Skip to main content Accessibility help

Overlap of heritable influences between cannabis use disorder, frequency of use and opportunity to use cannabis: trivariate twin modelling and implications for genetic design

  • Lindsey A. Hines (a1) (a2), Katherine I. Morley (a1) (a3), Fruhling Rijsdijk (a4), John Strang (a1), Arpana Agrawal (a5), Elliot C. Nelson (a5), Dixie Statham (a6), Nicholas G. Martin (a7) and Michael T. Lynskey (a1)...



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.


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.


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.


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.


Corresponding author

Author for correspondence: Lindsey A Hines, E-mail:


Hide All
Agrawal, A and Lynskey, MT (2006) The genetic epidemiology of cannabis use, abuse and dependence. Addiction 101, 801812.
Agrawal, A, Neale, MC, Jacobson, KC, Prescott, CA and Kendler, KS (2005) Illicit drug use and abuse/dependence: modeling of two-stage variables using the CCC approach. Addictive Behaviors 30, 10431048.
American Psychiatric Association (2000) Diagnostic and Statistical Manual of Mental Disorders: DSM-IV-TR, 4th edn., text revision. Washington DC: American Psychiatric Association.
American Psychiatric Association, DSM-5 Task Force (2013) Diagnostic and Statistical Manual of Mental Disorders: DSM-5. Arlington, VA: American Psychiatric Publishing.
Anthony, JC (2006) The epidemiology of Cannabis dependence. In Roffman, RA and Stephens, RS (eds). Cannabis Dependence: Its Nature, Consequences, and Treatment. New York: Cambridge University Press, pp. 58105.
Belsky, DW, Moffitt, TE, Baker, TB, Biddle, AK, Evans, JP, Harrington, H, et al. (2013) Polygenic risk and the developmental progression to heavy, persistent smoking and nicotine dependence: evidence from a 4-decade longitudinal study. JAMA Psychiatry 70, 534542.
Benyamina, A, Bonhomme-Faivre, L, Picard, V, Sabbagh, A, Richard, D, Blecha, L et al. (2009) Association between ABCB1 C3435T polymorphism and increased risk of cannabis dependence. Progress in Neuro-Psychopharmacology and Biological Psychiatry 33, 12701274.
Boker, SM, Neale, MC, Maes, HH, Wilde, MJ, Spiegel, M, Brick, TR et al. (2011) Openmx: an open source extended structural equation modeling framework. Psychometrika 76, 306317.
Broms, U, Silventoinen, K, Madden, PAF, Heath, AC and Kaprio, J (2006) Genetic architecture of smoking behavior: a study of Finnish adult twins. Twin Research and Human Genetics 9, 6472.
Bucholz, KK, Cadoret, R, Cloninger, CR, Dinwiddie, SH, Hesselbrock, VM, Nurnberger, J et al. (1994) A new, semi-structured psychiatric interview for use in genetic linkage studies: a report on the reliability of the SSAGA. Journal of Studies on Alcohol and Drugs 55, 149.
Cederlof, R, Friberg, L, Jonsson, E and Kaij, L (1961) Studies on similarity diagnosis in twins with the aid of mailed questionnaires. Acta Genetica Et Statistica Medica 11, 338362.
Chen, K, Kandel, DB and Davies, M (1997) Relationships between frequency and quantity of marijuana use and last year proxy dependence among adolescents and adults in the United States. Drug and Alcohol Dependence 46, 5367.
Darke, S (1998) Self-report among injecting drug users: a review. Drug and Alcohol Dependence 51, 253263.
Degenhardt, L, Whiteford, H and Hall, WD (2014) The global burden of disease projects: what have we learned about illicit drug use and dependence and their contribution to the global burden of disease? Drug and Alcohol Review 33, 412.
Dick, DM, Cho, SB, Latendresse, SJ, Aliev, F, Nurnberger, JI, Edenberg, HJ et al. (2014) Genetic influences on alcohol use across stages of development: GABRA2 and longitudinal trajectories of drunkenness from adolescence to young adulthood. Addiction Biology 19, 10551064.
Ensminger, ME, Juon, H-S and Green, KM (2007) Consistency between adolescent reports and adult retrospective reports of adolescent marijuana use: explanations of inconsistent reporting among an African American population. Drug & Alcohol Dependence 89, 1323.
Fowler, T, Lifford, K, Shelton, K, Rice, F, Thapar, A, Neale, MC et al. (2007) Exploring the relationship between genetic and environmental influences on initiation and progression of substance use. Addiction 102, 413422.
Gillespie, NA, Neale, MC, Jacobson, K and Kendler, KS (2009a) Modeling the genetic and environmental association between peer group deviance and cannabis use in male twins. Addiction 104, 420429.
Gillespie, NA, Neale, MC and Kendler, KS (2009b) Pathways to cannabis abuse: a multi-stage model from cannabis availability, cannabis initiation and progression to abuse. Addiction 104, 430438.
Hartman, CA, Hopfer, CJ, Haberstick, B, Rhee, SH, Crowley, TJ, Corley, RP et al. (2009) The association between cannabinoid receptor 1 gene (CNR1) and cannabis dependence symptoms in adolescents and young adults. Drug and Alcohol Dependence 104, 1116.
Hasin, DS, Saha, TD, Kerridge, BT, Goldstein, RB, Chou, SP, Zhang, H et al. (2015) Prevalence of marijuana use disorders in the United States between 2001–2002 and 2012–2013. JAMA Psychiatry 72, 12351242.
Heath, AC, Bucholz, KK, Madden, PA, Dinwiddie, SH, Slutske, WS, Bierut, LJ et al. (1997) Genetic and environmental contributions to alcohol dependence risk in a national twin sample: consistency of findings in women and men. Psychological Medicine 27, 13811396.
Heath, AC, Martin, NG, Lynskey, MT, Todorov, AA and Madden, PAF (2002) Estimating two-stage models for genetic influences on alcohol, tobacco or drug use initiation and dependence vulnerability in twin and family data. Twin Research: The Official Journal of the International Society for Twin Studies 5, 113124.
Hines, LA, Morley, KI, Mackie, C and Lynskey, M (2015a) Genetic and environmental interplay in adolescent substance use disorders. Current Addiction Reports 2, 122129.
Hines, LA, Morley, KI, Strang, J, Agrawal, A, Nelson, EC, Statham, D et al. (2015b) The association between speed of transition from initiation to subsequent use of cannabis and later problematic cannabis use, abuse and dependence. Addiction 110, 13111320.
Hines, LA, Morley, KI, Strang, J, Agrawal, A, Nelson, EC, Statham, D et al. (2016) Onset of opportunity to use cannabis and progression from opportunity to dependence: are influences consistent across transitions? Drug and Alcohol Dependence 160, 5764.
Hopfer, C (2014) Implications of marijuana legalization for adolescent substance use. Substance Abuse 35, 331335.
Johnson, TP and Mott, JA (2001) The reliability of self-reported age of onset of tobacco, alcohol and illicit drug use. Addiction (Abingdon, England) 96, 11871198.
Kasriel, J and Eaves, L (1976) The zygosity of twins: further evidence on the agreement between diagnosis by blood groups and written questionnaires. Journal of Biosocial Science 8, 263266.
Kendler, KS and Baker, JH (2007) Genetic influences on measures of the environment: a systematic review. Psychological Medicine 37, 615626.
Kendler, KS, Jacobson, KC, Prescott, CA and Neale, MC (2003) Specificity of genetic and environmental risk factors for use and abuse/dependence of cannabis, cocaine, hallucinogens, sedatives, stimulants, and opiates in male twins. American Journal of Psychiatry 160, 687695.
Kendler, KS, Neale, MC, Kessler, RC, Heath, AC and Eaves, LJ (1993) A test of the equal-environment assumption in twin studies of psychiatric illness. Behavior Genetics 23, 2127.
Kendler, KS, Neale, MC, Sullivan, P, Corey, LA, Gardner, CO and Prescott, CA (1999) A population-based twin study in women of smoking initiation and nicotine dependence. Psychological Medicine 29, 299308.
Kendler, KS, Pedersen, NL, Farahmand, BY and Persson, PG (1996) The treated incidence of psychotic and affective illness in twins compared with population expectation: a study in the Swedish Twin and Psychiatric Registries. Psychological Medicine 26, 11351144.
Laucht, M, Becker, K, Blomeyer, D and Schmidt, MH (2007) Novelty seeking involved in mediating the association between the dopamine D4 receptor gene exon III polymorphism and heavy drinking in male adolescents: results from a high-risk community sample. Biological Psychiatry 61, 8792.
Lynskey, MT and Agrawal, A (2009) Genetically informative studies of ‘environment’. Addiction 104, 439440.
Lynskey, MT, Agrawal, A, Henders, A, Nelson, EC, Madden, PAF and Martin, NG (2012) An Australian twin study of cannabis and other illicit drug use and misuse, and other psychopathology. Twin Research and Human Genetics 15, 631641.
Lynskey, MT, Heath, AC, Nelson, EC, Bucholz, KK, Madden, PAF, Slutske, WS et al. (2002) Genetic and environmental contributions to cannabis dependence in a national young adult twin sample. Psychological Medicine 32, 195207.
Malmberg, M, Overbeek, G, Monshouwer, K, Lammers, J, Vollebergh, WAM and Engels, RCME (2010) Substance use risk profiles and associations with early substance use in adolescence. Journal of Behavioral Medicine 33, 474485.
Morley, KI, Lynskey, MT, Madden, PAF, Treloar, SA, Heath, AC and Martin, NG (2007) Exploring the inter-relationship of smoking age-at-onset, cigarette consumption and smoking persistence: genes or environment? Psychological Medicine 37, 13571367.
Neale, M and Cardon, L (1992) Methodology for Genetic Studies of Twins and Families. Dordrecht, The Netherlands: Kluwer Academic Publications.
Neale, MC, Røysamb, E and Jacobson, K (2006) Multivariate genetic analysis of sex limitation and G × E interaction. Twin Research and Human Genetics: The Official Journal of the International Society for Twin Studies 9, 481489.
Nelson, EC, Lynskey, MT, Heath, AC, Wray, N, Agrawal, A, Shand, FL et al. (2013) ANKK1, TTC12, and NCAM1 polymorphisms and heroin dependence: importance of considering drug exposure. JAMA Psychiatry 70, 325333.
Neumark, Y, Lopez-Quintero, C and Bobashev, G (2012) Drug use opportunities as opportunities for drug use prevention: Bogota, Colombia a case in point. Drug and Alcohol Dependence 122, 127134.
Pagan, JL, Rose, RJ, Viken, RJ, Pulkkinen, L, Kaprio, J and Dick, DM (2006) Genetic and environmental influences on stages of alcohol use across adolescence and into young adulthood. Behavior Genetics 36, 483497.
Parra, GR, O'Neill, SE and Sher, KJ (2003) Reliability of self-reported age of substance involvement onset. Psychology of Addictive Behaviors 17, 211218.
Plomin, R, DeFries, JC, Knopik, VS and Neiderheiser, J (2013) Behavioral Genetics, 6th edn. New York: Worth Publishers.
R Core Team (2013) R: A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing.
Reboussin, BA, Ialongo, NS and Green, KM (2015) Influences of behavior and academic problems at school entry on marijuana use transitions during adolescence in an African American sample. Addictive Behaviors 41, 5157.
Reinartz, WJ, Haenlein, M and Henseler, J (2009) An Empirical Comparison of the Efficacy of Covariance-Based and Variance-Based SEM. Rochester, NY: Social Science Research Network. SSRN Scholarly Paper 27 August no. ID 1462666.
Sarna, S, Kaprio, J, Sistonen, P and Koskenvuo, M (1978) Diagnosis of twin zygosity by mailed questionnaire. Human Heredity 28, 241254.
Sartor, CE, Lynskey, MT, Bucholz, KK, Madden, PAF, Martin, NG and Heath, AC (2009) Timing of first alcohol use and alcohol dependence: evidence of common genetic influences. Addiction 104, 15121518.
Sartor, CE, Lynskey, MT, Heath, AC, Jacob, T and True, W (2007) The role of childhood risk factors in initiation of alcohol use and progression to alcohol dependence. Addiction 102, 216225.
Shi, Y, Lenzi, M and An, R (2015) Cannabis liberalization and adolescent cannabis use: a cross-national study in 38 countries. PLoS ONE 10, e0143562.
Shillington, AM, Cottler, LB, Mager, DE and Compton, WM III (1995) Self-report stability for substance use over 10 years: data from the St. Louis epidemiologic catchment study. Drug and Alcohol Dependence 40, 103109.
Storr, CL, Wagner, FA, Chen, CY and Anthony, JC (2011) Childhood predictors of first chance to use and use of cannabis by young adulthood. Drug and Alcohol Dependence 117, 715.
Verweij, KJH, Zietsch, BP, Lynskey, MT, Medland, SE, Neale, MC, Martin, NG et al. (2010) Genetic and environmental influences on cannabis use initiation and problematic use: a meta-analysis of twin studies. Addiction 105, 417430.
Wagner, FA and Anthony, JC (2002) Into the world of illegal drug use: exposure opportunity and other mechanisms linking the use of alcohol, tobacco, marijuana, and cocaine. Journal of Epidemiology 155, 918925.
Ystrom, E, Reichborn-Kjennerud, T, Neale, MC and Kendler, KS (2014) Genetic and environmental risk factors for illicit substance use and use disorders: joint analysis of self and co-twin ratings. Behavior Genetics 44, 113.


Related content

Powered by UNSILO
Type Description Title
Supplementary materials

Hines et al. supplementary material 1
Hines et al. supplementary material

 Word (13 KB)
13 KB

Overlap of heritable influences between cannabis use disorder, frequency of use and opportunity to use cannabis: trivariate twin modelling and implications for genetic design

  • Lindsey A. Hines (a1) (a2), Katherine I. Morley (a1) (a3), Fruhling Rijsdijk (a4), John Strang (a1), Arpana Agrawal (a5), Elliot C. Nelson (a5), Dixie Statham (a6), Nicholas G. Martin (a7) and Michael T. Lynskey (a1)...


Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed.