GENOME-WIDE ASSOCIATION META-ANALYSIS OF AGE AT FIRST CANNABIS USE

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Abstract

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. Here we estimate the heritability of age at first cannabis use and identify associations with genetic variants. 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 cohorts, and a replication sample of 3,735 individuals. 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 (r 2 >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. Age at cannabis initiation is moderately heritable, 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.

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Journal

Title: Addiction

Abbreviated Title: Addiction

Publisher: Wiley

ISSN: 09652140

Publication date (Electronic): July 13 2018

Affiliations

[1 ]Department of Biological Psychology/Netherlands Twin Register; VU University; Amsterdam The Netherlands

[2 ]Behavioral Science Institute, Radboud University; Nijmegen The Netherlands

[3 ]Department of Epidemiology; University of Groningen, University Medical Center Groningen; Groningen The Netherlands

[4 ]Hospital for Sick Children Research Institute; Toronto Canada

[5 ]Department of Neurology; Brain Center Rudolf Magnus, University Medical Center Utrecht; Utrecht The Netherlands

[6 ]Psychiatric Genetics, QIMR Berghofer Medical Research Institute; Brisbane Queensland Australia

[7 ]Institute for Behavioral Genetics, Department of Psychology and Neuroscience; University of Colorado Boulder; Boulder Colorado USA

[8 ]Vrije Universiteit Amsterdam; Department of Clinical Developmental Psychology; Amsterdam The Netherlands

[9 ]GGZ inGeest and Department of Psychiatry; Amsterdam Public Health research institute, VU University Medical Center; Amsterdam The Netherlands

[10 ]Institute for Molecular Medicine Finland (FIMM), University of Helsinki; Helsinki Finland

[11 ]Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona; Barcelona Catalonia Spain

[12 ]Department of Psychiatry; Hospital Universitari Vall d’Hebron; Barcelona Spain

[13 ]Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III; Madrid Spain

[14 ]Biomedical Genetics Department; Boston University School of Medicine; Boston Massachusetts USA

[15 ]MRC Integrative Epidemiology Unit (IEU), University of Bristol; Bristol UK

[16 ]School of Social and Community Medicine, University of Bristol; Bristol UK

[17 ]Analytic and Translational Genetics Unit, Massachusetts General Hospital; Boston Massachusetts USA

[18 ]Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard; Cambridge Massachusetts USA

[19 ]Department of Medicine; Harvard Medical School; Boston Massachusetts USA

[20 ]Department of Psychiatry; Virginia Institute for Psychiatric and Behavior Genetics, Virginia Commonwealth University; Richmond Virginia USA

[21 ]Research Centre Adolescent Development, Utrecht University; Utrecht the Netherlands

[22 ]Department of Psychology and Psychiatry; University of California San Diego, La Jolla; California USA

[23 ]Department of Psychiatry and Legal Medicine; Universitat Autònoma de Barcelona; Barcelona Spain

[24 ]Avera Institute for Human Genetics, Sioux Falls; South Dakota USA

[25 ]Department of Medicine (Biomedical Genetics); Boston University School of Medicine; Boston Massachusetts USA

[26 ]Genetic Epidemiology, QIMR Berghofer Medical Research Institute; Brisbane Queensland Australia

[27 ]Department of Psychiatry; University of Groningen, University Medical Center Groningen; Groningen The Netherlands

[28 ]Department of Psychiatry; Washington University School of Medicine; St Louis Missouri USA

[29 ]Brain & Mind Research Institute, University of Sydney; Sydney NSW Australia

[30 ]Department of Psychiatry; University of Colorado Denver; Aurora Colorado USA

[31 ]Department of Psychiatry; Brain Center Rudolf Magnus, University Medical Center Utrecht; Utrecht The Netherlands

[32 ]Department of Public Health; University of Helsinki; Helsinki Finland

[33 ]University of Eastern Finland, Institute of Public Health & Clinical Nutrition; Kuopio Finland

[34 ]Department of Psychiatry; University of Pennsylvania Perelman School of Medicine; Philadelphia USA

[35 ]Department of Molecular, Cellular and Developmental Biology; University of Colorado Boulder; Boulder Colorado USA

[36 ]Department of Psychology, Education & Child Studies; Erasmus University Rotterdam; Rotterdam the Netherlands

[37 ]Department of Psychiatry and School of Medicine; Virginia Commonwealth University; Richmond Virginia USA

[38 ]Developmental Psychology, Tilburg University; Tilburg The Netherlands

[39 ]Institute for Molecular Bioscience, The University of Queensland; Brisbane Queensland Australia

[40 ]Physiology and Nutritional Sciences, University of Toronto; Toronto Canada

[41 ]Department of Psychological & Brain Sciences; Indiana University; Bloomington Indiana USA

[42 ]Department of Psychiatry; University of California San Diego La Jolla; California USA

[43 ]Queensland Brain Institute, The University of Queensland, Brisbane; Queensland Australia

[44 ]Department of Biostatistics; Yale School of Public Health & VA CT; New Haven Connecticut USA

[45 ]Rotman Research Institute Baycrest; Toronto Canada

[46 ]Psychology and Psychiatry, University of Toronto; Toronto Canada

[47 ]Center for the Developing Brain, Child Mind Institute, New York; New York USA

[48 ]UK Centre for Tobacco and Alcohol Studies, School of Experimental Psychology, University of Bristol; Bristol UK

[49 ]Psychiatry, Genetics, & Neuroscience, Yale University School of Medicine & VA CT; West Haven Connecticut USA

[50 ]Department of Psychiatry; Academic Medical Centre; Amsterdam The Netherlands

[51 ]Translational Neurogenomics group, QIMR Berghofer Medical Research Institute; Brisbane Queensland Australia

Article

DOI: 10.1111/add.14368

PMC ID: 7087375

PubMed ID: 30003630

SO-VID: 60e2f99f-07ca-481b-b82b-7e1ab5180b96

License:

http://doi.wiley.com/10.1002/tdm_license_1.1

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