
- 27023175
- DOI
- 10.1038/tp.2016.36
- PMCID
- PMC4872459
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. Furthermore, we showed that, combined across the genome, all common SNPs explained 13-20% (P<0.001) of the liability of lifetime cannabis use. Finally, there was a strong genetic correlation (rg=0.83; P=1.85 Γ 10(-8)) between lifetime cannabis use and lifetime cigarette smoking implying that the SNP effect sizes of the two traits are highly correlated. This is the largest meta-analysis of cannabis GWA studies to date, revealing important new insights into the genetic pathways of lifetime cannabis use. Future functional studies should explore the impact of the identified genes on the biological mechanisms of cannabis use.
The Manhattan (a) and the QQ plot (b) based on results of the gene-based analysis performed in the discovery sample using HYST (hybrid set-based test).
LLM interpretation
Figure (a) is a Manhattan plot showing $-\log_{10}(P)$ values across chromosomes, with significant peaks labeled for genes *KCNT2*, *CADM2*, *SCOC/SCOC-AS1*, and *NCAM1*. Figure (b) is a QQ plot comparing observed versus expected $-\log_{10}(P)$ values for the HYST set-based test (blue) and a gene-based test (magenta). In the QQ plot, both test curves deviate upward from the diagonal null line, indicating a higher-than-expected number of significant associations.
Forest plot for the top-SNP rs4471463 in the NCAM1 gene on chromosome 11. SNP, single-nucleotide polymorphism.
LLM interpretation
This is a forest plot showing the effect of the SNP rs4471463 (11:112983534 [T]) in the NCAM1 gene across 14 different samples and a final meta-analysis. The x-axis represents the log(Odds Ratio), with individual sample effects shown as points with 95% confidence interval bars. The meta-analysis result, indicated by a red diamond, shows a combined log(Odds Ratio) of -0.10 [-0.14, -0.06], which does not cross the zero line of no effect.
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| Understanding the Mechanisms of Action and Effects of Drugs of Abuse. | CiucΔ Anghel DM et al. | β | 2023 | β |
| A Randomized Controlled Trial to Evaluate the Safety and Efficacy of a Novel Inhaled Biologic Therapeutic in Adults with Respiratory Distress Secondary to COVID-19 Infection. | Roshon M et al. | β | 2022 | β |
| Cannabis Use in Autism: Reasons for Concern about Risk for Psychosis. | Bortoletto R et al. | β | 2022 | β |
| Childhood maltreatment mediates the effect of the genetic background on psychosis risk in young adults. | Marchi M et al. | β | 2022 | β |
| Diminished Structural Brain Integrity in Long-term Cannabis Users Reflects a History of Polysubstance Use. | Knodt AR et al. | β | 2022 | β |
| Examining pathways between genetic liability for schizophrenia and patterns of tobacco and cannabis use in adolescence. | Jones HJ et al. | β | 2022 | β |
| Genetic predispositions to psychiatric disorders and the risk of COVID-19. | Chen W et al. | β | 2022 | β |
| Influences on the Genetic Relationship Between Cannabis Use and Schizophrenia: The Role of the Externalizing Spectrum. | Wormington B et al. | β | 2022 | β |
| Reward Deficiency Syndrome (RDS) Surprisingly Is Evolutionary and Found Everywhere: Is It "Blowin' in the Wind"? | Blum K et al. | β | 2022 | β |
| Strong and weak cross-inheritance of substance use disorders in a nationally representative sample. | Zhang H et al. | β | 2022 | β |
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| The genetic aetiology of cannabis use: from twin models to genome-wide association studies and beyond. | Verweij KJH et al. | β | 2022 | β |
| A Mapping Literature Review of Medical Cannabis Clinical Outcomes and Quality of Evidence in Approved Conditions in the USA from 2016 to 2019. | Jugl S et al. | β | 2021 | β |
| Associations between the CADM2 gene, substance use, risky sexual behavior, and self-control: A phenome-wide association study. | Arends RM et al. | β | 2021 | β |
| Cannabis use and cannabis use disorder. | Connor JP et al. | β | 2021 | β |
| Cannabis Use and the Risk of Cardiovascular Diseases: A Mendelian Randomization Study. | Zhao J et al. | β | 2021 | β |
| Cannabis use in college: Genetic predispositions, peers, and activity participation. | Thomas NS et al. | β | 2021 | β |
| Correlates of Cannabis Use Disorders among urban women of color: childhood abuse, relationship with spouse/partner, and media exposure. | Lee JY et al. | β | 2021 | β |
| Detection of altered methylation of MB-COMT promotor and DRD2 gene in cannabinoid or synthetic cannabinoid use disorder regarding gene variants and clinical parameters. | Oyaci Y et al. | β | 2021 | β |
| Genetic basis of cannabis use: a systematic review. | Hillmer A et al. | β | 2021 | β |
| Genetic Modulation of Initial Sensitivity to Ξ9-Tetrahydrocannabinol (THC) Among the BXD Family of Mice. | Parks C et al. | β | 2021 | β |
| Genetics of substance use disorders in the era of big data. | Gelernter J et al. | β | 2021 | β |
| Genome-wide association study of early-onset bipolar I disorder in the Han Taiwanese population. | Wu LS et al. | β | 2021 | β |
| Resource profile and user guide of the Polygenic Index Repository. | Becker J et al. | β | 2021 | β |
| Significant, replicable, and functional associations between KTN1 variants and alcohol and drug codependence. | Luo X et al. | β | 2021 | β |
| Sleep deficits and cannabis use behaviors: an analysis of shared genetics using linkage disequilibrium score regression and polygenic risk prediction. | Winiger EA et al. | β | 2021 | β |
| The intermediary role of adolescent temperamental and behavioral traits on the prospective associations between polygenic risk and cannabis use among young adults of European Ancestry. | Brick LA et al. | β | 2021 | β |
| Unraveling the Association Between Schizophrenia and Substance Use Disorder-Predictors, Mechanisms and Treatment Modifications: A Systematic Review. | Masroor A et al. | β | 2021 | β |
| Using Mendelian randomization analysis to better understand the relationship between mental health and substance use: a systematic review. | Treur JL et al. | β | 2021 | β |
| Attention-deficit/hyperactivity disorder and lifetime cannabis use: genetic overlap and causality. | Soler Artigas M et al. | β | 2020 | β |
| Cannabinoids and psychotic symptoms: A potential role for a genetic variant in the P2X purinoceptor 7 (P2RX7) gene. | Boks MP et al. | β | 2020 | β |
| Cannabis use, depression and self-harm: phenotypic and genetic relationships. | Hodgson K et al. | β | 2020 | β |
| Cocaine'omics: Genome-wide and transcriptome-wide analyses provide biological insight into cocaine use and dependence. | Huggett SB et al. | β | 2020 | β |
| Deconstructing the neurobiology of cannabis use disorder. | Ferland JN et al. | β | 2020 | β |
| Exploring Phenotypic and Genetic Overlap Between Cannabis Use and Schizotypy. | Vaissiere J et al. | β | 2020 | β |
| Genetic Associations Between Executive Functions and a General Factor of Psychopathology. | Harden KP et al. | β | 2020 | β |
| Genetic determinants of cannabis use: a systematic review protocol. | Hillmer A et al. | β | 2020 | β |
| Genome-wide DNA methylation analysis of heavy cannabis exposure in a New Zealand longitudinal cohort. | Osborne AJ et al. | β | 2020 | β |
| Identification of Functional Genetic Variants Associated With Alcohol Dependence and Related Phenotypes Using a High-Throughput Assay. | Thapa KS et al. | β | 2020 | β |
| <i>KTN1</i> Variants Underlying Putamen Gray Matter Volumes and Parkinson's Disease. | Mao Q et al. | β | 2020 | β |
| Onset of regular cannabis use and young adult insomnia: an analysis of shared genetic liability. | Winiger EA et al. | β | 2020 | β |
| Potential influence of socioeconomic status on genetic correlations between alcohol consumption measures and mental health. | Marees AT et al. | β | 2020 | β |
| Sex and Strain Variation in Initial Sensitivity and Rapid Tolerance to Ξ9-Tetrahydrocannabinol. | Parks C et al. | β | 2020 | β |
| Studying individual risk factors for self-harm in the UK Biobank: A polygenic scoring and Mendelian randomisation study. | Lim KX et al. | β | 2020 | β |
| A Contagion Model for Within-Family Transmission of Drug Abuse. | Kendler KS et al. | β | 2019 | β |
| Association between polygenic risk for tobacco or alcohol consumption and liability to licit and illicit substance use in young Australian adults. | Chang LH et al. | β | 2019 | β |
| Effects of DRD2 splicing-regulatory polymorphism and DRD4 48Β bp VNTR on crack cocaine addiction. | Stolf AR et al. | β | 2019 | β |
| Exploring the relationship between polygenic risk for cannabis use, peer cannabis use and the longitudinal course of cannabis involvement. | Johnson EC et al. | β | 2019 | β |
| Genetic and Environmental Risk Factors for Cannabis Use: Preliminary Results for the Role of Parental Care Perception. | Gerra MC et al. | β | 2019 | β |
| Genetic correlations of psychiatric traits with body composition and glycemic traits are sex- and age-dependent. | HΓΌbel C et al. | β | 2019 | β |
| Genetic determinants of beverage consumption: Implications for nutrition and health. | Cornelis MC | β | 2019 | β |
| Genetic Vulnerability for Smoking and Cannabis Use: Associations With E-Cigarette and Water Pipe Use. | Allegrini AG et al. | β | 2019 | β |
| Genome-wide association analyses of risk tolerance and risky behaviors in over 1 million individuals identify hundreds of loci and shared genetic influences. | Karlsson LinnΓ©r R et al. | β | 2019 | β |
| Genome-Wide Association Studies of Impulsive Personality Traits (BIS-11 and UPPS-P) and Drug Experimentation in up to 22,861 Adult Research Participants Identify Loci in the <i>CACNA1I</i> and <i>CADM2</i> genes. | Sanchez-Roige S et al. | β | 2019 | β |
| Genome-wide association study implicates CHRNA2 in cannabis use disorder. | Demontis D et al. | β | 2019 | β |
| GWAS of Behavioral Traits. | Mehta D et al. | β | 2019 | β |
| <i>CNR1</i> and <i>FAAH</i> variation and affective states induced by marijuana smoking. | Palmer RHC et al. | β | 2019 | β |
| Identifying Potential Causal Risk Factors for Self-Harm: A Polygenic Risk Scoring and Mendelian Randomisation Approach | Lim KX et al. | β | 2019 | β |
| Onset of regular cannabis use and adult sleep duration: Genetic variation and the implications of a predictive relationship. | Winiger EA et al. | β | 2019 | β |
| Psychosocial moderation of polygenic risk for cannabis involvement: the role of trauma exposure and frequency of religious service attendance. | Meyers JL et al. | β | 2019 | β |
| The Colorado Twin Registry: 2019 Update. | Corley RP et al. | β | 2019 | β |
| The <i>CADM2</i> gene is associated with processing speed performance - evidence among elderly with type 2 diabetes. | Greenbaum L et al. | β | 2019 | β |
| Tobacco and cannabis use in college students are predicted by sex-dimorphic interactions between MAOA genotype and child abuse. | Fite PJ et al. | β | 2019 | β |
| Associations between personality disorders and cannabis use and cannabis use disorder: a population-based twin study. | Gillespie NA et al. | β | 2018 | β |
| Cannabis use and risk of schizophrenia: a Mendelian randomization study. | Vaucher J et al. | β | 2018 | β |
| Genetic vulnerability to schizophrenia is associated with cannabis use patterns during adolescence. | Hiemstra M et al. | β | 2018 | β |
| Gene variants and educational attainment in cannabis use: mediating role of DNA methylation. | Gerra MC et al. | β | 2018 | β |
| Genome-wide analysis of self-reported risk-taking behaviour and cross-disorder genetic correlations in the UK Biobank cohort. | Strawbridge RJ et al. | β | 2018 | β |
| Genome-wide association meta-analysis of age at first cannabis use. | MinicΔ CC et al. | β | 2018 | β |
| Genome-wide association study identifies a novel locus for cannabis dependence. | Agrawal A et al. | β | 2018 | β |
| GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophrenia. | Pasman JA et al. | β | 2018 | β |
| Human Genetics of Addiction: New Insights and Future Directions. | Hancock DB et al. | β | 2018 | β |
| Investigating causal associations between use of nicotine, alcohol, caffeine and cannabis: a two-sample bidirectional Mendelian randomization study. | Verweij KJH et al. | β | 2018 | β |
| Patterns and Correlates of Tobacco and Cannabis co-use by Tobacco Product Type: Findings from the Virginia Youth Survey. | Cobb CO et al. | β | 2018 | β |
| THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. | Guennewig B et al. | β | 2018 | β |
| The Modulating Role of Sex and Anabolic-Androgenic Steroid Hormones in Cannabinoid Sensitivity. | Struik D et al. | β | 2018 | β |
| The Role of Cell Adhesion Molecule Genes Regulating Neuroplasticity in Addiction. | Muskiewicz DE et al. | β | 2018 | β |
| Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders. | Walters RK et al. | β | 2018 | β |
| Using genetic data to strengthen causal inference in observational research. | Pingault JB et al. | β | 2018 | β |
| Whole genome sequence study of cannabis dependence in two independent cohorts. | Gizer IR et al. | β | 2018 | β |
| Assessing causality in associations between cannabis use and schizophrenia risk: a two-sample Mendelian randomization study. | Gage SH et al. | β | 2017 | β |
| Developmentally Specific Associations Between CNR1 Genotype and Cannabis Use Across Emerging Adulthood. | Ashenhurst JR et al. | β | 2017 | β |
| Evidence for the Risks and Consequences of Adolescent Cannabis Exposure. | Levine A et al. | β | 2017 | β |
| Genetic influences on the human oral microbiome. | Demmitt BA et al. | β | 2017 | β |
| Genome-wide association study of alcohol consumption and genetic overlap with other health-related traits in UK Biobank (N=112β117). | Clarke TK et al. | β | 2017 | β |
| <i>S100A10</i> identified in a genome-wide gene Γ cannabis dependence interaction analysis of risky sexual behaviours. | Polimanti R et al. | β | 2017 | β |
| Schizophrenia and substance use comorbidity: a genome-wide perspective. | Polimanti R et al. | β | 2017 | β |
| Short communication: Genetic association between schizophrenia and cannabis use. | Verweij KJ et al. | β | 2017 | β |
| The genetic basis of the comorbidity between cannabis use and major depression. | Hodgson K et al. | β | 2017 | β |
| The genetic epidemiology of substance use disorder: A review. | Prom-Wormley EC et al. | β | 2017 | β |
| Connecting the dots, genome-wide association studies in substance use. | Nivard MG et al. | β | 2016 | β |
| Genetic variation in FAAH is associated with cannabis use disorders in a young adult sample of Mexican Americans. | Melroy-Greif WE et al. | β | 2016 | β |