Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals.
- Authors
- Zhou, Hang; Kember, Rachel L; Deak, Joseph D; Xu, Heng; Toikumo, Sylvanus; Yuan, Kai; Lind, Penelope A; Farajzadeh, Leila; Wang, Lu; Hatoum, Alexander S; Johnson, Jessica; Lee, Hyunjoon; Mallard, Travis T; Xu, Jiayi; Johnston, Keira J A; Johnson, Emma C; Nielsen, Trine Tollerup; Galimberti, Marco; Dao, Cecilia; Levey, Daniel F; Overstreet, Cassie; Byrne, Enda M; Gillespie, Nathan A; Gordon, Scott; Hickie, Ian B; Whitfield, John B; Xu, Ke; Zhao, Hongyu; Huckins, Laura M; Davis, Lea K; Sanchez-Roige, Sandra; Madden, Pamela A F; Heath, Andrew C; Medland, Sarah E; Martin, Nicholas G; Ge, Tian; Smoller, Jordan W; Hougaard, David M; BΓΈrglum, Anders D; Demontis, Ditte; Krystal, John H; Gaziano, J Michael; Edenberg, Howard J; Agrawal, Arpana; Million Veteran Program; Justice, Amy C; Stein, Murray B; Kranzler, Henry R; Gelernter, Joel
- Year
- 2023
- Journal
- Nature medicine
- PMID
- 38062264
- DOI
- 10.1038/s41591-023-02653-5
- PMCID
- PMC10719093
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, Nβ=β903,147; African, Nβ=β122,571; Latin American, Nβ=β38,962; East Asian, Nβ=β13,551; and South Asian, Nβ=β1,716 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.
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 Γ 10β9). Twenty-three variants were nominally significant (P < 0.05) in AFR and six were significant after multiple correction (P < 0.05/76 = 6.58 Γ 10β4). 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 (Οge) and genetic-impact correlation (Οgi) 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 Γ 10β8.
LLM interpretation
This figure presents the genetic architecture of Problematic Alcohol Use (PAU) across multiple ancestries. It includes a pie chart of sample distribution (a), a line plot showing the relationship between sample size and identified variants (b), a horizontal bar chart detailing variant replication in AFR populations (c), and dot plots with 95% confidence intervals for SNP-based heritability (d) and genetic correlations (e). Panel (f) is a Manhattan plot showing genome-wide association results, highlighting a highly significant peak at *ADH1B* ($P = 2.22 \times 10^{-283}$) above the red significance threshold of $5 \times 10^{-8}$.
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.
LLM interpretation
This figure presents fine-mapping results for PAU across different ancestries. Panels **a** and **b** are horizontal stacked bar charts showing the distribution of credible set lengths (ranging from 1 to >20) for 85 EUR regions and a comparison of 92 regions between cross-ancestry and EUR-only analyses. Panel **c** is a scatter plot comparing the best posterior inclusion probabilities (PIPs) between cross-ancestry and EUR-only fine mapping, with color-coded dots indicating the specific ancestry combinations used (EUR, AFR, and LA).
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 Γ 10β3 are genetically correlated with AUD (N = 122,571) after Bonferroni correction. The error bar is the 95% confidence interval.
LLM interpretation
This figure is a forest plot showing the genetic correlations between Alcohol Use Disorder (AUD) and various traits in an African population. The x-axis represents the genetic correlation coefficient, with blue squares indicating the point estimate and horizontal lines representing the 95% confidence intervals. Positive genetic correlations are observed for maximum habitual alcohol intake, OUD, and smoking trajectory, all of which have p-values below the Bonferroni-corrected threshold ($P < 3.85 \times 10^{-3}$).
| Name | Type |
|---|---|
| 1000 Genomes Project | cohort |
| 1000 Genomes Project phase 3 EUR LD reference local | cohort |
| acamprosate | drug |
| AD8 local | phenotype |
| ADH1B | gene |
| ADH1C | gene |
| ADH5 | gene |
| ADH gene cluster | gene |
| adult midbrain dopaminergic local | anatomy |
| Affymetrix Axiom biobank array local | drug |
| AFR | cohort |
| AFR ancestries local | cohort |
| AFR ancestry | cohort |
| African American | cohort |
| AFR meta-analysis local | cohort |
| AGDS | cohort |
| alcohol | phenotype |
| alcohol dependence | phenotype |
| Alcohol-induced blackouts local | phenotype |
| alcohol-related problems | phenotype |
| Alcohol Use | phenotype |
| Alcohol Use Disorder | phenotype |
| alcohol use disorders | phenotype |
| alcohol withdrawal | phenotype |
| alcohol withdrawal-related anxiety local | phenotype |
| ALDH2 region local | gene |
| All of Us Research Program | cohort |
| Alzheimer's disease | phenotype |
| amlodipine | drug |
| AMT local | gene |
| amygdala | anatomy |
| attention deficit hyperactivity disorder | phenotype |
| AUD | phenotype |
| AUD/AD local | phenotype |
| AUDIT-P | phenotype |
| AUD PRS local | cohort |
| AUD PRS | drug |
| Australian Genetics of Bipolar Disorder Study local | cohort |
| autism spectrum disorder | phenotype |
| Bdnf | gene |
| biobanks | cohort |
| BioMe biobank local | cohort |
| BioVU | cohort |
| bipolar disorder | phenotype |
| brain | anatomy |
| brain-linked gene local | gene |
| brain tissue | anatomy |
| BRAP | phenotype |
| BRD3 local | gene |
| Brisbane Longitudinal Twin Study | cohort |
| CACNA1C | gene |
| cannabis use | phenotype |
| cannabis use disorder | phenotype |
| caudate nucleus | anatomy |
| causal variant | cohort |
| cerebellar hemisphere | anatomy |
| cerebellum | anatomy |
| CEU | cohort |
| CHB | cohort |
| CHD9 | gene |
| CLMN local | gene |
| clomethiazole local | drug |
| Clomethiazole local | drug |
| cocaine | phenotype |
| conditionally independent variants local | variant |
| Core+Exome family chip local | drug |
| cortical neurons | anatomy |
| cross-ancestry meta-analysis local | cohort |
| Cross-ancestry meta-analysis local | cohort |
| CTA-223H9.9 local | gene |
| Denmark birth cohort 1981-2008 local | cohort |
| disulfiram | drug |
| dorsolateral prefrontal cortex | anatomy |
| DPYD | gene |
| DRD2 | gene |
| DSM-5 AUD | phenotype |
| DSM-5 AUD criterion count local | phenotype |
| DSM-IV alcohol dependence | phenotype |
| DYPD | gene |
| EA | cohort |
| Eagle2 | drug |
| EAs | cohort |
| EAS ancestry local | cohort |
| East Asian | cohort |
| East Asian cohorts local | cohort |
| educational attainment | phenotype |
| EUR | cohort |
| EUR lead SNP local | variant |
| EUR meta-analysis local | cohort |
| European ancestry | cohort |
| Europeans | cohort |
| EVI2A local | gene |
| EVI2B local | gene |
| excessive alcohol consumption | phenotype |
| externalizing behavior | phenotype |
| fetal brain | anatomy |
| FinnGen | cohort |
| frequency of alcohol use | phenotype |
| FTO | gene |
| gabapentin | drug |
| Gabra4 | gene |
| GBP local | cohort |
| GBP study local | cohort |
| GCKR | gene |
| Global Biobank Meta-analysis Initiative local | cohort |
| Global Screening Array v1 local | drug |
| Global Screening Array v2 | drug |
| glycemic traits | phenotype |
| GSA local | drug |
| GTEx79 local | cohort |
| Han ChineseβCyto local | cohort |
| Han ChineseβGSA local | cohort |
| Han ChineseβIllumina Cyto12 array local | cohort |
| Han ChineseβIllumina Global Screening Array local | cohort |
| Haplotype Reference Consortium | cohort |
| HapMap3 | cohort |
| HapMap3 dataset local | cohort |
| height | phenotype |
| hg19 | drug |
| Hispanic | phenotype |
| hypothalamus | anatomy |
| ICD-10 | phenotype |
| ICD-9 local | phenotype |
| Illumina 2.5M chip local | drug |
| Illumina Global Screening Array local | drug |
| Illumina GSA v.2 local | drug |
| Illumina HapMap-derived chip 317K local | drug |
| Illumina HapMap-derived chip 370K local | drug |
| Illumina HapMap-derived chip 610K local | drug |
| Illumina HapMap-derived chip 660K local | drug |
| Illumina MEGEX array local | drug |
| Illumina Omni local | drug |
| Illumina PsychArray local | drug |
| iPSC-derived astrocyte local | anatomy |
| iPSC-derived neuron local | anatomy |
| iPSYCH | cohort |
| iPSYCH1 local | cohort |
| iPSYCH2 local | cohort |
| iPSYCH cohort | cohort |
| iPSYCH study local | cohort |
| Klb | gene |
| L1000 local | drug |
| LA | cohort |
| LA ancestry local | cohort |
| LA samples from MVP local | cohort |
| lead SNP | cohort |
| lead variants | variant |
| major depressive disorder | phenotype |
| Mapt | gene |
| Mass General Brigham Biobank | cohort |
| Maximum Habitual Alcohol Intake | phenotype |
| MEGA | drug |
| melperone local | drug |
| methamphetamine | drug |
| methamphetamine dependence | phenotype |
| Michigan Imputation Server | drug |
| Million Veteran Program | cohort |
| Minimac4 local | drug |
| Mount Sinai (BioMe) local | cohort |
| MsCAVIAR local | drug |
| MTCH2 | gene |
| multi-ancestry GWAS local | cohort |
| Multiple cohorts local | cohort |
| MVP | cohort |
| MVP AUD local | cohort |
| MVPAUD local | cohort |
| MVP EAS local | cohort |
| MVP release 4 local | cohort |
| naltrexone | drug |
| National Survey on Drug Use and Health | cohort |
| NCAM1 | gene |
| Nineteen and Up study local | cohort |
| Nondependent use local | phenotype |
| non-EUR | cohort |
| non-EUR ancestry local | cohort |
| non-EUR groups local | cohort |
| non-EUR GWAS local | cohort |
| non-European ancestry | cohort |
| nonpsychiatric traits local | phenotype |
| nucleus accumbens | anatomy |
| OmniExpress local | drug |
| opioid | drug |
| opioid dependence | phenotype |
| OPRM1 | cohort |
| OUD | phenotype |
| PAU | phenotype |
| PAU PRS local | cohort |
| PAU PRS | phenotype |
| PAU PRS local | variant |
| PAU risk local | phenotype |
| Pde4b | gene |
| Penn Medicine Biobank | cohort |
| PGC | cohort |
| PGC AD | cohort |
| PGC study local | cohort |
| phecode | phenotype |
| PheWAS local | phenotype |
| physical traits local | phenotype |
| Plink | drug |
| PLINK v1.9 local | drug |
| PMBB | cohort |
| PredictDB | cohort |
| problematic alcohol use | phenotype |
| proxy SNPs | variant |
| PRSAFR local | drug |
| PRSEUR local | drug |
| PRSfinal local | drug |
| PRSLA local | drug |
| PRSsingle local | drug |
| PsychArray local | drug |
| PsycheMERGE local | cohort |
| PsycheMERGE Network local | cohort |
| psychiatric disorders | phenotype |
| Psychiatric Genomics Consortium | cohort |
| psychiatric traits | phenotype |
| psychosocial traits local | phenotype |
| putamen | anatomy |
| QIMR | cohort |
| QIMR AGDS local | cohort |
| QIMR Berghofer local | cohort |
| QIMR Berghofer Australian Genetics of Depression Study local | cohort |
| QIMR Berghofer cohorts local | cohort |
| QIMR Berghofer study local | cohort |
| QIMR GBP local | cohort |
| QIMR TWINS local | cohort |
| rare variant | cohort |
| ricopili pipeline | drug |
| risk allele | cohort |
| rs10032906 local | variant |
| rs113464470 local | variant |
| rs12048727 local | variant |
| rs1229984 | variant |
| rs12354219 local | variant |
| rs1260326 | variant |
| rs12677811 local | variant |
| rs13107325 | variant |
| rs142346138 local | variant |
| rs1799971 | variant |
| rs181007867 local | variant |
| rs199537352 local | variant |
| rs2066702 | variant |
| rs2098112 local | variant |
| rs2699453 local | variant |
| rs2942194 local | variant |
| rs3782886 | variant |
| rs472140 local | variant |
| rs6265 | variant |
| rs72772203 local | variant |
| rs7531138 local | variant |
| rs75967634 | variant |
| SAIGE | drug |
| SAS | cohort |
| SAS ancestry local | cohort |
| SAS meta-analysis local | cohort |
| schizophrenia | phenotype |
| SLC25A37 local | gene |
| SLC25A48 local | gene |
| SLC39A8 | gene |
| SLC4A8 local | gene |
| smartpca61 local | drug |
| smoking phenotypes | phenotype |
| smoking trajectory local | phenotype |
| Smoking trajectory local | phenotype |
| S-MultiXcan | drug |
| SNP | cohort |
| socioeconomic status | phenotype |
| South Asian | cohort |
| spironolactone local | drug |
| Spironolactone local | drug |
| S-PrediXcan | drug |
| substance use | phenotype |
| Substance use traits local | phenotype |
| SUD | phenotype |
| Thai METH local | cohort |
| Thai METHβGSA local | cohort |
| Thai METHβMEGA local | cohort |
| TLK2 local | gene |
| tobacco dependence | phenotype |
| tobacco use | phenotype |
| topiramate | drug |
| TOPMed Imputation Server | drug |
| TOPMed-r2 reference panel local | drug |
| trichostatin-a local | drug |
| Trichostatin-a local | drug |
| triflupromazine local | drug |
| TRIM54 local | gene |
| Twin cohort | cohort |
| UKB | cohort |
| UKB-EUR1 local | cohort |
| UKBβEUR1 local | cohort |
| UKB-EUR2 local | cohort |
| UKBβEUR2 local | cohort |
| UK Biobank | cohort |
| UKBβSAS local | cohort |
| United States | cohort |
| variant | cohort |
| Yale-Penn | cohort |
| YaleβPenn | cohort |
| YaleβPenn 3 local | cohort |
| YaleβPenn 3 individuals local | cohort |
| YaleβPenn AFR subsample local | cohort |
| YaleβPenn EUR subsample local | cohort |
| YaleβPenn study local | cohort |
| YP3 local | cohort |
| YPEL3 local | gene |
| YRI | cohort |
| ZNF184 | gene |
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In this knowledge base
External
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