{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T22:50:37Z","timestamp":1790895037074,"version":"4.1.0"},"reference-count":76,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2018,8,19]],"date-time":"2018-08-19T00:00:00Z","timestamp":1534636800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000874","name":"Brain and Behavior Research Foundation","doi-asserted-by":"publisher","award":["NARSAD Young Investigator Grant"],"award-info":[{"award-number":["NARSAD Young Investigator Grant"]}],"id":[{"id":"10.13039\/100000874","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010663","name":"H2020 European Research Council","doi-asserted-by":"publisher","award":["ERC\u2010284167"],"award-info":[{"award-number":["ERC\u2010284167"]}],"id":[{"id":"10.13039\/100010663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NSF BCS\u20101229450"],"award-info":[{"award-number":["NSF BCS\u20101229450"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NIH U01 MH094432"],"award-info":[{"award-number":["NIH U01 MH094432"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003246","name":"Nederlandse Organisatie voor Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["NWO 480\u201005\u2010003"],"award-info":[{"award-number":["NWO 480\u201005\u2010003"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000026","name":"National Institute on Drug Abuse","doi-asserted-by":"publisher","award":["DA\u2010018673"],"award-info":[{"award-number":["DA\u2010018673"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Addiction"],"published-print":{"date-parts":[[2018,11]]},"abstract":"Abstract<\/jats:title>Background and aims<\/jats:title>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\u2010substance use and dependence. This study estimated the heritability of age at first cannabis use and identified associations with genetic variants.<\/jats:p><\/jats:sec>Methods<\/jats:title>A twin\u2010based heritability analysis using 8055 twins from three cohorts was performed. We then carried out a genome\u2010wide association meta\u2010analysis of age at first cannabis use in a discovery sample of 24\u2009953 individuals from nine European, North American and Australian cohorts, and a replication sample of 3735 individuals.<\/jats:p><\/jats:sec>Results<\/jats:title>The twin\u2010based heritability for age at first cannabis use was 38% [95% confidence interval (CI)\u00a0=\u00a019\u201360%]. Shared and unique environmental factors explained 39% (95% CI\u00a0=\u00a020\u201356%) and 22% (95% CI\u00a0=\u00a016\u201329%). The genome\u2010wide association meta\u2010analysis identified five single nucleotide polymorphisms (SNPs) on chromosome 16 within the calcium\u2010transporting ATPase gene (ATP2C2)<\/jats:italic> at P<\/jats:italic>\u00a0<\u00a05E\u201008. All five SNPs are in high linkage disequilibrium (LD) (r<\/jats:italic>2<\/jats:sup>\u00a0>\u00a00.8), with the strongest association at the intronic variant rs1574587 (P<\/jats:italic>\u00a0=\u00a04.09E\u201009). Gene\u2010based tests of association identified the ATP2C2<\/jats:italic> gene on 16q24.1 (P<\/jats:italic>\u00a0=\u00a01.33e\u201006). Although the five SNPs and ATP2C2<\/jats:italic> did not replicate, ATP2C2<\/jats:italic> has been associated with cocaine dependence in a previous study. ATP2B2<\/jats:italic>, which is a member of the same calcium signalling pathway, has been associated previously with opioid dependence. SNP\u2010based heritability for age at first cannabis use was non\u2010significant.<\/jats:p><\/jats:sec>Conclusion<\/jats:title>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<\/jats:italic> is consistent with the role of calcium signalling mechanisms in substance use disorders.<\/jats:p><\/jats:sec>","DOI":"10.1111\/add.14368","type":"journal-article","created":{"date-parts":[[2018,7,13]],"date-time":"2018-07-13T09:04:21Z","timestamp":1531472661000},"page":"2073-2086","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Genome\u2010wide association meta\u2010analysis of age at first cannabis use"],"prefix":"10.1111","volume":"113","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7140-8167","authenticated-orcid":false,"given":"Camelia C.","family":"Minic\u0103","sequence":"first","affiliation":[{"name":"Department of Biological Psychology\/Netherlands Twin Register VU University Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9868-7821","authenticated-orcid":false,"given":"Karin J. H.","family":"Verweij","sequence":"additional","affiliation":[{"name":"Department of Biological Psychology\/Netherlands Twin Register VU University Amsterdam the Netherlands"},{"name":"Behavioral Science Institute Radboud University Nijmegen the Netherlands"},{"name":"Amsterdam UMC, University of Amsterdam Department of Psychiatry Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8450-3518","authenticated-orcid":false,"given":"Peter J.","family":"van der Most","sequence":"additional","affiliation":[{"name":"Department of Epidemiology University of Groningen, University Medical Center Groningen Groningen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamdi","family":"Mbarek","sequence":"additional","affiliation":[{"name":"Department of Biological Psychology\/Netherlands Twin Register VU University Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manon","family":"Bernard","sequence":"additional","affiliation":[{"name":"Hospital for Sick Children Research Institute Toronto Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristel R.","family":"van Eijk","sequence":"additional","affiliation":[{"name":"Department of Neurology, Brain Center Rudolf Magnus University Medical Center Utrecht Utrecht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Penelope A.","family":"Lind","sequence":"additional","affiliation":[{"name":"Psychiatric Genetics QIMR Berghofer Medical Research Institute Brisbane Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng Zhen","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute for Behavioral Genetics, Department of Psychology and Neuroscience University of Colorado Boulder Boulder CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominique F.","family":"Maciejewski","sequence":"additional","affiliation":[{"name":"Department of Clinical Developmental Psychology Vrije Universiteit Amsterdam Amsterdam the Netherlands"},{"name":"GGZ inGeest and Department of Psychiatry, Amsterdam Public Health Research Institute VU University Medical Center Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teemu","family":"Palviainen","sequence":"additional","affiliation":[{"name":"Institute for Molecular Medicine Finland (FIMM) University of Helsinki Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"S\u00e1nchez\u2010Mora","sequence":"additional","affiliation":[{"name":"Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d'Hebron Research Institute (VHIR) Universitat Aut\u00f2noma de Barcelona Barcelona Spain"},{"name":"Department of Psychiatry Hospital Universitari Vall d'Hebron Barcelona Spain"},{"name":"Biomedical Network Research Centre on Mental Health (CIBERSAM) Instituto de Salud Carlos III Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Sherva","sequence":"additional","affiliation":[{"name":"Biomedical Genetics Department Boston University School of Medicine Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Taylor","sequence":"additional","affiliation":[{"name":"MRC Integrative Epidemiology Unit (IEU) University of Bristol Bristol UK"},{"name":"School of Social and Community Medicine University of Bristol Bristol UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond K.","family":"Walters","sequence":"additional","affiliation":[{"name":"Analytic and Translational Genetics Unit Massachusetts General Hospital Boston MA USA"},{"name":"Stanley Center for Psychiatric Research Broad Institute of MIT and Harvard Cambridge MA USA"},{"name":"Department of Medicine Harvard Medical School Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdel","family":"Abdellaoui","sequence":"additional","affiliation":[{"name":"Department of Biological Psychology\/Netherlands Twin Register VU University Amsterdam the Netherlands"},{"name":"Amsterdam UMC, University of Amsterdam Department of Psychiatry Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy B.","family":"Bigdeli","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Virginia Institute for Psychiatric and Behavior Genetics Virginia Commonwealth University Richmond VA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan J. 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