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[Preprint]. 2023 Jan 30:2023.01.24.23284960.

doi: 10.1101/2023.01.24.23284960.

Multi-ancestry study of the genetics of problematic alcohol use in >1 million individuals

Hang Zhou^{1

2

3}, Rachel L Kember^{4

5

3}, Joseph D Deak^{1

2}, Heng Xu⁵, Sylvanus Toikumo^{4

5}, Kai Yuan^{6

7}, Penelope A Lind^{8

9

10}, Leila Farajzadeh^{11

12

13}, Lu Wang^{1

2}, Alexander S Hatoum¹⁴, Jessica Johnson^{15

16}, Hyunjoon Lee¹⁷, Travis T Mallard^{6

17

18}, Jiayi Xu¹, Keira J A Johnston¹, Emma C Johnson¹⁹, Marco Galimberti^{1

2}, Cecilia Dao^{2

20}, Daniel F Levey^{1

2}, Cassie Overstreet^{1

2}, Enda M Byrne²¹, Nathan A Gillespie²², Scott Gordon²³, Ian B Hickie²⁴, John B Whitfield²³, Ke Xu^{1

2}, Hongyu Zhao^{25

26}, Laura M Huckins¹, Lea K Davis^{27

28

29}, Sandra Sanchez-Roige^{28

30}, Pamela A F Madden¹⁹, Andrew C Heath¹⁹, Sarah E Medland^{8

10

31}, Nicholas G Martin²³, Tian Ge^{6

17

32}, Jordan W Smoller^{6

17

18}, David M Hougaard^{12

33}, Anders D Børglum^{11

12

13}, Ditte Demontis^{11

12

13}, John H Krystal^{1

2

34

35}, J Michael Gaziano^{36

37

38}, Howard J Edenberg^{39

40}, Arpana Agrawal¹⁹; Million Veteran Program; Amy C Justice^{2

41

42}, Murray B Stein^{30

43

44}, Henry R Kranzler^{4

5

45}, Joel Gelernter^{1

2

25

34

45}

Affiliations

¹ Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.
² Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA.
³ These authors contributed equally.
⁴ Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA.
⁵ Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁶ Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁷ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁸ Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
⁹ School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia.
¹⁰ Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.
¹¹ Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, Denmark.
¹² The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.
¹³ Center for Genomics and Personalized Medicine, Aarhus, Denmark.
¹⁴ Department of Psychological and Brain Sciences, Washington University in St. Louis, Saint Louis, MO, USA.
¹⁵ Pamela Sklar Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁶ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁷ Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹⁸ Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹⁹ Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, USA.
²⁰ Department of Chronic Disease Epidemiology, Yale University School of Public Health, New Haven, CT, USA.
²¹ Child Health Research Centre, The University of Queensland, Brisbane, QLD, Australia.
²² Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA.
²³ Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
²⁴ Brain and Mind Centre, University of Sydney, Camperdown, NSW, Australia.
²⁵ Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA.
²⁶ Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
²⁷ Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
²⁸ Department of Medicine, Division of Medical Genetics, Vanderbilt University Medical Center, Nashville, TN, USA.
²⁹ Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.
³⁰ Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
³¹ School of Psychology, University of Queensland, Brisbane, QLD, Australia.
³² Center for Precision Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
³³ Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
³⁴ Department of Neuroscience, Yale University School of Medicine, New Haven, CT, USA.
³⁵ National Center for PTSD, US Department of Veterans Affairs, West Haven, CT, USA.
³⁶ Massachusetts Veterans Epidemiology and Research Information Center (MAVERIC), Boston Veterans Affairs Healthcare System, Boston, MA, USA.
³⁷ Department of Medicine, Divisions of Aging and Preventative Medicine, Brigham and Women's Hospital, Boston, MA, USA.
³⁸ Department of Medicine, Harvard Medical School, Boston, MA, USA.
³⁹ Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
⁴⁰ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
⁴¹ Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
⁴² Center for Interdisciplinary Research on AIDS, Yale School of Public Health, New Haven, CT, USA.
⁴³ VA San Diego Healthcare System, Psychiatry Service, San Diego, CA, USA.
⁴⁴ Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, CA, USA.
⁴⁵ These authors jointly supervised this work.

PMID: 36747741
PMCID: PMC9901058
DOI: 10.1101/2023.01.24.23284960

Multi-ancestry study of the genetics of problematic alcohol use in >1 million individuals

Hang Zhou et al. medRxiv. 2023.

[Preprint]. 2023 Jan 30:2023.01.24.23284960.

doi: 10.1101/2023.01.24.23284960.

Authors

Affiliations

¹ Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.
² Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA.
³ These authors contributed equally.
⁴ Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA.
⁵ Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁶ Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁷ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁸ Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
⁹ School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia.
¹⁰ Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.
¹¹ Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, Denmark.
¹² The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.
¹³ Center for Genomics and Personalized Medicine, Aarhus, Denmark.
¹⁴ Department of Psychological and Brain Sciences, Washington University in St. Louis, Saint Louis, MO, USA.
¹⁵ Pamela Sklar Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁶ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁷ Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹⁸ Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹⁹ Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, USA.
²⁰ Department of Chronic Disease Epidemiology, Yale University School of Public Health, New Haven, CT, USA.
²¹ Child Health Research Centre, The University of Queensland, Brisbane, QLD, Australia.
²² Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA.
²³ Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
²⁴ Brain and Mind Centre, University of Sydney, Camperdown, NSW, Australia.
²⁵ Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA.
²⁶ Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
²⁷ Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
²⁸ Department of Medicine, Division of Medical Genetics, Vanderbilt University Medical Center, Nashville, TN, USA.
²⁹ Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.
³⁰ Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
³¹ School of Psychology, University of Queensland, Brisbane, QLD, Australia.
³² Center for Precision Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
³³ Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
³⁴ Department of Neuroscience, Yale University School of Medicine, New Haven, CT, USA.
³⁵ National Center for PTSD, US Department of Veterans Affairs, West Haven, CT, USA.
³⁶ Massachusetts Veterans Epidemiology and Research Information Center (MAVERIC), Boston Veterans Affairs Healthcare System, Boston, MA, USA.
³⁷ Department of Medicine, Divisions of Aging and Preventative Medicine, Brigham and Women's Hospital, Boston, MA, USA.
³⁸ Department of Medicine, Harvard Medical School, Boston, MA, USA.
³⁹ Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
⁴⁰ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
⁴¹ Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
⁴² Center for Interdisciplinary Research on AIDS, Yale School of Public Health, New Haven, CT, USA.
⁴³ VA San Diego Healthcare System, Psychiatry Service, San Diego, CA, USA.
⁴⁴ Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, CA, USA.
⁴⁵ These authors jointly supervised this work.

PMID: 36747741
PMCID: PMC9901058
DOI: 10.1101/2023.01.24.23284960

Update in

Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals.
Zhou H, Kember RL, Deak JD, Xu H, Toikumo S, Yuan K, Lind PA, Farajzadeh L, Wang L, Hatoum AS, Johnson J, Lee H, Mallard TT, Xu J, Johnston KJA, Johnson EC, Nielsen TT, Galimberti M, Dao C, Levey DF, Overstreet C, Byrne EM, Gillespie NA, Gordon S, Hickie IB, Whitfield JB, Xu K, Zhao H, Huckins LM, Davis LK, Sanchez-Roige S, Madden PAF, Heath AC, Medland SE, Martin NG, Ge T, Smoller JW, Hougaard DM, Børglum AD, Demontis D, Krystal JH, Gaziano JM, Edenberg HJ, Agrawal A; Million Veteran Program; Justice AC, Stein MB, Kranzler HR, Gelernter J. Zhou H, et al. Nat Med. 2023 Dec;29(12):3184-3192. doi: 10.1038/s41591-023-02653-5. Epub 2023 Dec 7. Nat Med. 2023. PMID: 38062264 Free PMC article.

Abstract

Problematic alcohol use (PAU) is a leading cause of death and disability worldwide. To improve our understanding of the genetics of PAU, we conducted a large cross-ancestry meta-analysis of PAU in 1,079,947 individuals. We observed a high degree of cross-ancestral similarity in the genetic architecture of PAU and identified 110 independent risk variants in within- and cross-ancestry analyses. Cross-ancestry fine-mapping improved the identification of likely causal variants. Prioritizing genes through gene expression and/or chromatin interaction in brain tissues identified multiple genes associated with PAU. We identified existing medications for potential pharmacological studies by drug repurposing analysis. Cross-ancestry polygenic risk scores (PRS) showed better performance in independent sample than single-ancestry PRS. Genetic correlations between PAU and other traits were observed in multiple ancestries, with other substance use traits having the highest correlations. The analysis of diverse ancestries contributed significantly to the findings, and fills an important gap in the literature.

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Conflict of interest statement

Disclosure: H.R.K. is a member of advisory boards for Dicerna Pharmaceuticals, Sophrosyne Pharmaceuticals, and Enthion Pharmaceuticals; a consultant to Sobrera Pharmaceuticals; the recipient of research funding and medication supplies for an investigator-initiated study from Alkermes; and a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which was supported in the past 3 years by Alkermes, Dicerna, Ethypharm, Lundbeck, Mitsubishi, Otsuka, and Pear Therapeutics. M.B.S. has in the past 3 years been a consultant for Actelion, Acadia Pharmaceuticals, Aptinyx, Bionomics, BioXcel Therapeutics, Clexio, EmpowerPharm, Epivario, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, Roche/Genentech and Oxeia Biopharmaceuticals. M.B.S. has stock options in Oxeia Biopharmaceuticals and Epivario. He also receives payment from the following entities for editorial work: Biological Psychiatry (published by Elsevier), Depression and Anxiety (published by Wiley) and UpToDate. J.G. and H.R.K. hold US patent 10,900,082 titled: “Genotype-guided dosing of opioid agonists,” issued January 26, 2021. J.G. is paid for his editorial work on the journal Complex Psychiatry. J.H.K. has consulting agreements (less than US$10,000 per year) with the following: AstraZeneca Pharmaceuticals, Biogen, Idec, MA, Biomedisyn Corporation, Bionomics, Limited (Australia), Boehringer Ingelheim International, COMPASS Pathways, Limited, United Kingdom, Concert Pharmaceuticals, Inc., Epiodyne, Inc., EpiVario, Inc., Heptares Therapeutics, Limited (UK), Janssen Research & Development, Otsuka America, Pharmaceutical, Inc., Perception Neuroscience Holdings, Inc., Spring Care, Inc., Sunovion Pharmaceuticals, Inc., Takeda Industries and Taisho Pharmaceutical Co., Ltd. J.H.K. serves on the scientific advisory boards of Bioasis Technologies, Inc., Biohaven Pharmaceuticals, BioXcel Therapeutics, Inc. (Clinical Advisory Board), BlackThorn Therapeutics, Inc., Cadent Therapeutics (Clinical Advisory Board), Cerevel Therapeutics, LLC., EpiVario, Inc., Lohocla Research Corporation, PsychoGenics, Inc.; is on the board of directors of Inheris Biopharma, Inc.; has stock options with Biohaven Pharmaceuticals Medical Sciences, BlackThorn Therapeutics, Inc., EpiVario, Inc. and Terran Life Sciences; and is editor of Biological Psychiatry with income greater than $10,000. I.B.H. is the Co-Director of Health and Policy at the Brain and Mind Centre (BMC) University of Sydney. The BMC operates an early-intervention youth services at Camperdown under contract to Headspace. He is the Chief Scientific Advisor to, and a 3.2% equity shareholder in, InnoWell Pty Ltd. InnoWell was formed by the University of Sydney (45% equity) and PwC (Australia; 45% equity) to deliver the $30 M Australian Government-funded Project Synergy (2017-20; a three-year program for the transformation of mental health services) and to lead transformation of mental health services internationally through the use of innovative technologies. J.W.S. is a member of the Leon Levy Foundation Neuroscience Advisory Board, the Scientific Advisory Board of Sensorium Therapeutics (with equity), and has received grant support from Biogen, Inc. He is PI of a collaborative study of the genetics of depression and bipolar disorder sponsored by 23andMe for which 23andMe provides analysis time as in-kind support but no payments. All other authors report no biomedical financial interests or potential conflicts of interest.

Figures

**Figure 1.. Genetic architecture of problematic alcohol use (PAU).**
a, Sample sizes in different ancestral groups. b, Relationship between sample size and number of independent variants identified. Kranzler et al., 2019: cross-ancestry meta-analysis for AUD; Zhou et al., 2020: PAU in EUR. c, Lookup for cross-ancestry replication in AFR for the 85 independent variants in EUR meta-analysis. Of the 85 variants, 76 could be analyzed in AFR (see Methods). Sign test was performed for the number of variants with same direction of effect (64/76, p=1.0×10⁻⁹). 23 variants were nominally significant in AFR and 6 were significant after multiple correction (p<0.05/76). d, Observed-scale and liability-scale SNP-based heritability (h²) in multiple ancestries. e, Cross-ancestry genetic-effect correlation (ρ_ge) and genetic-impact correlation (ρ_gi) between EUR, AFR and LA ancestries. Error bar is the 95% confidence interval. f, Genome-wide association results for PAU in the cross-ancestry meta-analysis. Red line is significance threshold of 5×10⁻⁸. EUR, European; AFR, African; LA, Latin American; EAS, East Asian; SAS, South Asian; GWS, genome-wide significant.

**Figure 2.. Fine-mapping for PAU.**
a, Fine-mapping of causal variants in 85 regions in EUR. b, 92 regions in cross-ancestry analysis were fine-mapped and a direct comparison was done for these regions in EUR. c, Comparison for the highest PIPs from cross-ancestry and EUR-only fine-mapping in the 92 regions. Red dots are the regions fine-mapped across EUR, AFR, and LA; blue dots are the regions fine-mapped across EUR and AFR; green dots are the regions fine-mapped across EUR and LA; black dots are the regions only fine-mapped in EUR. FM, fine-mapping.

**Figure 3.. Genetic correlations between AUD and traits in AFR.**
totalPCL, total index of recent symptom severity by PTSD checklist for DSM-IV. Traits labeled in bold font are genetically correlated with AUD after Bonferroni correction (p<3.83×10⁻³). Error bar is 95% confidence interval.

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References

1. Grant B.F., et al. Epidemiology of DSM-5 Alcohol Use Disorder: Results From the National Epidemiologic Survey on Alcohol and Related Conditions III. JAMA Psychiatry 72, 757–766 (2015). - PMC - PubMed
1. Verhulst B., Neale M.C. & Kendler K.S. The heritability of alcohol use disorders: a meta-analysis of twin and adoption studies. Psychol Med 45, 1061–1072 (2015). - PMC - PubMed
1. Gelernter J. & Polimanti R. Genetics of substance use disorders in the era of big data. Nat Rev Genet 22, 712–729 (2021). - PMC - PubMed
1. Sanchez-Roige S., et al. Genome-Wide Association Study Meta-Analysis of the Alcohol Use Disorders Identification Test (AUDIT) in Two Population-Based Cohorts. Am J Psychiatry 176, 107–118 (2019). - PMC - PubMed
1. Walters R.K., et al. Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders. Nat Neurosci 21, 1656–1669 (2018). - PMC - PubMed

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This is a preprint.

Multi-ancestry study of the genetics of problematic alcohol use in >1 million individuals

Affiliations

Multi-ancestry study of the genetics of problematic alcohol use in >1 million individuals

Authors

Affiliations

Update in

Abstract

Conflict of interest statement

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