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

Camelia C. Minică, Karin J.H. Verweij, Peter J. van der Most, Hamdi Mbarek, Manon Bernard, Kristel R. van Eijk, Penelope A. Lind, Meng Zhen Liu, Dominique F. Maciejewski, Teemu Palviainen, Cristina Sánchez-Mora, Richard Sherva, Michelle Taylor, Raymond K. Walters, Abdel Abdellaoui, Timothy B. Bigdeli, Susan J.T. Branje, Sandra A. Brown, Miguel Casas, Robin P. Corley & 50 others George Davey-Smith, Gareth E. Davies, Erik A. Ehli, Lindsay Farrer, Iryna O. Fedko, Iris Garcia-Martínez, Scott D. Gordon, Catharina A. Hartman, Andrew C. Heath, Ian B. Hickie, Matthew Hickman, Christian J. Hopfer, Jouke Jan Hottenga, René S. Kahn, Jaakko Kaprio, Tellervo Korhonen, Henry R. Kranzler, Ken Krauter, Pol A.C. van Lier, Pamela A.F. Madden, Sarah E. Medland, Michael C. Neale, Wim H.J. Meeus, Grant W. Montgomery, Ilja M. Nolte, Albertine J. Oldehinkel, Zdenka Pausova, Josep A. Ramos-Quiroga, Vanesa Richarte, Richard J. Rose, Jean Shin, Michael C. Stallings, Tamara L. Wall, Jennifer J. Ware, Margaret J. Wright, Hongyu Zhao, Hans M. Koot, Tomas Paus, John K. Hewitt, Marta Ribasés, Anu Loukola, Marco P. Boks, Harold Snieder, Marcus R. Munafò, Joel Gelernter, Dorret I. Boomsma, Nicholas G. Martin, Nathan A. Gillespie, Jacqueline M. Vink, Eske M. Derks

Research output: Contribution to JournalArticleAcademicpeer-review

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 languageEnglish
Pages (from-to)2073-2086
Number of pages14
JournalAddiction
Volume113
Issue number11
Early online date13 Jul 2018
DOIs
Publication statusPublished - Nov 2018

Fingerprint

Genome-Wide Association Study
Cannabis
Meta-Analysis
Single Nucleotide Polymorphism
Calcium Signaling
Confidence Intervals
Survival Analysis
Substance-Related Disorders
Genome
Genes
Chromosomes, Human, Pair 16
Cocaine-Related Disorders
Calcium-Transporting ATPases
Individuality
Opioid Analgesics
Young Adult

Keywords

  • Age at first use
  • ATP2C2
  • cannabis initiation
  • genome-wide association
  • heritability
  • substance use

Cite this

Minică, C. C., Verweij, K. J. H., van der Most, P. J., Mbarek, H., Bernard, M., van Eijk, K. R., ... Derks, E. M. (2018). Genome-wide association meta-analysis of age at first cannabis use. Addiction, 113(11), 2073-2086. https://doi.org/10.1111/add.14368
Minică, Camelia C. ; Verweij, Karin J.H. ; van der Most, Peter J. ; Mbarek, Hamdi ; Bernard, Manon ; van Eijk, Kristel R. ; Lind, Penelope A. ; Liu, Meng Zhen ; Maciejewski, Dominique F. ; Palviainen, Teemu ; Sánchez-Mora, Cristina ; Sherva, Richard ; Taylor, Michelle ; Walters, Raymond K. ; Abdellaoui, Abdel ; Bigdeli, Timothy B. ; Branje, Susan J.T. ; Brown, Sandra A. ; Casas, Miguel ; Corley, Robin P. ; Davey-Smith, George ; Davies, Gareth E. ; Ehli, Erik A. ; Farrer, Lindsay ; Fedko, Iryna O. ; Garcia-Martínez, Iris ; Gordon, Scott D. ; Hartman, Catharina A. ; Heath, Andrew C. ; Hickie, Ian B. ; Hickman, Matthew ; Hopfer, Christian J. ; Hottenga, Jouke Jan ; Kahn, René S. ; Kaprio, Jaakko ; Korhonen, Tellervo ; Kranzler, Henry R. ; Krauter, Ken ; van Lier, Pol A.C. ; Madden, Pamela A.F. ; Medland, Sarah E. ; Neale, Michael C. ; Meeus, Wim H.J. ; Montgomery, Grant W. ; Nolte, Ilja M. ; Oldehinkel, Albertine J. ; Pausova, Zdenka ; Ramos-Quiroga, Josep A. ; Richarte, Vanesa ; Rose, Richard J. ; Shin, Jean ; Stallings, Michael C. ; Wall, Tamara L. ; Ware, Jennifer J. ; Wright, Margaret J. ; Zhao, Hongyu ; Koot, Hans M. ; Paus, Tomas ; Hewitt, John K. ; Ribasés, Marta ; Loukola, Anu ; Boks, Marco P. ; Snieder, Harold ; Munafò, Marcus R. ; Gelernter, Joel ; Boomsma, Dorret I. ; Martin, Nicholas G. ; Gillespie, Nathan A. ; Vink, Jacqueline M. ; Derks, Eske M. / Genome-wide association meta-analysis of age at first cannabis use. In: Addiction. 2018 ; Vol. 113, No. 11. pp. 2073-2086.
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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.",
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author = "Minică, {Camelia C.} and Verweij, {Karin J.H.} and {van der Most}, {Peter J.} and Hamdi Mbarek and Manon Bernard and {van Eijk}, {Kristel R.} and Lind, {Penelope A.} and Liu, {Meng Zhen} and Maciejewski, {Dominique F.} and Teemu Palviainen and Cristina S{\'a}nchez-Mora and Richard Sherva and Michelle Taylor and Walters, {Raymond K.} and Abdel Abdellaoui and Bigdeli, {Timothy B.} and Branje, {Susan J.T.} and Brown, {Sandra A.} and Miguel Casas and Corley, {Robin P.} and George Davey-Smith and Davies, {Gareth E.} and Ehli, {Erik A.} and Lindsay Farrer and Fedko, {Iryna O.} and Iris Garcia-Mart{\'i}nez and Gordon, {Scott D.} and Hartman, {Catharina A.} and Heath, {Andrew C.} and Hickie, {Ian B.} and Matthew Hickman and Hopfer, {Christian J.} and Hottenga, {Jouke Jan} and Kahn, {Ren{\'e} S.} and Jaakko Kaprio and Tellervo Korhonen and Kranzler, {Henry R.} and Ken Krauter and {van Lier}, {Pol A.C.} and Madden, {Pamela A.F.} and Medland, {Sarah E.} and Neale, {Michael C.} and Meeus, {Wim H.J.} and Montgomery, {Grant W.} and Nolte, {Ilja M.} and Oldehinkel, {Albertine J.} and Zdenka Pausova and Ramos-Quiroga, {Josep A.} and Vanesa Richarte and Rose, {Richard J.} and Jean Shin and Stallings, {Michael C.} and Wall, {Tamara L.} and Ware, {Jennifer J.} and Wright, {Margaret J.} and Hongyu Zhao and Koot, {Hans M.} and Tomas Paus and Hewitt, {John K.} and Marta Ribas{\'e}s and Anu Loukola and Boks, {Marco P.} and Harold Snieder and Munaf{\`o}, {Marcus R.} and Joel Gelernter and Boomsma, {Dorret I.} and Martin, {Nicholas G.} and Gillespie, {Nathan A.} and Vink, {Jacqueline M.} and Derks, {Eske M.}",
note = "This article is protected by copyright. All rights reserved.",
year = "2018",
month = "11",
doi = "10.1111/add.14368",
language = "English",
volume = "113",
pages = "2073--2086",
journal = "Addiction",
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Minică, CC, Verweij, KJH, van der Most, PJ, Mbarek, H, Bernard, M, van Eijk, KR, Lind, PA, Liu, MZ, Maciejewski, DF, Palviainen, T, Sánchez-Mora, C, Sherva, R, Taylor, M, Walters, RK, Abdellaoui, A, Bigdeli, TB, Branje, SJT, Brown, SA, Casas, M, Corley, RP, Davey-Smith, G, Davies, GE, Ehli, EA, Farrer, L, Fedko, IO, Garcia-Martínez, I, Gordon, SD, Hartman, CA, Heath, AC, Hickie, IB, Hickman, M, Hopfer, CJ, Hottenga, JJ, Kahn, RS, Kaprio, J, Korhonen, T, Kranzler, HR, Krauter, K, van Lier, PAC, Madden, PAF, Medland, SE, Neale, MC, Meeus, WHJ, Montgomery, GW, Nolte, IM, Oldehinkel, AJ, Pausova, Z, Ramos-Quiroga, JA, Richarte, V, Rose, RJ, Shin, J, Stallings, MC, Wall, TL, Ware, JJ, Wright, MJ, Zhao, H, Koot, HM, Paus, T, Hewitt, JK, Ribasés, M, Loukola, A, Boks, MP, Snieder, H, Munafò, MR, Gelernter, J, Boomsma, DI, Martin, NG, Gillespie, NA, Vink, JM & Derks, EM 2018, 'Genome-wide association meta-analysis of age at first cannabis use' Addiction, vol. 113, no. 11, pp. 2073-2086. https://doi.org/10.1111/add.14368

Genome-wide association meta-analysis of age at first cannabis use. / Minică, Camelia C.; Verweij, Karin J.H.; van der Most, Peter J.; Mbarek, Hamdi; Bernard, Manon; van Eijk, Kristel R.; Lind, Penelope A.; Liu, Meng Zhen; Maciejewski, Dominique F.; Palviainen, Teemu; Sánchez-Mora, Cristina; Sherva, Richard; Taylor, Michelle; Walters, Raymond K.; Abdellaoui, Abdel; Bigdeli, Timothy B.; Branje, Susan J.T.; Brown, Sandra A.; Casas, Miguel; Corley, Robin P.; Davey-Smith, George; Davies, Gareth E.; Ehli, Erik A.; Farrer, Lindsay; Fedko, Iryna O.; Garcia-Martínez, Iris; Gordon, Scott D.; Hartman, Catharina A.; Heath, Andrew C.; Hickie, Ian B.; Hickman, Matthew; Hopfer, Christian J.; Hottenga, Jouke Jan; Kahn, René S.; Kaprio, Jaakko; Korhonen, Tellervo; Kranzler, Henry R.; Krauter, Ken; van Lier, Pol A.C.; Madden, Pamela A.F.; Medland, Sarah E.; Neale, Michael C.; Meeus, Wim H.J.; Montgomery, Grant W.; Nolte, Ilja M.; Oldehinkel, Albertine J.; Pausova, Zdenka; Ramos-Quiroga, Josep A.; Richarte, Vanesa; Rose, Richard J.; Shin, Jean; Stallings, Michael C.; Wall, Tamara L.; Ware, Jennifer J.; Wright, Margaret J.; Zhao, Hongyu; Koot, Hans M.; Paus, Tomas; Hewitt, John K.; Ribasés, Marta; Loukola, Anu; Boks, Marco P.; Snieder, Harold; Munafò, Marcus R.; Gelernter, Joel; Boomsma, Dorret I.; Martin, Nicholas G.; Gillespie, Nathan A.; Vink, Jacqueline M.; Derks, Eske M.

In: Addiction, Vol. 113, No. 11, 11.2018, p. 2073-2086.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

T1 - Genome-wide association meta-analysis of age at first cannabis use

AU - Minică, Camelia C.

AU - Verweij, Karin J.H.

AU - van der Most, Peter J.

AU - Mbarek, Hamdi

AU - Bernard, Manon

AU - van Eijk, Kristel R.

AU - Lind, Penelope A.

AU - Liu, Meng Zhen

AU - Maciejewski, Dominique F.

AU - Palviainen, Teemu

AU - Sánchez-Mora, Cristina

AU - Sherva, Richard

AU - Taylor, Michelle

AU - Walters, Raymond K.

AU - Abdellaoui, Abdel

AU - Bigdeli, Timothy B.

AU - Branje, Susan J.T.

AU - Brown, Sandra A.

AU - Casas, Miguel

AU - Corley, Robin P.

AU - Davey-Smith, George

AU - Davies, Gareth E.

AU - Ehli, Erik A.

AU - Farrer, Lindsay

AU - Fedko, Iryna O.

AU - Garcia-Martínez, Iris

AU - Gordon, Scott D.

AU - Hartman, Catharina A.

AU - Heath, Andrew C.

AU - Hickie, Ian B.

AU - Hickman, Matthew

AU - Hopfer, Christian J.

AU - Hottenga, Jouke Jan

AU - Kahn, René S.

AU - Kaprio, Jaakko

AU - Korhonen, Tellervo

AU - Kranzler, Henry R.

AU - Krauter, Ken

AU - van Lier, Pol A.C.

AU - Madden, Pamela A.F.

AU - Medland, Sarah E.

AU - Neale, Michael C.

AU - Meeus, Wim H.J.

AU - Montgomery, Grant W.

AU - Nolte, Ilja M.

AU - Oldehinkel, Albertine J.

AU - Pausova, Zdenka

AU - Ramos-Quiroga, Josep A.

AU - Richarte, Vanesa

AU - Rose, Richard J.

AU - Shin, Jean

AU - Stallings, Michael C.

AU - Wall, Tamara L.

AU - Ware, Jennifer J.

AU - Wright, Margaret J.

AU - Zhao, Hongyu

AU - Koot, Hans M.

AU - Paus, Tomas

AU - Hewitt, John K.

AU - Ribasés, Marta

AU - Loukola, Anu

AU - Boks, Marco P.

AU - Snieder, Harold

AU - Munafò, Marcus R.

AU - Gelernter, Joel

AU - Boomsma, Dorret I.

AU - Martin, Nicholas G.

AU - Gillespie, Nathan A.

AU - Vink, Jacqueline M.

AU - Derks, Eske M.

N1 - This article is protected by copyright. All rights reserved.

PY - 2018/11

Y1 - 2018/11

N2 - 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.

AB - 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.

KW - Age at first use

KW - ATP2C2

KW - cannabis initiation

KW - genome-wide association

KW - heritability

KW - substance use

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U2 - 10.1111/add.14368

DO - 10.1111/add.14368

M3 - Article

VL - 113

SP - 2073

EP - 2086

JO - Addiction

JF - Addiction

SN - 0965-2140

IS - 11

ER -

Minică CC, Verweij KJH, van der Most PJ, Mbarek H, Bernard M, van Eijk KR et al. Genome-wide association meta-analysis of age at first cannabis use. Addiction. 2018 Nov;113(11):2073-2086. https://doi.org/10.1111/add.14368