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

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.

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Acknowledgements

AA acknowledges support from the National Institute on Drug Abuse (NIDA) for the core research pertaining to this study, via K02DA032573 and R01DA023668. CEC received support from the National Science Foundation (DGE-1143954) and the Mr and Mrs Spencer T Olin Fellowship Program. DAAB acknowledges NIMH (T32-GM008151) and NSF (DGE-1745038). JLM acknowledges K01DA037914. LD is supported by an Australian National Health and Medical Research Council (NHMRC) Principal Research Fellowship (1041472). LJB acknowledges R01DA036583. RB receives additional support from the National Institutes of Health (R01-AG045231, R01-HD083614 and U01-AG052564).

COGA: The Collaborative Study on the Genetics of Alcoholism (COGA), Principal Investigators B Porjesz, V Hesselbrock, H Edenberg, L Bierut, includes 11 different centers: University of Connecticut (V Hesselbrock); Indiana University (HJ Edenberg, J Nurnberger Jr and T Foroud); University of Iowa (S Kuperman and J Kramer); SUNY Downstate (B Porjesz); Washington University in St Louis (L Bierut, J Rice, K Bucholz and A Agrawal); University of California at San Diego (M Schuckit); Rutgers University (J Tischfield and A Brooks); Department of Biomedical and Health Informatics, The Children’s Hospital of Philadelphia; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA (L Almasy), Virginia Commonwealth University (D Dick), Icahn School of Medicine at Mount Sinai (A Goate) and Howard University (R Taylor). Other COGA collaborators include: L Bauer (University of Connecticut); J McClintick, L Wetherill, X Xuei, Y Liu, D Lai, S O’Connor, M Plawecki, S Lourens (Indiana University); G Chan (University of Iowa; University of Connecticut); J Meyers, D Chorlian, C Kamarajan, A Pandey, J Zhang (SUNY Downstate); J-C Wang, M Kapoor, S Bertelsen (Icahn School of Medicine at Mount Sinai); A Anokhin, V McCutcheon, S Saccone (Washington University); J Salvatore, F Aliev, B Cho (Virginia Commonwealth University); and Mark Kos (University of Texas Rio Grande Valley). A Parsian and M Reilly are the NIAAA Staff Collaborators.

Funding support for GWAS genotyping performed at the Johns Hopkins University Center for Inherited Disease Research was provided by the National Institute on Alcohol Abuse and Alcoholism, the NIH GEI (U01HG004438) and the NIH contract ‘High throughput genotyping for studying the genetic contributions to human disease’ (HHSN268200782096C). GWAS genotyping was also performed at the Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine, which is partially supported by NCI Cancer Center Support Grant P30 CA91842 to the Siteman Cancer Center and by ICTS/CTSA Grant UL1RR024992 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) and NIH Roadmap for Medical Research. COGA-f genotypic data are available via dbGaP: phs000763.v1.p1 and COGA-c genotypic data are available via phs000125.v1.p1

We continue to be inspired by our memories of Henri Begleiter and Theodore Reich, founding PI and Co-PI of COGA, and also owe a debt of gratitude to other past organizers of COGA, including Ting-Kai Li, P Michael Conneally, Raymond Crowe and Wendy Reich, for their critical contributions. This national collaborative study is supported by NIH Grant U10AA008401 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute on Drug Abuse (NIDA).

CATS (dbGaP: phs000277.v1.p1): Funding support for the Comorbidity and Trauma Study (CATS) was provided by the National Institute on Drug Abuse (R01 DA17305); GWAS genotyping services at the Center for Inherited Disease Research (CIDR) at The Johns Hopkins University were supported by the National Institutes of Health (contract N01-HG-65403). The National Drug and Alcohol Research Centre at the University of New South Wales is supported by funding from the Australian Government under the Substance Misuse Prevention and Service Improvements Grants Fund.

SAGE (dbGaP: phs000092.v1.p1): Funding support for the Study of Addiction: Genetics and Environment (SAGE) was provided through the NIH Genes, Environment and Health Initiative (GEI) (U01 HG004422). SAGE is one of the GWASs funded as part of the Gene Environment Association Studies (GENEVA) under GEI. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01 HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Support for collection of datasets and samples was provided by the Collaborative Study on the Genetics of Alcoholism (COGA; U10 AA008401), the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392) and the Family Study of Cocaine Dependence (FSCD; R01 DA013423, R01 DA019963). Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI (U01HG004438), the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, and the NIH contract ‘High throughput genotyping for studying the genetic contributions to human disease’(HHSN268200782096C).

OZALC+ (dbGaP: phs000181.v1.p1): Supported by NIH grants AA07535, AA07728, AA13320, AA13321, AA14041, AA11998, AA17688, DA012854, DA019951; by grants from the Australian National Health and Medical Research Council (241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 552485, 552498); by grants from the Australian Research Council (A7960034, A79906588, A79801419, DP0770096, DP0212016, DP0343921); and by the FP-5 GenomEUtwin Project (QLG2-CT-2002–01254). GWAS genotyping at CIDR was supported by a grant to the late Richard Todd, PhD, MD, former PI of grant AA13320 and a key contributor to research described in this manuscript. Project 7 data collection was also supported by AA011998_5978.

Yale-Penn: This study was supported by grants RC2 DA028909, R01 DA12690, R01 DA12849, R01 DA18432, R01 AA11330 and R01 AA017535 from the National Institutes of Health (NIH), the Veterans Affairs Connecticut Healthcare Center and the Philadelphia Veterans Affairs Mental Illness Research, Education and Clinical Center. A portion of the data are available via dbGaP (phs000277.v1.p1).

DNS: The Duke Neurogenetics Study is supported by Duke University and National Institute on Drug Abuse grant DA033369.

The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health. Additional funds were provided by the NCI, NHGRI, NHLBI, NIDA, NIMH and NINDS. Donors were enrolled at Biospecimen Source Sites funded by NCI\SAIC-Frederick, Inc. (SAIC-F) subcontracts to the National Disease Research Interchange (10XS170), Roswell Park Cancer Institute (10XS171) and Science Care, Inc. (X10S172). The Laboratory, Data Analysis and Coordinating Center (LDACC) was funded through a contract (HHSN268201000029C) to The Broad Institute, Inc. Biorepository operations were funded through an SAIC-F subcontract to Van Andel Institute (10ST1035). Additional data repository and project management were provided by SAIC-F (HHSN261200800001E). The Brain Bank was supported by a supplements to University of Miami grants DA006227 and DA033684, and to contract N01MH000028. Statistical Methods development grants were made to the University of Geneva (MH090941 and MH101814), the University of Chicago (MH090951, MH090937, MH101820 and MH101825), the University of North Carolina—Chapel Hill (MH090936 and MH101819), Harvard University (MH090948), Stanford University (MH101782), Washington University St Louis (MH101810) and the University of Pennsylvania (MH101822). The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 09/24/2016.

Data were generated as part of the CommonMind Consortium supported by funding from Takeda Pharmaceuticals Company Limited, F Hoffman-La Roche Ltd and NIH grants R01MH085542, R01MH093725, P50MH066392, P50MH080405, R01MH097276, RO1-MH-075916, P50M096891, P50MH084053S1, R37MH057881 and R37MH057881S1, HHSN271201300031C, AG02219, AG05138 and MH06692. Brain tissue for the study was obtained from the following brain bank collections: the Mount Sinai NIH Brain and Tissue Repository, the University of Pennsylvania Alzheimer’s Disease Core Center, the University of Pittsburgh NeuroBioBank and Brain and Tissue Repositories and the NIMH Human Brain Collection Core. CMC Leadership: Pamela Sklar, Joseph Buxbaum (Icahn School of Medicine at Mount Sinai), Bernie Devlin, David Lewis (University of Pittsburgh), Raquel Gur, Chang-Gyu Hahn (University of Pennsylvania), Keisuke Hirai, Hiroyoshi Toyoshiba (Takeda Pharmaceuticals Company Limited), Enrico Domenici, Laurent Essioux (F. Hoffman-La Roche Ltd), Lara Mangravite, Mette Peters (Sage Bionetworks), Thomas Lehner, Barbara Lipska (NIMH).

Expression and covariate data for the methylation eQTL analysis was derived from https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE15745. Genotypes were derived via authorized access to MK, JCW and AG from dbGaP (phs000249.v2.p1). Funding support for the ‘Brain eQTL (expression data) Study’ was provided through the Division of Aging Biology and the Division of Geriatrics and Clinical Gerontology, NIA. The Brain eQTL (expression data) Study includes a GWAS funded as part of the Intramural Research Program, NIA. Funding sources: Z01 AG000949-02 and Z01 AG000015-49.

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We disclose that Drs LJ Bierut, JP Rice, J-C Wang and AM Goate are listed as inventors on the patent ‘Markers for Addiction’ (US 20070258898) covering the use of certain SNPs in determining the diagnosis, prognosis and treatment of addiction. Dr Kranzler has been a consultant, advisory board member or CME speaker for Lundbeck, and Indivior. He is also a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative (ACTIVE), which was supported in the last three years by AbbVie, Alkermes, Ethypharm, Indivior, Lilly, Lundbeck, Otsuka, Pfizer, Arbor and Amygdala Neurosciences. Dr Nurnberger is an investigator for Assurex and a consultant for Janssen. All other authors declare no conflicts of interest.

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Agrawal, A., Chou, YL., Carey, C. et al. Genome-wide association study identifies a novel locus for cannabis dependence. Mol Psychiatry 23, 1293–1302 (2018). https://doi.org/10.1038/mp.2017.200

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