A large-scale genome-wide association study meta-analysis of cannabis use disorder

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Summary

Background

Variation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50–70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder.

Methods

To conduct this GWAS meta-analysis of cannabis use disorder and identify associations with genetic loci, we used samples from the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE (20 916 case samples, 363 116 control samples in total), contrasting cannabis use disorder cases with controls. To examine the genetic overlap between cannabis use disorder and 22 traits of interest (chosen because of previously published phenotypic correlations [eg, psychiatric disorders] or hypothesised associations [eg, chronotype] with cannabis use disorder), we used linkage disequilibrium score regression to calculate genetic correlations.

Findings

We identified two genome-wide significant loci: a novel chromosome 7 locus ( FOXP2, lead single-nucleotide polymorphism [SNP] rs7783012; odds ratio [OR] 1·11, 95% CI 1·07–1·15, p=1·84 × 10 ⁻⁹) and the previously identified chromosome 8 locus (near CHRNA2 and EPHX2, lead SNP rs4732724; OR 0·89, 95% CI 0·86–0·93, p=6·46 × 10 ⁻⁹). Cannabis use disorder and cannabis use were genetically correlated ( r _g 0·50, p=1·50 × 10 ⁻²¹), but they showed significantly different genetic correlations with 12 of the 22 traits we tested, suggesting at least partially different genetic underpinnings of cannabis use and cannabis use disorder. Cannabis use disorder was positively genetically correlated with other psychopathology, including ADHD, major depression, and schizophrenia.

Interpretation

These findings support the theory that cannabis use disorder has shared genetic liability with other psychopathology, and there is a distinction between genetic liability to cannabis use and cannabis use disorder.

Funding

National Institute of Mental Health; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing; The European Commission, Horizon 2020; National Institute of Child Health and Human Development; Health Research Council of New Zealand; National Institute on Aging; Wellcome Trust Case Control Consortium; UK Research and Innovation Medical Research Council (UKRI MRC); The Brain & Behavior Research Foundation; National Institute on Deafness and Other Communication Disorders; Substance Abuse and Mental Health Services Administration (SAMHSA); National Institute of Biomedical Imaging and Bioengineering; National Health and Medical Research Council (NHMRC) Australia; Tobacco-Related Disease Research Program of the University of California; Families for Borderline Personality Disorder Research (Beth and Rob Elliott) 2018 NARSAD Young Investigator Grant; The National Child Health Research Foundation (Cure Kids); The Canterbury Medical Research Foundation; The New Zealand Lottery Grants Board; The University of Otago; The Carney Centre for Pharmacogenomics; The James Hume Bequest Fund; National Institutes of Health: Genes, Environment and Health Initiative; National Institutes of Health; National Cancer Institute; The William T Grant Foundation; Australian Research Council; The Virginia Tobacco Settlement Foundation; The VISN 1 and VISN 4 Mental Illness Research, Education, and Clinical Centers of the US Department of Veterans Affairs; The 5th Framework Programme (FP-5) GenomEUtwin Project; The Lundbeck Foundation; NIH-funded Shared Instrumentation Grant S10RR025141; Clinical Translational Sciences Award grants; National Institute of Neurological Disorders and Stroke; National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences.

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Most cited references 66

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Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles

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Although genomewide RNA expression analysis has become a routine tool in biomedical research, extracting biological insight from such information remains a major challenge. Here, we describe a powerful analytical method called Gene Set Enrichment Analysis (GSEA) for interpreting gene expression data. The method derives its power by focusing on gene sets, that is, groups of genes that share common biological function, chromosomal location, or regulation. We demonstrate how GSEA yields insights into several cancer-related data sets, including leukemia and lung cancer. Notably, where single-gene analysis finds little similarity between two independent studies of patient survival in lung cancer, GSEA reveals many biological pathways in common. The GSEA method is embodied in a freely available software package, together with an initial database of 1,325 biologically defined gene sets.

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A global reference for human genetic variation

Lachlan Coin, Robert Garry, Oleksyk Taras (2018)

The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies.

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The Genotype-Tissue Expression (GTEx) project.

John M. Lonsdale, Jeffrey Thomas, Mike Salvatore … (2014)

Genome-wide association studies have identified thousands of loci for common diseases, but, for the majority of these, the mechanisms underlying disease susceptibility remain unknown. Most associated variants are not correlated with protein-coding changes, suggesting that polymorphisms in regulatory regions probably contribute to many disease phenotypes. Here we describe the Genotype-Tissue Expression (GTEx) project, which will establish a resource database and associated tissue bank for the scientific community to study the relationship between genetic variation and gene expression in human tissues.

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Author and article information

Contributors

Emma C Johnson

Journal

Journal ID (nlm-ta): Lancet Psychiatry

Journal ID (iso-abbrev): Lancet Psychiatry

Title: The Lancet. Psychiatry

Publisher: Elsevier

ISSN (Print): 2215-0366

ISSN (Electronic): 2215-0374

Publication date PMC-release: 1 December 2020

Publication date (Print): December 2020

Volume: 7

Issue: 12

Pages: 1032-1045

Affiliations

[a ]Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA

[b ]Department of Genetics, Washington University School of Medicine, St Louis, MO, USA

[c ]Division of Biostatistics, Washington University School of Medicine, St Louis, MO, USA

[d ]Department of Biomedicine—Human Genetics and Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark

[e ]National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark

[f ]Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark

[g ]The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark

[h ]Center for Genomics and Personalized Medicine, Aarhus, Denmark

[i ]CNS Department, Reykjavik, Iceland

[j ]Statistics Department, Reykjavik, Iceland

[k ]deCODE Genetics/Amgen, Reykjavik, Iceland

[l ]Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

[m ]Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA

[n ]Division of Human Genetics, Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA

[o ]Department of Genetics, and Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA

[p ]Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA

[q ]Department of Psychiatry, University of California San Diego, La Jolla, CA, USA

[r ]Department of Psychology and Office of Research Affairs, University of California San Diego, La Jolla, CA, USA

[s ]Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

[t ]Department of Psychiatry and Behavioral Sciences, and Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA

[u ]Department of Psychological and Brain Sciences, Washington University in Saint Louis, St. Louis, MO, USA

[v ]Division of Psychiatry, University of Edinburgh, Edinburgh, UK

[w ]Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA

[x ]Department of Psychiatry, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

[y ]School of Engineering and Natural Sciences, Iceland University, Reykjavik, Iceland

[z ]Department of Psychiatry, University of Utah, Salt Lake City, UT, USA

[aa ]Department of Psychology, Virginia Commonwealth University, Richmond, VA, USA

[ab ]Department of Human & Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA

[ac ]College Behavioral and Emotional Health Institute, Virginia Commonwealth University, Richmond, VA, USA

[ad ]Virginia Commonwealth University Alcohol Research Center, Virginia Commonwealth University, Richmond, VA, USA

[ae ]Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA

[af ]Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY, USA

[ag ]Department of Psychological Medicine, University of Otago, Christchurch, New Zealand

[ah ]Biostatistics and Computational Biology Unit, University of Otago, Christchurch, New Zealand

[ai ]Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand

[aj ]Department for Congenital Disorders, Center for Neonatal Screening, Statens Serum Institut, Copenhagen, Denmark

[ak ]Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, CO, USA

[al ]Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA

[am ]Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA

[an ]University of Colorado Boulder, Boulder, CO, USA

[ao ]National Drug and Alcohol Research Centre, University of New South Wales, Sydney, NSW, Australia

[ap ]Stanford University Graduate School of Education, Stanford University, Stanford, CA, USA

[aq ]Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA

[ar ]Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA

[as ]QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia

[at ]GenOmics, Bioinformatics, and Translational Research Center, Biostatistics and Epidemiology Division, RTI International, Research Triangle Park, Durham, NC, USA

[au ]Brain and Mind Centre, University of Sydney, Sydney, Australia

[av ]Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA

[aw ]Henri Begleiter Neurodynamics Laboratory, SUNY Downstate Health Sciences University, Brooklyn, NY, USA

[ax ]Institute for Molecular Bioscience, University of Queensland, QLD, Australia

[ay ]Queensland Brain Institute, University of Queensland, QLD, Australia

[az ]Psychosis Research Unit, Aarhus University Hospital, Aarhus, Denmark

[ba ]Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, University of Copenhagen, Copenhagen, Denmark

[bb ]School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA

[bc ]SAA—National Center of Addiction Medicine, Vogur Hospital, Reykjavik, Iceland

[bd ]Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA

[be ]Institute of Biological Psychiatry, Mental Health Services, Copenhagen University Hospital, Copenhagen, Denmark

[bf ]Department of Clinical Medicine, and Center for GeoGenetics, GLOBE Institute, University of Copenhagen, Copenhagen, Denmark

[bg ]Department of Psychology, University of Minnesota, Minneapolis, MN, USA

[bh ]Institute of Behavioral Science and Department of Sociology, University of Colorado Boulder, Boulder, CO, USA

[bi ]Department of Psychiatry, University of Vermont Medical Center, Burlington, VT, USA

[bj ]Department of Sociology, and The Carolina Population Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

[bk ]Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT, USA

[bl ]Department of Psychiatry, University of Colorado Denver, Aurora, CO, USA

[bm ]Center for Studies of Addiction, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

[bn ]VISN 4 MIRECC, Crescenz VAMC, Philadelphia, PA, USA

[bo ]Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

[bp ]Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland

Author notes

[* ]Correspondence to: Dr Emma C Johnson, Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO 63110, USA emma.c.johnson@ 123456wustl.edu

[*]

Contributed equally

[†]

Jointly supervised this work

Article

Publisher Item ID: S2215-0366(20)30339-4

DOI: 10.1016/S2215-0366(20)30339-4

PMC ID: 7674631

PubMed ID: 33096046

SO-VID: 0a892f5d-033b-4a82-94ae-d4738239fee3

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

A large-scale genome-wide association study meta-analysis of cannabis use disorder

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Summary

Background

Methods

Findings

Interpretation

Funding

Related collections

Core Readings in Statistical Mediation Analysis

Most cited references 66

Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles

A global reference for human genetic variation

The Genotype-Tissue Expression (GTEx) project.

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