Genome-wide Association Study of Cannabis Dependence Severity, Novel Risk Variants, and Shared Genetic Risks.
paper
Primary
Public
- Authors
- Sherva, Richard; Wang, Qian; Kranzler, Henry; Zhao, Hongyu; Koesterer, Ryan; Herman, Aryeh; Farrer, Lindsay A; Gelernter, Joel
- Year
- 2016
- Journal
- JAMA psychiatry
- PMID
- 27028160
- DOI
- 10.1001/jamapsychiatry.2016.0036
- PMCID
- PMC4974817
IMPORTANCE: Cannabis dependence (CAD) is a serious problem worldwide and is of growing importance in the United States because cannabis is increasingly available legally. Although genetic factors contribute substantially to CAD risk, at present no well-established specific genetic risk factors for CAD have been elucidated. OBJECTIVE: To report findings for DSM-IV CAD criteria from association analyses performed in large cohorts of African American and European American participants from 3 studies of substance use disorder genetics. DESIGN, SETTING, AND PARTICIPANTS: This genome-wide association study for DSM-IV CAD criterion count was performed in 3 independent substance dependence cohorts (the Yale-Penn Study, Study of Addiction: Genetics and Environment [SAGE], and International Consortium on the Genetics of Heroin Dependence [ICGHD]). A referral sample and volunteers recruited in the community and from substance abuse treatment centers included 6000 African American and 8754 European American participants, including some from small families. Participants from the Yale-Penn Study were recruited from 2000 to 2013. Data were collected for the SAGE trial from 1990 to 2007 and for the ICGHD from 2004 to 2009. Data were analyzed from January 2, 2013, to November 9, 2015. MAIN OUTCOMES AND MEASURES: Criterion count for DSM-IV CAD. RESULTS: Among the 14 754 participants, 7879 were male, 6875 were female, and the mean (SD) age was 39.2 (10.2) years. Three independent regions with genome-wide significant single-nucleotide polymorphism associations were identified, considering the largest possible sample. These included rs143244591 (Ξ²β=β0.54, Pβ=β4.32βΓβ10-10 for the meta-analysis) in novel antisense transcript RP11-206M11.7;rs146091982 (Ξ²β=β0.54, Pβ=β1.33βΓβ10-9 for the meta-analysis) in the solute carrier family 35 member G1 gene (SLC35G1); and rs77378271 (Ξ²β=β0.29, Pβ=β2.13βΓβ10-8 for the meta-analysis) in the CUB and Sushi multiple domains 1 gene (CSMD1). Also noted was evidence of genome-level pleiotropy between CAD and major depressive disorder and for an association with single-nucleotide polymorphisms in genes associated with schizophrenia risk. Several of the genes identified have functions related to neuronal calcium homeostasis or central nervous system development. CONCLUSIONS AND RELEVANCE: These results are the first, to our knowledge, to identify specific CAD risk alleles and potential genetic factors contributing to the comorbidity of CAD with major depression and schizophrenia.
Regional Manhattan Plots of Association Results for DSM-IV Cannabis Dependence Criterion Count in 4 Genomic RegionsAssociation results from single-nucleotide polymorphisms (SNPs) in 4 regions. A, The 148.8- to 149.2-MB region encompassing RP11-206M11.7 on chromosome 3 in the Yale-Penn and Study of Addiction: Genetics and Environment (SAGE) African American participants. B, The 95.3- to 96-MB region encompassing SLC35G1 on chromosome 10 in the Yale-Penn and SAGE African American participants. C, The 2.8- to 4.8-MB region on chromosome 8 encompassing CSMD1 in the Yale-Penn, SAGE, and International Consortium on the Genetics of Heroin Dependence (ICGHD) African American and European American participants. D, The 25.07- to 25.43-MB region encompassing PI4K2B on chromosome 4 in the Yale-Penn, SAGE, and ICGHD African American and European American participants. In A and B, the SNPs are color coded according to the correlation coefficient (r2) in the 1000 Genomes African samples with the most significant SNP. In C and D, results from the African American and European American participants were combined, and no linkage disequilibrium information was displayed. The light purple circle represents the βlog10 P value for the most significant regional SNP in the meta-analysis of the discovery samples; the purple diamond, the result for that SNP after meta-analysis with the replication sample(s). The light blue line and right y-axis show the observed recombination rate.
1β20 of 24
Next β
| Name | Type |
|---|---|
| African American | cohort |
| African American meta-analysis local | cohort |
| African American-specific SNPs local | variant |
| alcohol | phenotype |
| alcohol dependence | phenotype |
| Alzheimer's disease | phenotype |
| attention deficit hyperactivity disorder | phenotype |
| Australian ICGHD replication cohort local | cohort |
| autism spectrum disorder | phenotype |
| bipolar disorder | phenotype |
| CAD | drug |
| calcium | drug |
| cannabinoids | drug |
| cannabis dependence | phenotype |
| cannabis exposure local | drug |
| Cannabis-only users local | phenotype |
| cannabis use | phenotype |
| cannabis use disorder | phenotype |
| CD | phenotype |
| CD20 local | phenotype |
| cocaine | phenotype |
| Combined EA/AA sample local | cohort |
| coronary artery disease | phenotype |
| CR1 | gene |
| CSMD1 | gene |
| developing mammalian neurons local | anatomy |
| discovery phase local | cohort |
| discovery sample | cohort |
| DSM-IV CAD criteria local | phenotype |
| EA population | cohort |
| European American meta-analysis local | cohort |
| European ancestry | cohort |
| general population | cohort |
| growth cones of developing central nervous system neurons local | anatomy |
| heavy drinking | phenotype |
| ICGHD local | cohort |
| ICGHD data local | cohort |
| imputed minor allele dosage local | variant |
| International Consortium on the Genetics of Heroin Dependence local | cohort |
| lifetime CAD local | phenotype |
| major depressive disorder | phenotype |
| major psychiatric traits local | phenotype |
| MEF2C | gene |
| mood disorders | phenotype |
| nicotine | drug |
| nicotine dependence | phenotype |
| NRG1 | gene |
| OD | phenotype |
| OD19 local | phenotype |
| opioid dependence | phenotype |
| PI4K2B local | gene |
| polysubstance dependence | phenotype |
| POR local | gene |
| psychiatric disorders | phenotype |
| Psychiatric Genomics Consortium | cohort |
| replication phase local | cohort |
| replication sample | cohort |
| RIMS1 local | gene |
| RP11-206M11.7 local | gene |
| rs10954732 local | variant |
| rs142305709 local | variant |
| rs143244591 | variant |
| rs146091982 | variant |
| rs147170184 local | variant |
| rs186825689 local | variant |
| rs74823926 local | variant |
| rs77378271 | variant |
| S100B local | gene |
| SAGE | cohort |
| SAGE African American local | cohort |
| SAGE dataset | cohort |
| SAGE trial local | cohort |
| schizophrenia | phenotype |
| SCZ | phenotype |
| single-nucleotide polymorphisms | variant |
| SLC35G1 | gene |
| SNP in SLC35G1 local | variant |
| STIM1 local | gene |
| study cohort | cohort |
| Study of Addiction: Genetics and Environment | cohort |
| substance use | phenotype |
| Yale-Penn | cohort |
| Yale-Penn 1 local | cohort |
| Yale-Penn 2 local | cohort |
| Yale-Penn 3 local | cohort |
| Yale-Penn African American local | cohort |
| Yale-Penn cohort | cohort |
| Yale-Penn sample | cohort |
| Yale-Penn study | cohort |
| Ξ³-aminobutyric acid | drug |
No uploaded files.
Not in any collection.
In this knowledge base
External
| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
| Genome-wide association studies of lifetime and frequency of cannabis use in 131,895 individuals. | Thorpe HHA et al. | β | 2026 | β |
| Addiction Susceptibility: Genetic Factors, Personality Traits, and Epigenetic Interactions with the Gut Microbiome. | Borrego-Ruiz A et al. | β | 2025 | β |
| Epigenetic and genetic profiling of comorbidity patterns among substance dependence diagnoses. | Pathak GA et al. | β | 2025 | β |
| Sex-Dependent Effects of <i>MAOA</i> Genotypes on the Relations Between Childhood Sexual Abuse, Aggression, and Cannabis Use in Emerging Adults. | Fite PJ et al. | β | 2025 | β |
| A genome-wide investigation into the underlying genetic architecture of personality traits and overlap with psychopathology. | Gupta P et al. | β | 2024 | β |
| Application of polygenic scores to a deeply phenotyped sample enriched for substance use disorders reveals extensive pleiotropy with psychiatric and somatic traits. | Hartwell EE et al. | β | 2024 | β |
| Avatar Intervention in Virtual Reality for Cannabis Use Disorder in Individuals With Severe Mental Disorders: Results From a 1-Year, Single-Arm Clinical Trial. | Giguere S et al. | β | 2024 | β |
| Cannabis use disorder: from neurobiology to treatment. | Le Foll B et al. | β | 2024 | β |
| CSMD1 regulates brain complement activity and circuit development. | Baum ML et al. | β | 2024 | β |
| Epigenetic and Genetic Profiling of Comorbidity Patterns among Substance Dependence Diagnoses | Pathak GA et al. | β | 2024 | β |
| Genetic and non-genetic predictors of risk for opioid dependence. | Na PJ et al. | β | 2024 | β |
| The genetic landscape of substance use disorders. | Gerring ZF et al. | β | 2024 | β |
| Cannabis Pharmacogenomics: A Path to Personalized Medicine. | Babayeva M et al. | β | 2023 | β |
| Discovery and Validation of Novel Genes in a Large Chinese Autism Spectrum Disorder Cohort. | Wang J et al. | β | 2023 | β |
| Multi-ancestry genome-wide association study of cannabis use disorder yields insight into disease biology and public health implications. | Levey DF et al. | β | 2023 | β |
| Multivariate genome-wide association meta-analysis of over 1 million subjects identifies loci underlying multiple substance use disorders. | Hatoum AS et al. | β | 2023 | β |
| Phenome-wide Association Analysis of Substance Use Disorders in a Deeply Phenotyped Sample. | Kember RL et al. | β | 2023 | β |
| Pleiotropic loci for cannabis use disorder severity in multi-ancestry high-risk populations. | Peng Q et al. | β | 2023 | β |
| Polysubstance addiction patterns among 7,989 individuals with cocaine use disorder. | Stiltner B et al. | β | 2023 | β |
| Association between platelet MAO activity and lifetime drug use in a longitudinal birth cohort study. | Sakala K et al. | β | 2022 | β |
| Chronic adolescent exposure to cannabis in mice leads to sex-biased changes in gene expression networks across brain regions. | Zuo Y et al. | β | 2022 | β |
| Common and distinguishing genetic factors for substance use behavior and disorder: an integrated analysis of genomic and transcriptomic studies from both human and animal studies. | Chang XW et al. | β | 2022 | β |
| Comorbidity and Coaggregation of Major Depressive Disorder and Bipolar Disorder and Cannabis Use Disorder in a Controlled Family Study. | Quick CR et al. | β | 2022 | β |
| Prevalence and correlates of cannabis use disorder among Australians using cannabis products to treat a medical condition. | Mills L 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 |
| The genetic aetiology of cannabis use: from twin models to genome-wide association studies and beyond. | Verweij KJH et al. | β | 2022 | β |
| Who Is at Risk of Developing Cannabis Dependence? Findings From an Extensive Online Study on Cannabis Users. | Binkowska AA 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 |
| Bibliometric Insights in Genetic Factors of Substance-Related Disorders: Intellectual Developments, Turning Points, and Emerging Trends. | Wang K et al. | β | 2021 | β |
| Cannabis use, abuse, and withdrawal: Cannabinergic mechanisms, clinical, and preclinical findings. | Kesner AJ et al. | β | 2021 | β |
| Cannabis use and cannabis use disorder. | Connor JP et al. | β | 2021 | β |
| Common genetic substrates of alcohol and substance use disorder severity revealed by pleiotropy detection against GWAS catalog in two populations. | Peng Q 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: a review. | Deak JD et al. | β | 2021 | β |
| Genetics of substance use disorders in the era of big data. | Gelernter J et al. | β | 2021 | β |
| Genetic underpinnings of affective temperaments: a pilot GWAS investigation identifies a new genome-wide significant SNP for anxious temperament in ADGRB3 gene. | Gonda X et al. | β | 2021 | β |
| Genome-wide association study of phenotypes measuring progression from first cocaine or opioid use to dependence reveals novel risk genes. | Sherva R et al. | β | 2021 | β |
| Genome-wide association study of stimulant dependence. | Cox J et al. | β | 2021 | β |
| Identifying risk factors involved in the common versus specific liabilities to substance use: A genetically informed approach. | Iob E et al. | β | 2021 | β |
| Molecular genetics of substance use disorders: An umbrella review. | Lopez-Leon S et al. | β | 2021 | β |
| Multi-environment gene interactions linked to the interplay between polysubstance dependence and suicidality. | Polimanti R 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 |
| A large-scale genome-wide association study meta-analysis of cannabis use disorder. | Johnson EC et al. | β | 2020 | β |
| An update on the role of common genetic variation underlying substance use disorders. | Johnson EC et al. | β | 2020 | β |
| Association between polygenic liability for schizophrenia and substance involvement: A nationwide population-based study in Taiwan. | Wang SH et al. | β | 2020 | β |
| Cannabis and psychosis: revisiting a nineteenth century study of 'Indian Hemp and Insanity' in Colonial British India. | Ayonrinde OA | β | 2020 | β |
| Deconstructing the neurobiology of cannabis use disorder. | Ferland JN et al. | β | 2020 | β |
| Depression level, not pain severity, is associated with smoked medical marijuana dosage among chronic pain patients. | Feingold D et al. | β | 2020 | β |
| Does Cannabis Intake Protect Against Non-alcoholic Fatty Liver Disease? A Two-Sample Mendelian Randomization Study. | Wang X et al. | β | 2020 | β |
| Genome-wide association studies of the self-rating of effects of ethanol (SRE). | Lai D et al. | β | 2020 | β |
| Genome-Wide Association Study of Opioid Cessation. | Cox JW et al. | β | 2020 | β |
| Genome-wide scan identifies opioid overdose risk locus close to MCOLN1. | Cheng Z et al. | β | 2020 | β |
| Heterogeneity and Polygenicity in Psychiatric Disorders: A Genome-Wide Perspective. | Wendt FR et al. | β | 2020 | β |
| Identifying factors associated with opioid cessation in a biracial sample using machine learning. | Cox JW et al. | β | 2020 | β |
| Polygenic Risk Scores for Subtyping of Schizophrenia. | Chen J 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 |
| Prospects for finding the mechanisms of sex differences in addiction with human and model organism genetic analysis. | Datta U 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 |
| The Co-existence of ADHD With Autism in Saudi Children: An Analysis Using Next-Generation DNA Sequencing. | Bogari NM et al. | β | 2020 | β |
| The complement system in schizophrenia: where are we now and what's next? | Woo JJ et al. | β | 2020 | β |
| Aberrant structural-functional coupling in adult cannabis users. | Kim DJ et al. | β | 2019 | β |
| A Contagion Model for Within-Family Transmission of Drug Abuse. | Kendler KS et al. | β | 2019 | β |
| A regulatory variant of CHRM3 is associated with cannabis-induced hallucinations in European Americans. | Cheng Z 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 |
| Cannabis and mental illness: a review. | Lowe DJE 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 |
| Exposure to cannabinoids can lead to persistent cognitive and psychiatric disorders. | Krebs MO 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 associations with suicide attempt severity and genetic overlap with major depression. | Levey DF et al. | β | 2019 | β |
| Genome-wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward-related ventral striatum activity in African- and European-Americans. | Wetherill L et al. | β | 2019 | β |
| Genome-wide association study implicates CHRNA2 in cannabis use disorder. | Demontis D et al. | β | 2019 | β |
| Genomewide Gene-by-Sex Interaction Scans Identify ADGRV1 for Sex Differences in Opioid Dependent African Americans. | Yang BZ 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 |
| Phosphoinositides: Regulators of Nervous System Function in Health and Disease. | Raghu P et al. | β | 2019 | β |
| Polygenic liability for schizophrenia predicts shifting-specific executive function deficits and tobacco use in a moderate drinking community sample. | Miller AP 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 |
| Several clock genes polymorphisms are meaningful risk factors in the development and severity of cannabis addiction. | Saffroy R et al. | β | 2019 | β |
| Adolescent cannabis use, baseline prodromal symptoms and the risk of psychosis. | Mustonen A et al. | β | 2018 | β |
| A genome-wide gene-by-trauma interaction study of alcohol misuse in two independent cohorts identifies PRKG1 as a risk locus. | Polimanti R et al. | β | 2018 | β |
| An ensemble-based likelihood ratio approach for family-based genomic risk prediction. | An H et al. | β | 2018 | β |
| Effects on gene expression and behavior of untagged short tandem repeats: the case of arginine vasopressin receptor 1a (AVPR1a) and externalizing behaviors. | Landefeld CC 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 association study identifies a novel locus for cannabis dependence. | Agrawal A et al. | β | 2018 | β |
| Genome-wide Association Study Identifies a Regulatory Variant of RGMA Associated With Opioid Dependence in European Americans. | Cheng Z et al. | β | 2018 | β |
| Genome-wide association study identifies glutamate ionotropic receptor GRIA4 as a risk gene for comorbid nicotine dependence and major depression. | Zhou H et al. | β | 2018 | β |
| Genome-wide association study of cognitive flexibility assessed by the Wisconsin Card Sorting Test. | Zhang H et al. | β | 2018 | β |
| Genome-wide meta-analysis of copy number variations with alcohol dependence. | Sulovari 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 |
| Mechanisms of cortisol - Substance use development associations: Hypothesis generation through gene enrichment analysis. | Marceau K et al. | β | 2018 | β |
| Psychotic patients who used cannabis frequently before illness onset have higher genetic predisposition to schizophrenia than those who did not. | Aas M 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 |
| Towards diversity in genomics: The emergence of neurogenomics in Africa? | Quansah E et al. | β | 2018 | β |
| Translational studies support a role for serotonin 2B receptor (HTR2B) gene in aggression-related cannabis response. | Montalvo-Ortiz JL et al. | β | 2018 | β |
| US Epidemiology of Cannabis Use and Associated Problems. | Hasin DS | β | 2018 | β |
| Whole genome sequence study of cannabis dependence in two independent cohorts. | Gizer IR et al. | β | 2018 | β |
| A genetic association study of CSMD1 and CSMD2 with cognitive function. | Athanasiu L et al. | β | 2017 | β |
| Assessing causality in associations between cannabis use and schizophrenia risk: a two-sample Mendelian randomization study. | Gage SH et al. | β | 2017 | β |
| Association Between Substance Use Disorder and Polygenic Liability to Schizophrenia. | Hartz SM et al. | β | 2017 | β |
| Can a rapid measure of self-exposure to drugs of abuse provide dimensional information on depression comorbidity? | Butelman ER et al. | β | 2017 | β |
| Cannabinoids and Vanilloids in Schizophrenia: Neurophysiological Evidence and Directions for Basic Research. | Ruggiero RN et al. | β | 2017 | β |
| Cannabis and Depression: A Twin Model Approach to Co-morbidity. | Smolkina M et al. | β | 2017 | β |
| Developmentally Specific Associations Between CNR1 Genotype and Cannabis Use Across Emerging Adulthood. | Ashenhurst JR et al. | β | 2017 | β |
| Genetic Risk Variants Associated With Comorbid Alcohol Dependence and Major Depression. | Zhou H 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 |
| Neurosteroid Levels in Patients With Bipolar Disorder and a History of Cannabis Use Disorders. | Mason BL et al. | β | 2017 | β |
| [On the legalization debate of non-medical cannabis consumption : Position paper of the German Association for Psychiatry, Psychotherapy and Psychosomatics]. | Havemann-Reinecke U et al. | β | 2017 | β |
| Schizophrenia and substance use comorbidity: a genome-wide perspective. | Polimanti R et al. | β | 2017 | β |
| Seeing through the smoke: Human and animal studies of cannabis use and endocannabinoid signalling in corticolimbic networks. | Silveira MM 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 |
| The Interplay Between Risky Sexual Behaviors and Alcohol Dependence: Genome-Wide Association and Neuroimaging Support for LHPP as a Risk Gene. | Polimanti R et al. | β | 2017 | β |
| Alcohol-related genes show an enrichment of associations with a persistent externalizing factor. | Ashenhurst JR et al. | β | 2016 | β |
| Meta-Analyses of Genome-Wide Association Data Hold New Promise for Addiction Genetics. | Agrawal A et al. | β | 2016 | β |
| The Neurobiology of Cannabis Use Disorders: A Call for Evidence. | Lorenzetti V et al. | β | 2016 | β |