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.
| Original language | English |
|---|---|
| Pages (from-to) | 2073-2086 |
| Number of pages | 14 |
| Journal | Addiction |
| Volume | 113 |
| Issue number | 11 |
| Early online date | 13 Jul 2018 |
| DOIs | |
| Publication status | Published - Nov 2018 |
Funding
Saguenay Youth Study: The Canadian Institutes of Health Research and the Heart and Stroke Foundation of Canada fund the SYS (TP, ZP). T.P. is the Tanenbaum Chair in Population Neuroscience (University of Toronto) and the Dr John and Consuela Phelan Scholar (Child Mind Institute). HUVH: We are grateful to patients and controls who kindly participated in this research. Financial support was received from ‘Instituto de Salud Carlos III-FIS’ (PI12/01139, PI14/01700, PI15/01789, PI16/01505), and co-financed by the European Regional Development Fund (ERDF), Agència de Gestió d’Ajuts Universitaris i de Recerca-AGAUR, Generalitat de Catalunya (2014SGR1357), Departament de Salut, Government of Catalonia, Spain, the European College of Neuropsychopharmacology (ECNP network: ‘ADHD across the lifespan’), and a NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation. This project also received funding from the European Community’s Seventh Framework Programme (under grant agreement number 602805, Aggressotype) and from the European Community’s H2020 Programme (under grant agreement number 667302, CoCA). M.R. is a recipient of a Miguel de Servet contract from the Instituto de Salud Carlos III, Ministerio de Economía, Industria y Competitividad, Spain (CP09/00119 and CPII15/00023). I.G.-M. is a recipient of a contract from the 7th Framework Programme for Research, Technological Development and Demonstration, European Commission (AGGRESSOTYPE_FP7HEALTH2013/602805). C.S.-M. is a recipient of a Sara Borrell contract from the Spanish Ministerio de Economía y Competitividad (CD15/00199) and a mobility grant from the Spanish Ministerio de Economía y Competitividad, Instituto de Salud Carlos III (MV16/00039). Yale Penn: Genotyping services for a part of our GWAS study were provided by the Center for Inherited Disease Research (CIDR) and Yale University (Center for Genome Analysis). CIDR is funded fully through a federal contract from the National Institutes of Health to The Johns Hopkins University (contract number N01-HG-65403). This study was supported by National Institutes of Health grants RC2 DA028909, R01 DA12690, R01 DA12849, R01 DA18432, R01 AA11330, R01 AA017535 and the VA Connecticut and Philadelphia VA MIRECCs. BLTS: The BLTS was supported by grants from the United States National Institute on Drug Abuse (R00DA023549) awarded to N.A.G., by the Australian Research Council to M.W. (grants DP0343921, DP0664638 and DP1093900) and by Australian National Health and Medical Research Council Australia Fellowships awarded to I.A.B (no. 464914) and G.W.M. (no. 619667). We acknowledge and thank the following project staff: Anjali Henders, Leanne Wallace and Lisa Bowdler for the laboratory processing, genotyping and QC; Soad Hancock as Project Coordinator; Lenore Sullivan as Research Editor; our research interviewers Pieta-Marie Shertock and Jill Wood; and David Smyth for IT. We also thank the twins and their siblings for their willing cooperation. J.M.V., C.C.M. and H.M. are supported by the European Research Council (Beyond the Genetics of Addiction ERC-284167, Principal Investigator J.M.V.). E.M.D. is supported by the Foundation Volksbond Rotterdam. K.J.H.V. is supported by a 2014 NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation. N.A.G. is supported by US National Institutes of Health, National Institute on Drug Abuse R00DA023549. C.C.M. and M.C.N. are supported by NIDA grant DA-018673. R.W. is supported by NIH U01 MH094432 and NSF BCS-1229450. Statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara and supported financially by the Netherlands Organization for Scientific Research (NWO 480–05-003 Principal Investigator D. Posthuma), along with a supplement from the Dutch Brain Foundation and the VU University Amsterdam. ALSPAC: We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The UK Medical Research Council and the Wellcome Trust (grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. GWAS data was generated by Sample Logistics and Genotyping Facilities at the Wellcome Trust Sanger Institute and LabCorp (Laboratory Corportation of America) using support from 23andMe. J.J.W. is supported by a Postdoctoral Research Fellowship from the Oak Foundation. J.J.W. and M.R.M. are members of the MRC Integrative Epidemiology Unit at the University of Bristol, funded by the UK Medical Research Council (MC_UU_12013/6) and the University of Bristol. M.H. is a member of NIHR School of Public Health Research and NIHR Health Protection Research Unit in Evaluation. J.J.W. and M.R.M. are members of UK Centre for Tobacco and Alcohol Studies, and M.H. is a member of DeCIPHER (Development and Evaluation of Complex Interventions for Public Health Improvement)—which are both UKCRC Public Health Research: Centres of Excellence. Funding from British Heart Foundation, Cancer Research UK, Economic and Social Research Council, Medical Research Council and the National Institute for Health Research, under the auspices of the UKClinical Research Collaboration, is gratefully acknowledged. TRAILS: TRAILS (TRacking Adolescents’ Individual Lives Survey) is a collaborative project involving various departments of the University Medical Center and University of Groningen, the University of Utrecht, the Radboud Medical Center Nijmegen and the Parnassia Bavo group, all in the Netherlands. TRAILS has been supported financially by grants from the Netherlands Organization for Scientific Research NWO (Medical Research Council program grant GB-MW 940–38-011; ZonMW Brainpower grant 100–001-004; ZonMw Risk Behavior and Dependence grant 60–60 600– 97-118; ZonMw Culture and Health grant 261–98-710; Social Sciences Council medium-sized investment grants GB-MaGW 480–01-006 and GB-MaGW 480–07-001; Social Sciences Council project grants GB-MaGW 452–04-314 and GB-MaGW 452–06-004; NWO large-sized investment grant 175.010.2003.005; NWO Longitudinal Survey and Panel Funding 481–08-013 and 481–11-001); the Dutch Ministry of Justice (WODC), the European Science Foundation (EuroSTRESS project FP-006), Biobanking and Biomolecular Resources Research Infrastructure BBMRI-NL (CP 32), the participating universities and Accare Center for Child and Adolescent Psychiatry. We are grateful to all adolescents, their parents and teachers who participated in this research and to everyone who worked on this project and made it possible. Statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster.org), which is supported financially by the Netherlands Scientific Organization (NWO 480–05-003), along with a supplement from the Dutch Brain Foundation. CADD: The Center on Antisocial Drug Dependence (CADD) data reported here were funded by grants from the National Institute on Drug Abuse (P60 DA011015, R01 DA012845, R01 DA021913, R01 DA021905 and R01 DA035804). Utrecht: We are grateful to Chris Schubart and Willemijn van Gastel and numerous students for their work in the study. Foremost, we like to thank our study participants. This study was supported financially by a grant of the NWO (Netherlands Organization for Scientific Research), grant no. 91207039. The study was performed at the University Medical Centre Utrecht, the Netherlands. FinnTwin: We warmly thank the participating twin pairs and their family members for their contribution. We would like to express our appreciation to the skilled study interviewers A.-M. Iivonen, K. Karhu, H.-M. Kuha, U. Kulmala-Gråhn, M. Mantere, K. Saanakorpi, M. Saarinen, R. Sipilä, L. Viljanen and E. Voipio. Anja Häppölä and Kauko Heikkilä are acknowledged for their valuable contribution in recruitment, data collection and data management. Phenotyping and genotyping of the Finnish twin cohorts was supported by the Academy of Finland Center of Excellence in Complex Disease Genetics (grants 213 506, 129 680), the Academy of Finland (grants 100 499, 205 585, 118 555, 141 054, 265 240, 263 278 and 264 146 to J.K.), National Institute of Alcohol Abuse and Alcoholism (grants AA-12502, AA-00145, and AA-09203 to R.J.R. and AA15416 and K02AA018755 to D.M. Dick), Sigrid Juselius Foundation (to J.K), and the Welcome Trust Sanger Institute, UK. Antti-Pekka Sarin and Samuli Ripatti are acknowledged for genotype data quality controls and imputation. GWAS analyses were run at the ELIXIR Finland node hosted at CSC–IT Center for Science for ICT resources. RADAR: We thank all adolescents and their families and friends for their participation. Moreover, we want to thank the various assistants who helped in recruiting participants as well as collecting and cleaning the data. The research was funded partly by the Netherlands Organization for Scientific Research (Brain and Cognition, 056–21-010). RADAR has been supported financially by main grants from the Netherlands Organization for Scientific Research (GB-MAGW 480–03-005) and Stichting Achmea Slachtoffer en Samenleving (SASS), a grant from the Netherlands Organisation for Scientific Research to the Consortium Individual Development (CID; 024.001.003) and various other grants from the Netherlands Organisation for Scientific Research, the VU University Amsterdam and Utrecht University. A.J.H. is supported by the Netherlands Organization for Health Research and Development, ZonMW 31 160 212. QIMR: Supported by National Institutes of Health Grants AA07535, AA0758O, AA07728, AA10249, AA13320, AA13321, AA14041, AA11998, AA17688, DA012854, DA018267, DA018660, DA23668 and DA019951; by Grants from the Australian National Health and Medical Research Council (241 944, 339 462, 389 927, 389 875, 389 891, 389 892, 389 938, 442 915, 442 981, 496 739, 552 485, 552 498 and 628 911); by Grants from the Australian Research Council (A7960034, A79906588, A79801419, DP0770096, DP0212016 and DP0343921); and by the 5th Framework Programme (FP-5) GenomEUtwin Project (QLG2-CT-2002-01254). This research was further supported by the Centre for Research Excellence on Suicide Prevention (CRESP–Australia). We thank Anjali Henders, Richard Parker, Soad Hancock, Judith Moir, Sally Rodda, Pieta-Maree Shertock, Heather Park, Jill Wood, Pam Barton, Fran Husband, Adele Somerville, Ann Eldridge, Marlene Grace, Kerrie McAloney, Lisa Bowdler, Alexandre Todorov, Steven Crooks, David Smyth, Harry Beeby and Daniel Park. Lastl, we thank the twins and their families for their participation. NTR and NTR2: We thank the Netherlands Twin Register participants whose data we analysed in this study. This work was supported by grants from the Netherlands Organization for Scientific Research (ZonMW Addiction 31 160 008; ZonMW 940–37-024; NWO/SPI 56–464-14 192; NWO-400-05-717; NWO-MW 904–61-19; NWO-MagW 480–04-004; NWO-Veni 016–115-035), the European Research Council [Beyond the Genetics of Addiction ERC-284167; Genetics of Mental Illness: ERC-230374], the Centre for Medical Systems Biology (NWO Genomics) and Netherlands Bioinformatics Center/BioAssist/RK/2008.024. We acknowledge the EMGO+ Institute for Health and Care Research, the Neuroscience Campus Amsterdam, BBMRI–NL (184.021.007: Biobanking and Biomolecular Resources Research Infrastructure), the Avera Institute, Sioux Falls, South Dakota (USA) for support. Genotyping was funded in part by grants from the National Institutes of Health (4R37DA018673–06, RC2 MH089951), Rutgers University Cell and DNA Repository cooperative agreement (National Institute of Mental Health U24 MH068457–06), and the National Institutes of Health (NIH R01 HD042157-01A1, MH081802, Grand Opportunity grants 1RC2 MH089951 and 1RC2 MH089995) and the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health. The statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster.org) which is supported by the Netherlands Scientific Organization (NWO 480–05-003), the Dutch Brain Foundation and the Department of Psychology and Education of the VU University Amsterdam. J.M.V., C.C.M. and H.M. are supported by the European Research Council (Beyond the Genetics of Addiction ERC-284167, Principal Investigator J.M.V.). E.M.D. is supported by the Foundation Volksbond Rotterdam. K.J.H.V. is supported by a 2014 NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation. N.A.G. is supported by US National Institutes of Health, National Institute on Drug Abuse R00DA023549. C.C.M. and M.C.N. are supported by NIDA grant DA-018673. R.W. is supported by NIH U01 MH094432 and NSF BCS-1229450. Statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara and supported financially by the Netherlands Organization for Scientific Research (NWO 480?05-003 Principal Investigator D. Posthuma), along with a supplement from the Dutch Brain Foundation and the VU University Amsterdam. ALSPAC: We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The UK Medical Research Council and the Wellcome Trust (grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. GWAS data was generated by Sample Logistics and Genotyping Facilities at the Wellcome Trust Sanger Institute and LabCorp (Laboratory Corportation of America) using support from 23andMe. J.J.W. is supported by a Postdoctoral Research Fellowship from the Oak Foundation. J.J.W. and M.R.M. are members of the MRC Integrative Epidemiology Unit at the University of Bristol, funded by the UK Medical Research Council (MC_UU_12013/6) and the University of Bristol. M.H. is a member of NIHR School of Public Health Research and NIHR Health Protection Research Unit in Evaluation. J.J.W. and M.R.M. are members of UK Centre for Tobacco and Alcohol Studies, and M.H. is a member of DeCIPHER (Development and Evaluation of Complex Interventions for Public Health Improvement)?which are both UKCRC Public Health Research: Centres of Excellence.
| Funders | Funder number |
|---|---|
| 5th Framework Programme | FP-5, QLG2-CT-2002-01254 |
| 7th Framework Programme for Research, Technological Development and Demonstration | |
| Australian National Health and Medical Research Council | 464914, 552 485, 619667, 389 927, 389 938, 552 498, 628 911, 442 981, 389 875, 389 892, 389 891, 241 944, 339 462, 496 739, 442 915 |
| Biobanking and Biomolecular Resources Research Infrastructure BBMRI-NL | CP 32 |
| CRESP | |
| Centre for Research Excellence on Suicide Prevention | |
| Centre for Tobacco and Alcohol Studies | |
| Departament de Salut, Government of Catalonia, Spain | |
| Dutch Brain Foundation | |
| Dutch Ministry of Justice | |
| European Community’s H2020 Programme | 667302 |
| Foundation Volksbond Rotterdam | |
| LabCorp | |
| Netherlands Bioinformatics Center/BioAssist/RK | |
| Netherlands Organization for Health Research and Development | |
| Netherlands Organization for Scientific Research | NWO-MagW 480–04-004, 91207039, NWO/SPI 56–464-14 192, NWO-Veni 016–115-035, ZonMW 940–37-024, NWO 480–05-003, 056–21-010, GB-MAGW 480–03-005, NWO-400-05-717, NWO-MW 904–61-19 |
| Netherlands Organization for Scientific Research NWO | |
| Netherlands Scientific Organization | 480–05-003 |
| Sigrid Juselius Foundation | |
| Social Sciences Council | GB-MaGW 480–07-001, GB-MaGW 452–06-004, GB-MaGW 452–04-314, GB-MaGW 480–01-006 |
| Stichting Achmea Slachtoffer en Samenleving | |
| UK Medical Research Council | |
| VA Connecticut | |
| VU University Amsterdam and Utrecht University | |
| Welcome Trust Sanger Institute | |
| Wellcome Trust Sanger Institute | |
| ZonMw Culture and Health | 261–98-710 |
| National Science Foundation | BCS-1229450 |
| National Institutes of Health | 1RC2 MH089995, AA14041, DA019951, DA018267, AA13320, RC2 MH089951, AA07728, DA018660, AA07535, R01 HD042157-01A1, AA10249, AA11998, DA23668, DA012854, U01 MH094432, AA13321, AA0758O, AA17688, MH081802 |
| National Institute of Mental Health | U24 MH068457–06 |
| National Institute on Drug Abuse | R01 DA021905, R00DA023549, DA-018673, P60 DA011015, R01 DA021913, R01 DA012845, R01DA035804 |
| National Institute on Alcohol Abuse and Alcoholism | AA-00145, AA-09203, K02AA018755, AA-12502, AA15416 |
| Brain and Behavior Research Foundation | |
| Oak Foundation | |
| Heart and Stroke Foundation of Canada | |
| Johns Hopkins University | R01 DA12690, R01 DA12849, R01 AA017535, R01 DA18432, RC2 DA028909, N01-HG-65403, R01 AA11330 |
| National Alliance for Research on Schizophrenia and Depression | |
| Wellcome Trust | 102215/2/13/2 |
| Chiropractic and Osteopathic College of Australasia | |
| United Kingdom Clinical Research Collaboration | |
| Medical Research Council | GB-MW 940–38-011, MC_UU_12013/6 |
| Economic and Social Research Council | |
| National Institute for Health Research | |
| British Heart Foundation | |
| Cancer Research UK | |
| European Commission | AGGRESSOTYPE_FP7HEALTH2013/602805 |
| European Research Council | ERC-284167, ERC-230374 |
| European Science Foundation | FP-006 |
| University of Bristol | |
| Australian Research Council | A7960034, DP0212016, DP1093900, DP0664638, A79801419, DP0343921, A79906588, DP0770096 |
| ZonMw | 60–60 600– 97-118, 31 160 212, 100–001-004 |
| Vrije Universiteit Amsterdam | |
| Academy of Finland | 129 680, 141 054, 205 585, 100 499, 265 240, 263 278, 264 146, 213 506, 118 555 |
| Generalitat de Catalunya | 2014SGR1357 |
| Agència de Gestió d'Ajuts Universitaris i de Recerca | |
| Nederlandse Organisatie voor Wetenschappelijk Onderzoek | 024.001.003, 175.010.2003.005, 481–11-001, 481–08-013 |
| Ministerio de Economía y Competitividad | CD15/00199 |
| Instituto de Salud Carlos III | PI14/01700, PI12/01139, MV16/00039, PI16/01505, PI15/01789 |
| Seventh Framework Programme | 602805 |
| Wetenschappelijk Onderzoek- en Documentatiecentrum | |
| European College of Neuropsychopharmacology | |
| European Regional Development Fund | |
| National Institute of Development Administration | |
| Mauritius Research Council | |
| Centre for Medical Systems Biology |
Keywords
- Age at first use
- ATP2C2
- cannabis initiation
- genome-wide association
- heritability
- substance use
Cohort Studies
- Netherlands Twin Register (NTR)
