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 |
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Keywords
- Age at first use
- ATP2C2
- cannabis initiation
- genome-wide association
- heritability
- substance use
Cite this
}
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 Journal › Article › Academic › peer-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
UR - http://www.scopus.com/inward/record.url?scp=85052393915&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85052393915&partnerID=8YFLogxK
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 -