Genome-wide association study of lifetime cannabis use based on a large meta-analytic sample of 32330 subjects from the International Cannabis Consortium

S. Stringer; C. C. Minica; K. J. H. Verweij; H. Mbarek; M. Bernard; J. Derringer; K. R. van Eijk; J. D. Isen; A. Loukola; D. F. Maciejewski; E. Mihailov; P. J. van der Most; C. Sanchez-Mora; L. Roos; R. Sherva; R. Walters; J. J. Ware; A. Abdellaoui; T. B. Bigdeli; S. J. T. Branje; S. A. Brown; M. Bruinenberg; M. Casas; T. Esko; I. Garcia-Martinez; S. D. Gordon; J. M. Harris; C. A. Hartman; A. K. Henders; A. C. Heath; I. B. Hickie; M. Hickman; C. J. Hopfer; J. J. Hottenga; A. C. Huizink; D. E. Irons; R. S. Kahn; T. Korhonen; H. R. Kranzler; K. Krauter; P. A. C. van Lier; G. H. Lubke; P. A. F. Madden; R. Magi; M. K. McGue; S. E. Medland; W. H. J. Meeus; M. B. Miller; G. W. Montgomery; M. G. Nivard; I. M. Nolte; A. J. Oldehinkel; Z. Pausova; B. Qaiser; L. Quaye; J. A. Ramos-Quiroga; V. Richarte; R. J. Rose; J. Shin; M. C. Stallings; A. I. Stiby; T. L. Wall; M. J. Wright; H. M. Koot; T. Paus; J. K. Hewitt; M. Ribases; J. Kaprio; M. P. Boks; H. Snieder; T. Spector; M. R. Munafo; A. Metspalu; J. Gelernter; D. I. Boomsma; W. G. Iacono; N. G. Martin; N. A. Gillespie; E. M. Derks; J. M. Vink

doi:10.1038/tp.2016.36

Genome-wide association study of lifetime cannabis use based on a large meta-analytic sample of 32330 subjects from the International Cannabis Consortium

S. Stringer, C. C. Minica, K. J. H. Verweij, H. Mbarek, M. Bernard, J. Derringer, K. R. van Eijk, J. D. Isen, A. Loukola, D. F. Maciejewski, E. Mihailov, P. J. van der Most, C. Sanchez-Mora, L. Roos, R. Sherva, R. Walters, J. J. Ware, A. Abdellaoui, T. B. Bigdeli, S. J. T. BranjeS. A. Brown, M. Bruinenberg, M. Casas, T. Esko, I. Garcia-Martinez, S. D. Gordon, J. M. Harris, C. A. Hartman, A. K. Henders, A. C. Heath, I. B. Hickie, M. Hickman, C. J. Hopfer, J. J. Hottenga, A. C. Huizink, D. E. Irons, R. S. Kahn, T. Korhonen, H. R. Kranzler, K. Krauter, P. A. C. van Lier, G. H. Lubke, P. A. F. Madden, R. Magi, M. K. McGue, S. E. Medland, W. H. J. Meeus, M. B. Miller, G. W. Montgomery, M. G. Nivard, I. M. Nolte, A. J. Oldehinkel, Z. Pausova, B. Qaiser, L. Quaye, J. A. Ramos-Quiroga, V. Richarte, R. J. Rose, J. Shin, M. C. Stallings, A. I. Stiby, T. L. Wall, M. J. Wright, H. M. Koot, T. Paus, J. K. Hewitt, M. Ribases, J. Kaprio, M. P. Boks, H. Snieder, T. Spector, M. R. Munafo, A. Metspalu, J. Gelernter, D. I. Boomsma, W. G. Iacono, N. G. Martin, N. A. Gillespie, E. M. Derks, J. M. Vink

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Abstract

Cannabis is the most widely produced and consumed illicit psychoactive substance worldwide. Occasional cannabis use can progress to frequent use, abuse and dependence with all known adverse physical, psychological and social consequences. Individual differences in cannabis initiation are heritable (40–48%). The International Cannabis Consortium was established with the aim to identify genetic risk variants of cannabis use. We conducted a meta-analysis of genome-wide association data of 13 cohorts (N=32 330) and four replication samples (N=5627). In addition, we performed a gene-based test of association, estimated single-nucleotide polymorphism (SNP)-based heritability and explored the genetic correlation between lifetime cannabis use and cigarette use using LD score regression. No individual SNPs reached genome-wide significance. Nonetheless, gene-based tests identified four genes significantly associated with lifetime cannabis use: NCAM1, CADM2, SCOC and KCNT2. Previous studies reported associations of NCAM1 with cigarette smoking and other substance use, and those of CADM2 with body mass index, processing speed and autism disorders, which are phenotypes previously reported to be associated with cannabis use. Furthermore, we showed that, combined across the genome, all common SNPs explained 13–20% (P<0.001) of the liability of lifetime cannabis use. Finally, there was a strong genetic correlation (rg=0.83; P=1.85 × 10−8) between lifetime cannabis use and lifetime cigarette smoking implying that the SNP effect sizes of the two traits are highly correlated. This is the largest meta-analysis of cannabis GWA studies to date, revealing important new insights into the genetic pathways of lifetime cannabis use. Future functional studies should explore the impact of the identified genes on the biological mechanisms of cannabis use.

Original language	English
Article number	e769
Journal	Translational Psychiatry
Volume	6
DOIs	https://doi.org/10.1038/tp.2016.36
Publication status	Published - 29 Mar 2016

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Stringer, S., Minica, C. C., Verweij, K. J. H., Mbarek, H., Bernard, M., Derringer, J., van Eijk, K. R., Isen, J. D., Loukola, A., Maciejewski, D. F., Mihailov, E., van der Most, P. J., Sanchez-Mora, C., Roos, L., Sherva, R., Walters, R., Ware, J. J., Abdellaoui, A., Bigdeli, T. B., ... Vink, J. M. (2016). Genome-wide association study of lifetime cannabis use based on a large meta-analytic sample of 32330 subjects from the International Cannabis Consortium. Translational Psychiatry, 6, Article e769. https://doi.org/10.1038/tp.2016.36

@article{4f099549b17c4ac9971b4abc4707da5c,

title = "Genome-wide association study of lifetime cannabis use based on a large meta-analytic sample of 32330 subjects from the International Cannabis Consortium",

abstract = "Cannabis is the most widely produced and consumed illicit psychoactive substance worldwide. Occasional cannabis use can progress to frequent use, abuse and dependence with all known adverse physical, psychological and social consequences. Individual differences in cannabis initiation are heritable (40–48%). The International Cannabis Consortium was established with the aim to identify genetic risk variants of cannabis use. We conducted a meta-analysis of genome-wide association data of 13 cohorts (N=32 330) and four replication samples (N=5627). In addition, we performed a gene-based test of association, estimated single-nucleotide polymorphism (SNP)-based heritability and explored the genetic correlation between lifetime cannabis use and cigarette use using LD score regression. No individual SNPs reached genome-wide significance. Nonetheless, gene-based tests identified four genes significantly associated with lifetime cannabis use: NCAM1, CADM2, SCOC and KCNT2. Previous studies reported associations of NCAM1 with cigarette smoking and other substance use, and those of CADM2 with body mass index, processing speed and autism disorders, which are phenotypes previously reported to be associated with cannabis use. Furthermore, we showed that, combined across the genome, all common SNPs explained 13–20% (P<0.001) of the liability of lifetime cannabis use. Finally, there was a strong genetic correlation (rg=0.83; P=1.85 × 10−8) between lifetime cannabis use and lifetime cigarette smoking implying that the SNP effect sizes of the two traits are highly correlated. This is the largest meta-analysis of cannabis GWA studies to date, revealing important new insights into the genetic pathways of lifetime cannabis use. Future functional studies should explore the impact of the identified genes on the biological mechanisms of cannabis use.",

author = "S. Stringer and Minica, {C. C.} and Verweij, {K. J. H.} and H. Mbarek and M. Bernard and J. Derringer and {van Eijk}, {K. R.} and Isen, {J. D.} and A. Loukola and Maciejewski, {D. F.} and E. Mihailov and {van der Most}, {P. J.} and C. Sanchez-Mora and L. Roos and R. Sherva and R. Walters and Ware, {J. J.} and A. Abdellaoui and Bigdeli, {T. B.} and Branje, {S. J. T.} and Brown, {S. A.} and M. Bruinenberg and M. Casas and T. Esko and I. Garcia-Martinez and Gordon, {S. D.} and Harris, {J. M.} and Hartman, {C. A.} and Henders, {A. K.} and Heath, {A. C.} and Hickie, {I. B.} and M. Hickman and Hopfer, {C. J.} and Hottenga, {J. J.} and Huizink, {A. C.} and Irons, {D. E.} and Kahn, {R. S.} and T. Korhonen and Kranzler, {H. R.} and K. Krauter and {van Lier}, {P. A. C.} and Lubke, {G. H.} and Madden, {P. A. F.} and R. Magi and McGue, {M. K.} and Medland, {S. E.} and Meeus, {W. H. J.} and Miller, {M. B.} and Montgomery, {G. W.} and Nivard, {M. G.} and Nolte, {I. M.} and Oldehinkel, {A. J.} and Z. Pausova and B. Qaiser and L. Quaye and Ramos-Quiroga, {J. A.} and V. Richarte and Rose, {R. J.} and J. Shin and Stallings, {M. C.} and Stiby, {A. I.} and Wall, {T. L.} and Wright, {M. J.} and Koot, {H. M.} and T. Paus and Hewitt, {J. K.} and M. Ribases and J. Kaprio and Boks, {M. P.} and H. Snieder and T. Spector and Munafo, {M. R.} and A. Metspalu and J. Gelernter and Boomsma, {D. I.} and Iacono, {W. G.} and Martin, {N. G.} and Gillespie, {N. A.} and Derks, {E. M.} and Vink, {J. M.}",

year = "2016",

month = mar,

day = "29",

doi = "10.1038/tp.2016.36",

language = "English",

volume = "6",

journal = "Translational Psychiatry",

issn = "2158-3188",

publisher = "Nature Publishing Group",

}

Stringer, S, Minica, CC, Verweij, KJH, Mbarek, H, Bernard, M, Derringer, J, van Eijk, KR, Isen, JD, Loukola, A, Maciejewski, DF, Mihailov, E, van der Most, PJ, Sanchez-Mora, C, Roos, L, Sherva, R, Walters, R, Ware, JJ, Abdellaoui, A, Bigdeli, TB, Branje, SJT, Brown, SA, Bruinenberg, M, Casas, M, Esko, T, Garcia-Martinez, I, Gordon, SD, Harris, JM, Hartman, CA, Henders, AK, Heath, AC, Hickie, IB, Hickman, M, Hopfer, CJ, Hottenga, JJ, Huizink, AC, Irons, DE, Kahn, RS, Korhonen, T, Kranzler, HR, Krauter, K, van Lier, PAC, Lubke, GH, Madden, PAF, Magi, R, McGue, MK, Medland, SE, Meeus, WHJ, Miller, MB, Montgomery, GW, Nivard, MG, Nolte, IM, Oldehinkel, AJ, Pausova, Z, Qaiser, B, Quaye, L, Ramos-Quiroga, JA, Richarte, V, Rose, RJ, Shin, J, Stallings, MC, Stiby, AI, Wall, TL, Wright, MJ, Koot, HM, Paus, T, Hewitt, JK, Ribases, M, Kaprio, J, Boks, MP, Snieder, H, Spector, T, Munafo, MR, Metspalu, A, Gelernter, J, Boomsma, DI, Iacono, WG, Martin, NG, Gillespie, NA, Derks, EM & Vink, JM 2016, 'Genome-wide association study of lifetime cannabis use based on a large meta-analytic sample of 32330 subjects from the International Cannabis Consortium', Translational Psychiatry, vol. 6, e769. https://doi.org/10.1038/tp.2016.36

TY - JOUR

T1 - Genome-wide association study of lifetime cannabis use based on a large meta-analytic sample of 32330 subjects from the International Cannabis Consortium

AU - Stringer, S.

AU - Minica, C. C.

AU - Verweij, K. J. H.

AU - Mbarek, H.

AU - Bernard, M.

AU - Derringer, J.

AU - van Eijk, K. R.

AU - Isen, J. D.

AU - Loukola, A.

AU - Maciejewski, D. F.

AU - Mihailov, E.

AU - van der Most, P. J.

AU - Sanchez-Mora, C.

AU - Roos, L.

AU - Sherva, R.

AU - Walters, R.

AU - Ware, J. J.

AU - Abdellaoui, A.

AU - Bigdeli, T. B.

AU - Branje, S. J. T.

AU - Brown, S. A.

AU - Bruinenberg, M.

AU - Casas, M.

AU - Esko, T.

AU - Garcia-Martinez, I.

AU - Gordon, S. D.

AU - Harris, J. M.

AU - Hartman, C. A.

AU - Henders, A. K.

AU - Heath, A. C.

AU - Hickie, I. B.

AU - Hickman, M.

AU - Hopfer, C. J.

AU - Hottenga, J. J.

AU - Huizink, A. C.

AU - Irons, D. E.

AU - Kahn, R. S.

AU - Korhonen, T.

AU - Kranzler, H. R.

AU - Krauter, K.

AU - van Lier, P. A. C.

AU - Lubke, G. H.

AU - Madden, P. A. F.

AU - Magi, R.

AU - McGue, M. K.

AU - Medland, S. E.

AU - Meeus, W. H. J.

AU - Miller, M. B.

AU - Montgomery, G. W.

AU - Nivard, M. G.

AU - Nolte, I. M.

AU - Oldehinkel, A. J.

AU - Pausova, Z.

AU - Qaiser, B.

AU - Quaye, L.

AU - Ramos-Quiroga, J. A.

AU - Richarte, V.

AU - Rose, R. J.

AU - Shin, J.

AU - Stallings, M. C.

AU - Stiby, A. I.

AU - Wall, T. L.

AU - Wright, M. J.

AU - Koot, H. M.

AU - Paus, T.

AU - Hewitt, J. K.

AU - Ribases, M.

AU - Kaprio, J.

AU - Boks, M. P.

AU - Snieder, H.

AU - Spector, T.

AU - Munafo, M. R.

AU - Metspalu, A.

AU - Gelernter, J.

AU - Boomsma, D. I.

AU - Iacono, W. G.

AU - Martin, N. G.

AU - Gillespie, N. A.

AU - Derks, E. M.

AU - Vink, J. M.

PY - 2016/3/29

Y1 - 2016/3/29

N2 - Cannabis is the most widely produced and consumed illicit psychoactive substance worldwide. Occasional cannabis use can progress to frequent use, abuse and dependence with all known adverse physical, psychological and social consequences. Individual differences in cannabis initiation are heritable (40–48%). The International Cannabis Consortium was established with the aim to identify genetic risk variants of cannabis use. We conducted a meta-analysis of genome-wide association data of 13 cohorts (N=32 330) and four replication samples (N=5627). In addition, we performed a gene-based test of association, estimated single-nucleotide polymorphism (SNP)-based heritability and explored the genetic correlation between lifetime cannabis use and cigarette use using LD score regression. No individual SNPs reached genome-wide significance. Nonetheless, gene-based tests identified four genes significantly associated with lifetime cannabis use: NCAM1, CADM2, SCOC and KCNT2. Previous studies reported associations of NCAM1 with cigarette smoking and other substance use, and those of CADM2 with body mass index, processing speed and autism disorders, which are phenotypes previously reported to be associated with cannabis use. Furthermore, we showed that, combined across the genome, all common SNPs explained 13–20% (P<0.001) of the liability of lifetime cannabis use. Finally, there was a strong genetic correlation (rg=0.83; P=1.85 × 10−8) between lifetime cannabis use and lifetime cigarette smoking implying that the SNP effect sizes of the two traits are highly correlated. This is the largest meta-analysis of cannabis GWA studies to date, revealing important new insights into the genetic pathways of lifetime cannabis use. Future functional studies should explore the impact of the identified genes on the biological mechanisms of cannabis use.

AB - Cannabis is the most widely produced and consumed illicit psychoactive substance worldwide. Occasional cannabis use can progress to frequent use, abuse and dependence with all known adverse physical, psychological and social consequences. Individual differences in cannabis initiation are heritable (40–48%). The International Cannabis Consortium was established with the aim to identify genetic risk variants of cannabis use. We conducted a meta-analysis of genome-wide association data of 13 cohorts (N=32 330) and four replication samples (N=5627). In addition, we performed a gene-based test of association, estimated single-nucleotide polymorphism (SNP)-based heritability and explored the genetic correlation between lifetime cannabis use and cigarette use using LD score regression. No individual SNPs reached genome-wide significance. Nonetheless, gene-based tests identified four genes significantly associated with lifetime cannabis use: NCAM1, CADM2, SCOC and KCNT2. Previous studies reported associations of NCAM1 with cigarette smoking and other substance use, and those of CADM2 with body mass index, processing speed and autism disorders, which are phenotypes previously reported to be associated with cannabis use. Furthermore, we showed that, combined across the genome, all common SNPs explained 13–20% (P<0.001) of the liability of lifetime cannabis use. Finally, there was a strong genetic correlation (rg=0.83; P=1.85 × 10−8) between lifetime cannabis use and lifetime cigarette smoking implying that the SNP effect sizes of the two traits are highly correlated. This is the largest meta-analysis of cannabis GWA studies to date, revealing important new insights into the genetic pathways of lifetime cannabis use. Future functional studies should explore the impact of the identified genes on the biological mechanisms of cannabis use.

U2 - 10.1038/tp.2016.36

DO - 10.1038/tp.2016.36

M3 - Article

SN - 2158-3188

VL - 6

JO - Translational Psychiatry

JF - Translational Psychiatry

M1 - e769

ER -

Genome-wide association study of lifetime cannabis use based on a large meta-analytic sample of 32330 subjects from the International Cannabis Consortium

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