Genome-wide association study identifies a novel locus for cannabis dependence

A. Agrawal, Y. L. Chou, C. E. Carey, D. A.A. Baranger, B. Zhang, R. Sherva, L. Wetherill, M. Kapoor, J. C. Wang, S. Bertelsen, A. P. Anokhin, V. Hesselbrock, J. Kramer, M. T. Lynskey, J. L. Meyers, John Nurnberger, J. P. Rice, J. Tischfield, L. J. Bierut, L. DegenhardtL. A. Farrer, J. Gelernter, A. R. Hariri, A. C. Heath, H. R. Kranzler, P. A.F. Madden, N. G. Martin, G. W. Montgomery, B. Porjesz, T. Wang, J. B. Whitfield, Howard Edenberg, Tatiana Foroud, A. M. Goate, R. Bogdan, E. C. Nelson

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Despite moderate heritability, only one study has identified genome-wide significant loci for cannabis-related phenotypes. We conducted meta-analyses of genome-wide association study data on 2080 cannabis-dependent cases and 6435 cannabis-exposed controls of European descent. A cluster of correlated single-nucleotide polymorphisms (SNPs) in a novel region on chromosome 10 was genome-wide significant (lowest P=1.3E-8). Among the SNPs, rs1409568 showed enrichment for H3K4me1 and H3K427ac marks, suggesting its role as an enhancer in addiction-relevant brain regions, such as the dorsolateral prefrontal cortex and the angular and cingulate gyri. This SNP is also predicted to modify binding scores for several transcription factors. We found modest evidence for replication for rs1409568 in an independent cohort of African American (896 cases and 1591 controls; P=0.03) but not European American (EA; 781 cases and 1905 controls) participants. The combined meta-analysis (3757 cases and 9931 controls) indicated trend-level significance for rs1409568 (P=2.85E-7). No genome-wide significant loci emerged for cannabis dependence criterion count (n=8050). There was also evidence that the minor allele of rs1409568 was associated with a 2.1% increase in right hippocampal volume in an independent sample of 430 EA college students (fwe-P=0.008). The identification and characterization of genome-wide significant loci for cannabis dependence is among the first steps toward understanding the biological contributions to the etiology of this psychiatric disorder, which appears to be rising in some developed nations.

Original languageEnglish (US)
Pages (from-to)1293-1302
Number of pages10
JournalMolecular Psychiatry
Volume23
Issue number5
DOIs
StatePublished - May 1 2018

Fingerprint

Marijuana Abuse
Genome-Wide Association Study
Cannabis
Genome
Single Nucleotide Polymorphism
Meta-Analysis
Chromosomes, Human, Pair 10
Parietal Lobe
Gyrus Cinguli
Prefrontal Cortex
Developed Countries
African Americans
Psychiatry
Transcription Factors
Alleles
Students
Phenotype
Brain

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Agrawal, A., Chou, Y. L., Carey, C. E., Baranger, D. A. A., Zhang, B., Sherva, R., ... Nelson, E. C. (2018). Genome-wide association study identifies a novel locus for cannabis dependence. Molecular Psychiatry, 23(5), 1293-1302. https://doi.org/10.1038/mp.2017.200

Genome-wide association study identifies a novel locus for cannabis dependence. / Agrawal, A.; Chou, Y. L.; Carey, C. E.; Baranger, D. A.A.; Zhang, B.; Sherva, R.; Wetherill, L.; Kapoor, M.; Wang, J. C.; Bertelsen, S.; Anokhin, A. P.; Hesselbrock, V.; Kramer, J.; Lynskey, M. T.; Meyers, J. L.; Nurnberger, John; Rice, J. P.; Tischfield, J.; Bierut, L. J.; Degenhardt, L.; Farrer, L. A.; Gelernter, J.; Hariri, A. R.; Heath, A. C.; Kranzler, H. R.; Madden, P. A.F.; Martin, N. G.; Montgomery, G. W.; Porjesz, B.; Wang, T.; Whitfield, J. B.; Edenberg, Howard; Foroud, Tatiana; Goate, A. M.; Bogdan, R.; Nelson, E. C.

In: Molecular Psychiatry, Vol. 23, No. 5, 01.05.2018, p. 1293-1302.

Research output: Contribution to journalArticle

Agrawal, A, Chou, YL, Carey, CE, Baranger, DAA, Zhang, B, Sherva, R, Wetherill, L, Kapoor, M, Wang, JC, Bertelsen, S, Anokhin, AP, Hesselbrock, V, Kramer, J, Lynskey, MT, Meyers, JL, Nurnberger, J, Rice, JP, Tischfield, J, Bierut, LJ, Degenhardt, L, Farrer, LA, Gelernter, J, Hariri, AR, Heath, AC, Kranzler, HR, Madden, PAF, Martin, NG, Montgomery, GW, Porjesz, B, Wang, T, Whitfield, JB, Edenberg, H, Foroud, T, Goate, AM, Bogdan, R & Nelson, EC 2018, 'Genome-wide association study identifies a novel locus for cannabis dependence', Molecular Psychiatry, vol. 23, no. 5, pp. 1293-1302. https://doi.org/10.1038/mp.2017.200
Agrawal A, Chou YL, Carey CE, Baranger DAA, Zhang B, Sherva R et al. Genome-wide association study identifies a novel locus for cannabis dependence. Molecular Psychiatry. 2018 May 1;23(5):1293-1302. https://doi.org/10.1038/mp.2017.200
Agrawal, A. ; Chou, Y. L. ; Carey, C. E. ; Baranger, D. A.A. ; Zhang, B. ; Sherva, R. ; Wetherill, L. ; Kapoor, M. ; Wang, J. C. ; Bertelsen, S. ; Anokhin, A. P. ; Hesselbrock, V. ; Kramer, J. ; Lynskey, M. T. ; Meyers, J. L. ; Nurnberger, John ; Rice, J. P. ; Tischfield, J. ; Bierut, L. J. ; Degenhardt, L. ; Farrer, L. A. ; Gelernter, J. ; Hariri, A. R. ; Heath, A. C. ; Kranzler, H. R. ; Madden, P. A.F. ; Martin, N. G. ; Montgomery, G. W. ; Porjesz, B. ; Wang, T. ; Whitfield, J. B. ; Edenberg, Howard ; Foroud, Tatiana ; Goate, A. M. ; Bogdan, R. ; Nelson, E. C. / Genome-wide association study identifies a novel locus for cannabis dependence. In: Molecular Psychiatry. 2018 ; Vol. 23, No. 5. pp. 1293-1302.
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AU - Zhang, B.

AU - Sherva, R.

AU - Wetherill, L.

AU - Kapoor, M.

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AU - Bertelsen, S.

AU - Anokhin, A. P.

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AU - Degenhardt, L.

AU - Farrer, L. A.

AU - Gelernter, J.

AU - Hariri, A. R.

AU - Heath, A. C.

AU - Kranzler, H. R.

AU - Madden, P. A.F.

AU - Martin, N. G.

AU - Montgomery, G. W.

AU - Porjesz, B.

AU - Wang, T.

AU - Whitfield, J. B.

AU - Edenberg, Howard

AU - Foroud, Tatiana

AU - Goate, A. M.

AU - Bogdan, R.

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N2 - Despite moderate heritability, only one study has identified genome-wide significant loci for cannabis-related phenotypes. We conducted meta-analyses of genome-wide association study data on 2080 cannabis-dependent cases and 6435 cannabis-exposed controls of European descent. A cluster of correlated single-nucleotide polymorphisms (SNPs) in a novel region on chromosome 10 was genome-wide significant (lowest P=1.3E-8). Among the SNPs, rs1409568 showed enrichment for H3K4me1 and H3K427ac marks, suggesting its role as an enhancer in addiction-relevant brain regions, such as the dorsolateral prefrontal cortex and the angular and cingulate gyri. This SNP is also predicted to modify binding scores for several transcription factors. We found modest evidence for replication for rs1409568 in an independent cohort of African American (896 cases and 1591 controls; P=0.03) but not European American (EA; 781 cases and 1905 controls) participants. The combined meta-analysis (3757 cases and 9931 controls) indicated trend-level significance for rs1409568 (P=2.85E-7). No genome-wide significant loci emerged for cannabis dependence criterion count (n=8050). There was also evidence that the minor allele of rs1409568 was associated with a 2.1% increase in right hippocampal volume in an independent sample of 430 EA college students (fwe-P=0.008). The identification and characterization of genome-wide significant loci for cannabis dependence is among the first steps toward understanding the biological contributions to the etiology of this psychiatric disorder, which appears to be rising in some developed nations.

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