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Meta-Analysis
. 2023 Dec;29(12):3184-3192.
doi: 10.1038/s41591-023-02653-5. Epub 2023 Dec 7.

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

Hang Zhou #  1   2   3 , Rachel L Kember #  4   5 , Joseph D Deak  6   7 , Heng Xu  5 , Sylvanus Toikumo  4   5 , Kai Yuan  8   9 , Penelope A Lind  10   11   12 , Leila Farajzadeh  13   14   15 , Lu Wang  6   7 , Alexander S Hatoum  16 , Jessica Johnson  17   18 , Hyunjoon Lee  19 , Travis T Mallard  8   19   20 , Jiayi Xu  6 , Keira J A Johnston  6 , Emma C Johnson  21 , Trine Tollerup Nielsen  13   14   15 , Marco Galimberti  6   7 , Cecilia Dao  6   7 , Daniel F Levey  6   7 , Cassie Overstreet  6   7 , Enda M Byrne  22 , Nathan A Gillespie  23 , Scott Gordon  24 , Ian B Hickie  25 , John B Whitfield  24 , Ke Xu  6   7 , Hongyu Zhao  26   27 , Laura M Huckins  6 , Lea K Davis  28   29   30 , Sandra Sanchez-Roige  29   31 , Pamela A F Madden  21 , Andrew C Heath  21 , Sarah E Medland  10   12   32 , Nicholas G Martin  24 , Tian Ge  8   19   33 , Jordan W Smoller  8   20   33 , David M Hougaard  14   34 , Anders D Børglum  13   14   15 , Ditte Demontis  13   14   15   35 , John H Krystal  6   7   36   37   38   39 , J Michael Gaziano  40   41   42 , Howard J Edenberg  43   44 , Arpana Agrawal  21 ; Million Veteran Program; Amy C Justice  7   45   46 , Murray B Stein  31   47   48 , Henry R Kranzler  4   5 , Joel Gelernter  49   50   51   52
Collaborators, Affiliations
Meta-Analysis

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

Hang Zhou et al. Nat Med. 2023 Dec.

Abstract

Problematic alcohol use (PAU), a trait that combines alcohol use disorder and alcohol-related problems assessed with a questionnaire, is a leading cause of death and morbidity worldwide. Here we conducted a large cross-ancestry meta-analysis of PAU in 1,079,947 individuals (European, N = 903,147; African, N = 122,571; Latin American, N = 38,962; East Asian, N = 13,551; and South Asian, N = 1,716 ancestries). 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 chromatin interaction in brain tissues identified multiple genes associated with PAU. We identified existing medications for potential pharmacological studies by a computational drug repurposing analysis. Cross-ancestry polygenic risk scores showed better performance of association in independent samples than single-ancestry polygenic risk scores. Genetic correlations between PAU and other traits were observed in multiple ancestries, with other substance use traits having the highest correlations. This study advances our knowledge of the genetic etiology of PAU, and these findings may bring possible clinical applicability of genetics insights-together with neuroscience, biology and data science-closer.

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Conflict of interest statement

H.R.K. is a member of advisory boards for Dicerna Pharmaceuticals, Sophrosyne Pharmaceuticals, Enthion Pharmaceuticals and Clearmind Medicine; 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 United States patent 10,900,082 titled: ‘Genotype-guided dosing of opioid agonists,’ issued 26 January 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 (United Kingdom), 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 University of Sydney. The Brain and Mind Centre 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 3 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 principal investigator 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. D.D. has received a speaker fee from Medici Nordic. All other authors report no biomedical financial interests or potential conflicts of interest.

Figures

Fig. 1
Fig. 1. Genetic architecture of 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 the EUR meta-analysis. Of the 85 variants, 76 could be analyzed in AFR (Methods). A sign test was performed for the number of variants with same direction of effect (64/76, binomial test P = 1.0 × 10−9). Twenty-three variants were nominally significant (P < 0.05) in AFR and six were significant after multiple correction (P < 0.05/76 = 6.58 × 10−4). d, Observed-scale and liability-scale SNP-based heritability (h2) in multiple ancestries. For PAU in EUR, N = 903,147 and for AUD, N = 753,249 (EUR), N = 122,571 (AFR) and N = 38,962 (LA). The error bar is the 95% confidence interval. e, Cross-ancestry genetic-effect correlation (ρge) and genetic-impact correlation (ρgi) among EUR (N = 903,147), AFR (N = 122,571) and LA (N = 38,962) ancestries. The error bar is the 95% confidence interval. f, Genome-wide association results for PAU in the cross-ancestry meta-analysis (N = 1,079,947 and Neffective = 646,371). Effective sample size-weighted meta-analyses were performed using METAL. Red line is significance threshold of 5 × 10−8.
Fig. 2
Fig. 2. Fine mapping for PAU.
a, Fine mapping of causal variants in 85 regions in EUR. b, Ninety-two regions in a 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; and black dots are the regions only fine mapped in EUR. FM, fine mapping.
Fig. 3
Fig. 3. Genetic correlations between AUD and traits in AFR.
Total PCL is the total index of recent symptom severity by the post-traumatic stress disorder checklist for DSM-IV. Genetic correlations were estimated using LDSC. Traits with P < 3.85 × 10−3 are genetically correlated with AUD (N = 122,571) after Bonferroni correction. The error bar is the 95% confidence interval.
Extended Data Fig. 1
Extended Data Fig. 1. Manhattan and QQ plots for PAU/AUD meta-analyses in different ancestries.
a, PAU meta-analysis in European ancestry (N = 903,147, Neffective = 502,272). b, AUD meta-analysis in African ancestry (N = 122,571, Neffective = 105433). c, AUD in Latin Americans (N = 38,962, Neffective = 30,023) from MVP. d, PAU meta-analysis in South Asian ancestry (N = 1,716, Neffective = 1,556). Effective sample size-weighted meta-analyses were performed using METAL.
Extended Data Fig. 2
Extended Data Fig. 2. Manhattan and QQ plots for PAU sex-stratified meta-analyses in EUR.
a, PAU meta-analysis in males (N = 496,548, Neffective = 315,185). b, PAU meta-analysis in females (N = 143,198, Neffective = 115,717). Effective sample size-weighted meta-analyses were performed using METAL.
Extended Data Fig. 3
Extended Data Fig. 3. Phenome-wide associations with PAU PRS in PsycheMERGE EUR samples.
PheWAS results were meta-analyzed across biobanks (N = 131,500). Red line indicates significant after correction for multiple testing (P < 0.05/1493 = 3.35 × 10−5).
Extended Data Fig. 4
Extended Data Fig. 4. Phenome-wide associations with AUD PRS in PsycheMERGE AFR samples.
PheWAS results were meta-analyzed across biobanks (N = 27,494). Red line indicates significant after correction for multiple testing (P < 0.05/793 = 6.31 × 10−5).
Extended Data Fig. 5
Extended Data Fig. 5. Phenome-wide associations with PAU PRS in Yale-Penn EUR samples.
N = 5,692. Red line indicates significant after correction for multiple testing (P < 0.05/627 = 7.95 × 10−5).
Extended Data Fig. 6
Extended Data Fig. 6. Phenome-wide associations with AUD PRS in Yale-Penn AFR samples.
N = 4,918. Red line indicates significant after correction for multiple testing (P < 0.05/571 = 8.76 × 10−5).
See this image and copyright information in PMC

Update of

  • Multi-ancestry study of the genetics of problematic alcohol use in >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, 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. medRxiv [Preprint]. 2023 Jan 30:2023.01.24.23284960. doi: 10.1101/2023.01.24.23284960. medRxiv. 2023. Update in: Nat Med. 2023 Dec;29(12):3184-3192. doi: 10.1038/s41591-023-02653-5. PMID: 36747741 Free PMC article. Updated. Preprint.

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