|
|
| PMID |
|
|
| TITLE |
|
| Genome-wide association meta-analysis of age at first cannabis use. |
|
| 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 |
|
| 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. 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 |
|
| 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. 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. 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) (r > 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 |
|
| 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. 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. 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) (r > 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. 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. |
| © 2018 Society for the Study of Addiction. |
|
| DATE PUBLISHED |
|
|
| HISTORY |
|
| PUBSTATUS |
PUBSTATUSDATE |
| received |
2017/11/03 |
| revised |
2018/01/26 |
| accepted |
2018/06/11 |
| pubmed |
2018/07/14 06:00 |
| medline |
2019/12/18 06:00 |
| entrez |
2018/07/14 06:00 |
|
| AUTHORS |
|
| NAME |
COLLECTIVENAME |
LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
AFFILIATIONINFO |
| Minică CC |
|
Minică |
Camelia C |
CC |
|
Department of Biological Psychology/Netherlands Twin Register, VU University, Amsterdam, the Netherlands. |
| Verweij KJH |
|
Verweij |
Karin J H |
KJH |
|
Amsterdam UMC, University of Amsterdam, Department of Psychiatry, Amsterdam, the Netherlands. |
| van der Most PJ |
|
van der Most |
Peter J |
PJ |
|
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. |
| Mbarek H |
|
Mbarek |
Hamdi |
H |
|
Department of Biological Psychology/Netherlands Twin Register, VU University, Amsterdam, the Netherlands. |
| Bernard M |
|
Bernard |
Manon |
M |
|
Hospital for Sick Children Research Institute, Toronto, Canada. |
| van Eijk KR |
|
van Eijk |
Kristel R |
KR |
|
Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands. |
| Lind PA |
|
Lind |
Penelope A |
PA |
|
Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. |
| Liu MZ |
|
Liu |
Meng Zhen |
MZ |
|
Institute for Behavioral Genetics, Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, USA. |
| Maciejewski DF |
|
Maciejewski |
Dominique F |
DF |
|
GGZ inGeest and Department of Psychiatry, Amsterdam Public Health Research Institute, VU University Medical Center, Amsterdam, the Netherlands. |
| Palviainen T |
|
Palviainen |
Teemu |
T |
|
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. |
| Sánchez-Mora C |
|
Sánchez-Mora |
Cristina |
C |
|
Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain. |
| Sherva R |
|
Sherva |
Richard |
R |
|
Biomedical Genetics Department, Boston University School of Medicine, Boston, MA, USA. |
| Taylor M |
|
Taylor |
Michelle |
M |
|
School of Social and Community Medicine, University of Bristol, Bristol, UK. |
| Walters RK |
|
Walters |
Raymond K |
RK |
|
Department of Medicine, Harvard Medical School, Boston, MA, USA. |
| Abdellaoui A |
|
Abdellaoui |
Abdel |
A |
|
Amsterdam UMC, University of Amsterdam, Department of Psychiatry, Amsterdam, the Netherlands. |
| Bigdeli TB |
|
Bigdeli |
Timothy B |
TB |
|
Department of Psychiatry, Virginia Institute for Psychiatric and Behavior Genetics, Virginia Commonwealth University, Richmond, VA, USA. |
| Branje SJT |
|
Branje |
Susan J T |
SJT |
|
Research Centre Adolescent Development, Utrecht University, Utrecht, the Netherlands. |
| Brown SA |
|
Brown |
Sandra A |
SA |
|
Department of Psychology and Psychiatry, University of California San Diego, La Jolla, CA, USA. |
| Casas M |
|
Casas |
Miguel |
M |
|
Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain. |
| Corley RP |
|
Corley |
Robin P |
RP |
|
Institute for Behavioral Genetics, Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, USA. |
| Davey-Smith G |
|
Davey-Smith |
George |
G |
|
School of Social and Community Medicine, University of Bristol, Bristol, UK. |
| Davies GE |
|
Davies |
Gareth E |
GE |
|
Avera Institute for Human Genetics, Sioux Falls, SD, USA. |
| Ehli EA |
|
Ehli |
Erik A |
EA |
|
Avera Institute for Human Genetics, Sioux Falls, SD, USA. |
| Farrer L |
|
Farrer |
Lindsay |
L |
|
Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA. |
| Fedko IO |
|
Fedko |
Iryna O |
IO |
|
Department of Biological Psychology/Netherlands Twin Register, VU University, Amsterdam, the Netherlands. |
| Garcia-Martínez I |
|
Garcia-Martínez |
Iris |
I |
|
Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Spain. |
| Gordon SD |
|
Gordon |
Scott D |
SD |
|
Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. |
| Hartman CA |
|
Hartman |
Catharina A |
CA |
|
Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. |
| Heath AC |
|
Heath |
Andrew C |
AC |
|
Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA. |
| Hickie IB |
|
Hickie |
Ian B |
IB |
|
Brain and Mind Research Institute, University of Sydney, Sydney, NSW, Australia. |
| Hickman M |
|
Hickman |
Matthew |
M |
|
School of Social and Community Medicine, University of Bristol, Bristol, UK. |
| Hopfer CJ |
|
Hopfer |
Christian J |
CJ |
|
Department of Psychiatry, University of Colorado Denver, Aurora, CO, USA. |
| Hottenga JJ |
|
Hottenga |
Jouke Jan |
JJ |
|
Department of Biological Psychology/Netherlands Twin Register, VU University, Amsterdam, the Netherlands. |
| Kahn RS |
|
Kahn |
René S |
RS |
|
Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands. |
| Kaprio J |
|
Kaprio |
Jaakko |
J |
|
Department of Public Health, University of Helsinki, Helsinki, Finland. |
| Korhonen T |
|
Korhonen |
Tellervo |
T |
|
University of Eastern Finland, Institute of Public Health and Clinical Nutrition, Kuopio, Finland. |
| Kranzler HR |
|
Kranzler |
Henry R |
HR |
|
Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. |
| Krauter K |
|
Krauter |
Ken |
K |
|
Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, CO, USA. |
| van Lier PAC |
|
van Lier |
Pol A C |
PAC |
|
Department of Psychology, Education and Child Studies, Erasmus University Rotterdam, Rotterdam, the Netherlands. |
| Madden PAF |
|
Madden |
Pamela A F |
PAF |
|
Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA. |
| Medland SE |
|
Medland |
Sarah E |
SE |
|
Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. |
| Neale MC |
|
Neale |
Michael C |
MC |
|
Department of Psychiatry and School of Medicine, Virginia Commonwealth University, Richmond, VA, USA. |
| Meeus WHJ |
|
Meeus |
Wim H J |
WHJ |
|
Developmental Psychology, Tilburg University, Tilburg, the Netherlands. |
| Montgomery GW |
|
Montgomery |
Grant W |
GW |
|
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia. |
| Nolte IM |
|
Nolte |
Ilja M |
IM |
|
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. |
| Oldehinkel AJ |
|
Oldehinkel |
Albertine J |
AJ |
|
Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. |
| Pausova Z |
|
Pausova |
Zdenka |
Z |
|
Physiology and Nutritional Sciences, University of Toronto, Toronto, Canada. |
| Ramos-Quiroga JA |
|
Ramos-Quiroga |
Josep A |
JA |
|
Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain. |
| Richarte V |
|
Richarte |
Vanesa |
V |
|
Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain. |
| Rose RJ |
|
Rose |
Richard J |
RJ |
|
Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA. |
| Shin J |
|
Shin |
Jean |
J |
|
Hospital for Sick Children Research Institute, Toronto, Canada. |
| Stallings MC |
|
Stallings |
Michael C |
MC |
|
Institute for Behavioral Genetics, Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, USA. |
| Wall TL |
|
Wall |
Tamara L |
TL |
|
Department of Psychiatry, University of California San Diego, La Jolla, CA, USA. |
| Ware JJ |
|
Ware |
Jennifer J |
JJ |
|
School of Social and Community Medicine, University of Bristol, Bristol, UK. |
| Wright MJ |
|
Wright |
Margaret J |
MJ |
|
Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia. |
| Zhao H |
|
Zhao |
Hongyu |
H |
|
Department of Biostatistics, Yale School of Public Health and VA CT, New Haven, CT, USA. |
| Koot HM |
|
Koot |
Hans M |
HM |
|
Department of Clinical Developmental Psychology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands. |
| Paus T |
|
Paus |
Tomas |
T |
|
Center for the Developing Brain, Child Mind Institute, New York, NY, USA. |
| Hewitt JK |
|
Hewitt |
John K |
JK |
|
Institute for Behavioral Genetics, Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, USA. |
| Ribasés M |
|
Ribasés |
Marta |
M |
|
Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain. |
| Loukola A |
|
Loukola |
Anu |
A |
|
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. |
| Boks MP |
|
Boks |
Marco P |
MP |
|
Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands. |
| Snieder H |
|
Snieder |
Harold |
H |
|
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. |
| Munafò MR |
|
Munafò |
Marcus R |
MR |
|
UK Centre for Tobacco and Alcohol Studies, School of Experimental Psychology, University of Bristol, Bristol, UK. |
| Gelernter J |
|
Gelernter |
Joel |
J |
|
Psychiatry, Genetics, and Neuroscience, Yale University School of Medicine and VA CT, West Haven, CT, USA. |
| Boomsma DI |
|
Boomsma |
Dorret I |
DI |
|
Department of Biological Psychology/Netherlands Twin Register, VU University, Amsterdam, the Netherlands. |
| Martin NG |
|
Martin |
Nicholas G |
NG |
|
Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. |
| Gillespie NA |
|
Gillespie |
Nathan A |
NA |
|
Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. |
| Vink JM |
|
Vink |
Jacqueline M |
JM |
|
Behavioral Science Institute, Radboud University, Nijmegen, the Netherlands. |
| Derks EM |
|
Derks |
Eske M |
EM |
|
Translational Neurogenomics group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. |
|
| INVESTIGATORS |
|
|
| JOURNAL |
|
| VOLUME: 113 |
| ISSUE: 11 |
| TITLE: Addiction (Abingdon, England) |
| ISOABBREVIATION: Addiction |
| YEAR: 2018 |
| MONTH: 11 |
| DAY: |
| MEDLINEDATE: |
| SEASON: |
| CITEDMEDIUM: Internet |
| ISSN: 1360-0443 |
| ISSNTYPE: Electronic |
|
| MEDLINE JOURNAL |
|
| MEDLINETA: Addiction |
| COUNTRY: England |
| ISSNLINKING: 0965-2140 |
| NLMUNIQUEID: 9304118 |
|
| PUBLICATION TYPE |
|
| PUBLICATIONTYPE TEXT |
| Journal Article |
| Meta-Analysis |
| Research Support, N.I.H., Extramural |
| Research Support, Non-U.S. Gov't |
| Research Support, U.S. Gov't, Non-P.H.S. |
| Twin Study |
|
| COMMENTS AND CORRECTIONS |
|
|
| GRANTS |
|
| GRANTID |
AGENCY |
COUNTRY |
| R01 AA009203 |
NIAAA NIH HHS |
United States |
| R01 DA018267 |
NIDA NIH HHS |
United States |
| DA-018673 |
NIDA NIH HHS |
United States |
| R01 AA012502 |
NIAAA NIH HHS |
United States |
| R01 DA018673 |
NIDA NIH HHS |
United States |
| U01 MH094432 |
NIMH NIH HHS |
United States |
| R01 DA018660 |
NIDA NIH HHS |
United States |
| RC2 MH089951 |
NIMH NIH HHS |
United States |
| RC2 DA028909 |
NIDA NIH HHS |
United States |
| R01 AA007535 |
NIAAA NIH HHS |
United States |
| R01 DA035804 |
NIDA NIH HHS |
United States |
| R01 AA014041 |
NIAAA NIH HHS |
United States |
| R01 MH081802 |
NIMH NIH HHS |
United States |
| K05 AA017688 |
NIAAA NIH HHS |
United States |
| N01HG65403 |
NHGRI NIH HHS |
United States |
| R01 DA012690 |
NIDA NIH HHS |
United States |
| RC2 MH089995 |
NIMH NIH HHS |
United States |
| R01 DA012849 |
NIDA NIH HHS |
United States |
| P50 AA011998 |
NIAAA NIH HHS |
United States |
|
Foundation Volksbond Rotterdam |
International |
| R01 AA007728 |
NIAAA NIH HHS |
United States |
| MC_UU_12013/6 |
Medical Research Council |
United Kingdom |
| R01 DA023668 |
NIDA NIH HHS |
United States |
| R01 DA021905 |
NIDA NIH HHS |
United States |
| R01 DA021913 |
NIDA NIH HHS |
United States |
| MC_UU_00011/7 |
Medical Research Council |
United Kingdom |
| R01 HD042157 |
NICHD NIH HHS |
United States |
| MC_UU_00011/1 |
Medical Research Council |
United Kingdom |
| R56 DA012854 |
NIDA NIH HHS |
United States |
| T32 AA007580 |
NIAAA NIH HHS |
United States |
| R37 DA018673 |
NIDA NIH HHS |
United States |
| R01 AA013321 |
NIAAA NIH HHS |
United States |
| R01 DA018432 |
NIDA NIH HHS |
United States |
| MR/K023233/1 |
Medical Research Council |
United Kingdom |
| K02 AA018755 |
NIAAA NIH HHS |
United States |
| R01 DA012845 |
NIDA NIH HHS |
United States |
| U24 MH068457 |
NIMH NIH HHS |
United States |
| R01 AA011330 |
NIAAA NIH HHS |
United States |
| R01 DA012854 |
NIDA NIH HHS |
United States |
| K05 AA000145 |
NIAAA NIH HHS |
United States |
| R01 AA017535 |
NIAAA NIH HHS |
United States |
| R01 AA010249 |
NIAAA NIH HHS |
United States |
| NARSAD Young Investigator Grant |
Brain & Behavior Research Foundation |
International |
| G0802736 |
Medical Research Council |
United Kingdom |
| R00 DA023549 |
NIDA NIH HHS |
United States |
| K08 DA019951 |
NIDA NIH HHS |
United States |
|
Wellcome Trust |
United Kingdom |
| R01 AA015416 |
NIAAA NIH HHS |
United States |
| R37 AA007728 |
NIAAA NIH HHS |
United States |
| MR/L022206/1 |
Medical Research Council |
United Kingdom |
| R00DA023549 |
US National Institutes of Health, National Institute on Drug Abuse |
International |
| NWO 480-05-003 |
NWO |
International |
| ERC-284167 |
European Research Council |
International |
| G0800612 |
Medical Research Council |
United Kingdom |
| R01 AA013320 |
NIAAA NIH HHS |
United States |
| P60 DA011015 |
NIDA NIH HHS |
United States |
| R37 AA012502 |
NIAAA NIH HHS |
United States |
|
| GENERAL NOTE |
|
|
| KEYWORDS |
|
| KEYWORD |
| ATP2C2 |
| Age at first use |
| cannabis initiation |
| genome-wide association |
| heritability |
| substance use |
|
| MESH HEADINGS |
|
| DESCRIPTORNAME |
QUALIFIERNAME |
| Adolescent |
|
| Adult |
|
| Age of Onset |
|
| Calcium-Transporting ATPases |
genetics |
| Female |
genetics |
| Genome-Wide Association Study |
genetics |
| Humans |
genetics |
| Male |
genetics |
| Marijuana Use |
genetics |
| Middle Aged |
genetics |
| Polymorphism, Single Nucleotide |
genetics |
| Twins |
genetics |
| Young Adult |
genetics |
|
| SUPPLEMENTARY MESH |
|
|
| GENE SYMBOLS |
|
|
| CHEMICALS |
|
| REGISTRYNUMBER |
NAMEOFSUBSTANCE |
| EC 7.2.2.10 |
ATP2C2 protein, human |
| EC 7.2.2.10 |
Calcium-Transporting ATPases |
|
| OTHER ID's |
|
|
|
