Genome-wide association meta-analysis of age at first cannabis use

Camelia C Minică¹, Karin J H Verweij^{1

2

3}, Peter J van der Most⁴, Hamdi Mbarek¹, Manon Bernard⁵, Kristel R van Eijk⁶, Penelope A Lind⁷, Meng Zhen Liu⁸, Dominique F Maciejewski^{9

10}, Teemu Palviainen¹¹, Cristina Sánchez-Mora^{12

13

14}, Richard Sherva¹⁵, Michelle Taylor^{16

17}, Raymond K Walters^{18

19

20}, Abdel Abdellaoui^{1

3}, Timothy B Bigdeli²¹, Susan J T Branje²², Sandra A Brown²³, Miguel Casas^{12

13

14

24}, Robin P Corley⁸, George Davey-Smith^{16

17}, Gareth E Davies²⁵, Erik A Ehli²⁵, Lindsay Farrer²⁶, Iryna O Fedko¹, Iris Garcia-Martínez^{12

13}, Scott D Gordon²⁷, Catharina A Hartman²⁸, Andrew C Heath²⁹, Ian B Hickie³⁰, Matthew Hickman¹⁷, Christian J Hopfer³¹, Jouke Jan Hottenga¹, René S Kahn³², Jaakko Kaprio^{11

33}, Tellervo Korhonen^{11

34}, Henry R Kranzler³⁵, Ken Krauter³⁶, Pol A C van Lier^{9

37}, Pamela A F Madden²⁹, Sarah E Medland⁷, Michael C Neale³⁸, Wim H J Meeus^{22

39}, Grant W Montgomery⁴⁰, Ilja M Nolte⁴, Albertine J Oldehinkel²⁸, Zdenka Pausova^{5

41}, Josep A Ramos-Quiroga^{12

13

14

24}, Vanesa Richarte^{12

13

14}, Richard J Rose⁴², Jean Shin⁵, Michael C Stallings⁸, Tamara L Wall⁴³, Jennifer J Ware^{16

17}, Margaret J Wright⁴⁴, Hongyu Zhao⁴⁵, Hans M Koot⁹, Tomas Paus^{46

47

48}, John K Hewitt⁸, Marta Ribasés^{12

13

14}, Anu Loukola¹¹, Marco P Boks³², Harold Snieder⁴, Marcus R Munafò^{16

49}, Joel Gelernter⁵⁰, Dorret I Boomsma¹, Nicholas G Martin²⁷, Nathan A Gillespie^{21

27}, Jacqueline M Vink², Eske M Derks^{51

52}

Affiliations

¹ Department of Biological Psychology/Netherlands Twin Register, VU University, Amsterdam, the Netherlands.
² Behavioral Science Institute, Radboud University, Nijmegen, the Netherlands.
³ Amsterdam UMC, University of Amsterdam, Department of Psychiatry, Amsterdam, the Netherlands.
⁴ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
⁵ Hospital for Sick Children Research Institute, Toronto, Canada.
⁶ Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
⁷ Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁸ Institute for Behavioral Genetics, Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
⁹ Department of Clinical Developmental Psychology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
¹⁰ GGZ inGeest and Department of Psychiatry, Amsterdam Public Health Research Institute, VU University Medical Center, Amsterdam, the Netherlands.
¹¹ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
¹² Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
¹³ Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
¹⁴ Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain.
¹⁵ Biomedical Genetics Department, Boston University School of Medicine, Boston, MA, USA.
¹⁶ MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol, UK.
¹⁷ School of Social and Community Medicine, University of Bristol, Bristol, UK.
¹⁸ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
¹⁹ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
²⁰ Department of Medicine, Harvard Medical School, Boston, MA, USA.
²¹ Department of Psychiatry, Virginia Institute for Psychiatric and Behavior Genetics, Virginia Commonwealth University, Richmond, VA, USA.
²² Research Centre Adolescent Development, Utrecht University, Utrecht, the Netherlands.
²³ Department of Psychology and Psychiatry, University of California San Diego, La Jolla, CA, USA.
²⁴ Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
²⁵ Avera Institute for Human Genetics, Sioux Falls, SD, USA.
²⁶ Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA.
²⁷ Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
²⁸ Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
²⁹ Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.
³⁰ Brain and Mind Research Institute, University of Sydney, Sydney, NSW, Australia.
³¹ Department of Psychiatry, University of Colorado Denver, Aurora, CO, USA.
³² Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
³³ Department of Public Health, University of Helsinki, Helsinki, Finland.
³⁴ University of Eastern Finland, Institute of Public Health and Clinical Nutrition, Kuopio, Finland.
³⁵ Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
³⁶ Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, CO, USA.
³⁷ Department of Psychology, Education and Child Studies, Erasmus University Rotterdam, Rotterdam, the Netherlands.
³⁸ Department of Psychiatry and School of Medicine, Virginia Commonwealth University, Richmond, VA, USA.
³⁹ Developmental Psychology, Tilburg University, Tilburg, the Netherlands.
⁴⁰ Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
⁴¹ Physiology and Nutritional Sciences, University of Toronto, Toronto, Canada.
⁴² Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA.
⁴³ Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
⁴⁴ Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.
⁴⁵ Department of Biostatistics, Yale School of Public Health and VA CT, New Haven, CT, USA.
⁴⁶ Rotman Research Institute, Baycrest, Toronto, Canada.
⁴⁷ Psychology and Psychiatry, University of Toronto, Toronto, Canada.
⁴⁸ Center for the Developing Brain, Child Mind Institute, New York, NY, USA.
⁴⁹ UK Centre for Tobacco and Alcohol Studies, School of Experimental Psychology, University of Bristol, Bristol, UK.
⁵⁰ Psychiatry, Genetics, and Neuroscience, Yale University School of Medicine and VA CT, West Haven, CT, USA.
⁵¹ Department of Psychiatry, Academic Medical Centre, Amsterdam, the Netherlands.
⁵² Translational Neurogenomics group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

PMID: 30003630
PMCID: PMC7087375
DOI: 10.1111/add.14368

Meta-Analysis

Genome-wide association meta-analysis of age at first cannabis use

Camelia C Minică et al. Addiction. 2018 Nov.

. 2018 Nov;113(11):2073-2086.

doi: 10.1111/add.14368. Epub 2018 Aug 19.

Authors

Affiliations

¹ Department of Biological Psychology/Netherlands Twin Register, VU University, Amsterdam, the Netherlands.
² Behavioral Science Institute, Radboud University, Nijmegen, the Netherlands.
³ Amsterdam UMC, University of Amsterdam, Department of Psychiatry, Amsterdam, the Netherlands.
⁴ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
⁵ Hospital for Sick Children Research Institute, Toronto, Canada.
⁶ Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
⁷ Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁸ Institute for Behavioral Genetics, Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
⁹ Department of Clinical Developmental Psychology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
¹⁰ GGZ inGeest and Department of Psychiatry, Amsterdam Public Health Research Institute, VU University Medical Center, Amsterdam, the Netherlands.
¹¹ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
¹² Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
¹³ Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
¹⁴ Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain.
¹⁵ Biomedical Genetics Department, Boston University School of Medicine, Boston, MA, USA.
¹⁶ MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol, UK.
¹⁷ School of Social and Community Medicine, University of Bristol, Bristol, UK.
¹⁸ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
¹⁹ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
²⁰ Department of Medicine, Harvard Medical School, Boston, MA, USA.
²¹ Department of Psychiatry, Virginia Institute for Psychiatric and Behavior Genetics, Virginia Commonwealth University, Richmond, VA, USA.
²² Research Centre Adolescent Development, Utrecht University, Utrecht, the Netherlands.
²³ Department of Psychology and Psychiatry, University of California San Diego, La Jolla, CA, USA.
²⁴ Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
²⁵ Avera Institute for Human Genetics, Sioux Falls, SD, USA.
²⁶ Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA.
²⁷ Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
²⁸ Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
²⁹ Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.
³⁰ Brain and Mind Research Institute, University of Sydney, Sydney, NSW, Australia.
³¹ Department of Psychiatry, University of Colorado Denver, Aurora, CO, USA.
³² Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
³³ Department of Public Health, University of Helsinki, Helsinki, Finland.
³⁴ University of Eastern Finland, Institute of Public Health and Clinical Nutrition, Kuopio, Finland.
³⁵ Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
³⁶ Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, CO, USA.
³⁷ Department of Psychology, Education and Child Studies, Erasmus University Rotterdam, Rotterdam, the Netherlands.
³⁸ Department of Psychiatry and School of Medicine, Virginia Commonwealth University, Richmond, VA, USA.
³⁹ Developmental Psychology, Tilburg University, Tilburg, the Netherlands.
⁴⁰ Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
⁴¹ Physiology and Nutritional Sciences, University of Toronto, Toronto, Canada.
⁴² Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA.
⁴³ Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
⁴⁴ Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.
⁴⁵ Department of Biostatistics, Yale School of Public Health and VA CT, New Haven, CT, USA.
⁴⁶ Rotman Research Institute, Baycrest, Toronto, Canada.
⁴⁷ Psychology and Psychiatry, University of Toronto, Toronto, Canada.
⁴⁸ Center for the Developing Brain, Child Mind Institute, New York, NY, USA.
⁴⁹ UK Centre for Tobacco and Alcohol Studies, School of Experimental Psychology, University of Bristol, Bristol, UK.
⁵⁰ Psychiatry, Genetics, and Neuroscience, Yale University School of Medicine and VA CT, West Haven, CT, USA.
⁵¹ Department of Psychiatry, Academic Medical Centre, Amsterdam, the Netherlands.
⁵² Translational Neurogenomics group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

PMID: 30003630
PMCID: PMC7087375
DOI: 10.1111/add.14368

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 identified associations with genetic variants.

Methods: A twin-based heritability analysis using 8055 twins from three cohorts was performed. We then carried out a genome-wide association 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 3735 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 association meta-analysis identified five single nucleotide polymorphisms (SNPs) on chromosome 16 within the calcium-transporting ATPase gene (ATP2C2) at P < 5E-08. All five SNPs are in high linkage disequilibrium (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 associated previously 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.

Keywords: ATP2C2; Age at first use; cannabis initiation; genome-wide association; heritability; substance use.

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Figures

**Figure 1:**
The outline of the analysis steps, and references to the Supplementary Material relevant to each step. Abbreviations: AFC – age at first cannabis use; DE – density estimation; LDSR – linkage disequilibrium score regression.

**Figure 2:**
The Manhattan plot of the meta-analysis results for the discovery sample (a). In the Manhattan plot, the y-axis shows the strength of association (-log10(P)) and the x-axis indicates the chromosomal position. The blue line indicates suggestive significance level (P < 1E-05) while the red line indicates genome-wide significance level (P < 5E-08); (b) Forest plot of the top SNP (rs1574587) on Chromosome 16 in eight discovery cohorts.

**Figure 3:**
Results of the gene-based tests: (a) Manhattan plot for the gene-based tests; and (b) Regional plot around the significantly associated gene.

See this image and copyright information in PMC

References

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Genome-wide association meta-analysis of age at first cannabis use

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Genome-wide association meta-analysis of age at first cannabis use

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