Genome-wide association study of alcohol consumption and use disorder in 274,424 individuals from multiple populations.
- Authors
- Kranzler, Henry R; Zhou, Hang; Kember, Rachel L; Vickers Smith, Rachel; Justice, Amy C; Damrauer, Scott; Tsao, Philip S; Klarin, Derek; Baras, Aris; Reid, Jeffrey; Overton, John; Rader, Daniel J; Cheng, Zhongshan; Tate, Janet P; Becker, William C; Concato, John; Xu, Ke; Polimanti, Renato; Zhao, Hongyu; Gelernter, Joel
- Year
- 2019
- Journal
- Nature communications
- PMID
- 30940813
- DOI
- 10.1038/s41467-019-09480-8
- PMCID
- PMC6445072
Alcohol consumption level and alcohol use disorder (AUD) diagnosis are moderately heritable traits. We conduct genome-wide association studies of these traits using longitudinal Alcohol Use Disorder Identification Test-Consumption (AUDIT-C) scores and AUD diagnoses in a multi-ancestry Million Veteran Program sample (Nβ=β274,424). We identify 18 genome-wide significant loci: 5 associated with both traits, 8 associated with AUDIT-C only, and 5 associated with AUD diagnosis only. Polygenic Risk Scores (PRS) for both traits are associated with alcohol-related disorders in two independent samples. Although a significant genetic correlation reflects the overlap between the traits, genetic correlations for 188 non-alcohol-related traits differ significantly for the two traits, as do the phenotypes associated with the traits' PRS. Cell type group partitioning heritability enrichment analyses also differentiate the two traits. We conclude that, although heavy drinking is a key risk factor for AUD, it is not a sufficient cause of the disorder.
Manhattan plots for age-adjusted mean AUDIT-C score and AUD diagnosis. a Manhattan plot of the genome-wide association meta-analysis of AUDIT-C across all five populations (N = 272,842). b Manhattan plot of the genome-wide association meta-analysis of AUD across five populations (55,584 cases and 218,807 controls). Red lines show the genome-wide significance level (5.0 Γ 10β8). EA: European American, AA: African American, LA: Hispanic or Latino, EAA: East Asian American, SAA: South Asian American. Labeled genes at the top of the peaks indicate completely independent signals after conditional analysis in meta-analysis. Population-specific loci are labeled at the bottom of the circles in the lower part of each figure. []: no genes within 500 kb to the lead SNP
Heritability estimate, partitioning enrichments of heritability, and genetic correlation analyses using LD score regression. a SNP-based heritability for AUDIT-C and AUD in the three populations and sex-stratified samples adequate in size for the analysis. b Partitioned heritability enrichment of cell type groups for AUDIT-C and AUD. Ten cell types tested were corrected for multiple testing. The black dashed line is the cutoff for Bonferroni-corrected significance. The gray dashed line is the cutoff for FDR < 0.05. c Genetic correlations with other traits. Data from 714 publicly available datasets (221 published and 493 unpublished from UK Biobank) were tested and corrected for multiple comparisons. The significantly correlated traits presented are for published data. Black lines are the cutoff for Bonferroni-corrected significance, with asterisks showing traits significant after correction. The traits are grouped into different categories and sorted by the genetic correlations with AUDIT-C (upper panel) or AUD (lower panel). CNS central nervous system, ADHD attention deficit hyperactivity disorder, MDD major depressive disorder
| Name | Type |
|---|---|
| 1000 Genomes Project | cohort |
| 23andMe | cohort |
| AA | cohort |
| ADGRB2 local | gene |
| ADH1B | gene |
| ADH1B minor allele local | variant |
| ADH1C | gene |
| ADH4 | gene |
| ADH5 | gene |
| admixed American (AMR) local | cohort |
| Affymetrix Axiom Biobank Array local | drug |
| African | cohort |
| African American | cohort |
| age at menarche | phenotype |
| alcohol | phenotype |
| alcohol abuse | phenotype |
| alcohol dependence | phenotype |
| alcoholic liver damage local | phenotype |
| alcoholism | phenotype |
| alcohol-related phenotypes | phenotype |
| alcohol-related problems | phenotype |
| Alcohol Use Disorder | phenotype |
| alcohol use disorders | phenotype |
| ALDH2 | gene |
| anorexia nervosa | phenotype |
| anthropometric traits | phenotype |
| anxiety | phenotype |
| attention deficit hyperactivity disorder | phenotype |
| AUD | phenotype |
| AUD diagnosis codes local | phenotype |
| AUD diagnostic codes local | phenotype |
| AUDIT | phenotype |
| AUDIT-C | phenotype |
| AUDIT-C genetic analysis cohort local | cohort |
| AUDIT-P | phenotype |
| AUD PRS | drug |
| autism spectrum disorder | phenotype |
| BAHCC1 local | gene |
| bipolar disorder | phenotype |
| BMI | phenotype |
| BRAP | phenotype |
| C4orf17 | gene |
| Cadm2 | gene |
| Cahoy et al. dataset local | cohort |
| cannabis use | phenotype |
| cardiovascular disease | phenotype |
| chr10q25.1 variant local | variant |
| CNS | anatomy |
| comorbidity | phenotype |
| coronary artery disease | phenotype |
| DCLK2 local | gene |
| depression | phenotype |
| diabetes | phenotype |
| DIO1 local | gene |
| DNase I | drug |
| DRD2 | gene |
| drinking level | phenotype |
| DSM-IV alcohol dependence criterion counts local | phenotype |
| EA | cohort |
| EAAs local | cohort |
| EA females local | cohort |
| EA males local | cohort |
| EAs | cohort |
| East Asian | cohort |
| East Asian American local | cohort |
| East Asian American (EAA) local | cohort |
| East Asian Americans local | cohort |
| East Asian (EAS) local | cohort |
| educational attainment | phenotype |
| EHR cohort local | cohort |
| EIF4E local | gene |
| electronic health records | cohort |
| ethanol consumption | phenotype |
| European ancestry | cohort |
| European ancestry males local | cohort |
| European population | cohort |
| FAM69C | gene |
| Franke lab dataset | cohort |
| FTO | gene |
| FTO SNP local | variant |
| GCKR | gene |
| genes | gene |
| genetically defined populations local | cohort |
| Genetic risk for AUD local | phenotype |
| GTEx | cohort |
| GWS loci for AUD local | variant |
| GWS loci for AUDIT-C local | variant |
| GWS SNPs (AUD) local | variant |
| GWS SNPs (AUDIT-C) local | variant |
| h2 SNP local | variant |
| H3K4me1 | drug |
| H3K4me3 | drug |
| HapMap | cohort |
| Hazardous and harmful drinking local | phenotype |
| HDL cholesterol concentration local | phenotype |
| Health problems from drinking local | phenotype |
| heavy drinking | phenotype |
| Hispanic | phenotype |
| Hispanic and Latino American (LA) local | cohort |
| Hispanic and Latino Americans local | cohort |
| hyperglyceridemia local | phenotype |
| ICD-10 code F10.1 local | drug |
| ICD-10 code F10.2 local | drug |
| ICD-9 code 303.X local | drug |
| ICD-9 code 305β305.03 local | drug |
| IGF2BP1 local | gene |
| ImmGen | cohort |
| Independent Sample 1 local | cohort |
| Independent Sample 2 local | cohort |
| insomnia | phenotype |
| intelligence | phenotype |
| Isl1 | gene |
| JCAD | gene |
| Klb | gene |
| KRTCAP3 local | gene |
| LA | cohort |
| LAs local | cohort |
| Latino Americans local | cohort |
| LD Hub | cohort |
| LDSC27 local | drug |
| LOX | gene |
| major depressive disorder | phenotype |
| Major depressive disorder (MDD) local | phenotype |
| MAP2 | gene |
| MCC local | gene |
| medical consequences | phenotype |
| METAP1 | gene |
| Million Veteran Program | cohort |
| morbidity | phenotype |
| Mother's age at death local | phenotype |
| mouse brain | anatomy |
| MTTP local | gene |
| MVP | cohort |
| MVP hold-out sample local | cohort |
| MVP participants | cohort |
| MVP sample | cohort |
| MYL2 | gene |
| obesity | phenotype |
| Older clinical sample local | cohort |
| Other population groups local | cohort |
| overall health rating | phenotype |
| Penn Medicine Biobank | cohort |
| phecode | phenotype |
| phenotype | phenotype |
| phosphatidylethanol | drug |
| PMBB | cohort |
| polygenic risk score | cohort |
| Positive health outcomes local | phenotype |
| PPP1R3B | gene |
| prognosis | phenotype |
| PRS | drug |
| Psychiatric consequences local | phenotype |
| psychiatric disorders | phenotype |
| quitting smoking local | phenotype |
| Quitting smoking local | phenotype |
| RBX1 local | gene |
| Roadmap Epigenomics consortium | cohort |
| rs11075992 local | variant |
| rs1154433 local | variant |
| rs1229978 local | variant |
| rs1229984 | variant |
| rs12299844 | variant |
| rs1260326 | variant |
| rs12603262 local | variant |
| rs126399404 local | variant |
| rs131073254 local | variant |
| rs142108516 local | variant |
| rs1427830624 local | variant |
| rs14299768617 local | variant |
| rs16127354 local | variant |
| rs2066702 | variant |
| rs26836162 local | variant |
| rs29618165 local | variant |
| rs44238564 local | variant |
| rs48411328 local | variant |
| rs4936277 local | variant |
| rs5406062 local | variant |
| rs5860563 local | variant |
| rs58605634 local | variant |
| rs61902812 local | variant |
| rs6203340816 local | variant |
| rs7572334822 local | variant |
| rs790610410 local | variant |
| rs990251217 local | variant |
| rs9937709 local | variant |
| schizophrenia | phenotype |
| self-reported groups local | cohort |
| self-reported Non-Hispanic black local | cohort |
| self-reported Non-Hispanic white local | cohort |
| sex | phenotype |
| SIX3 | gene |
| SLC39A13 | gene |
| SLC39A8 | gene |
| Sleep disturbance | phenotype |
| smoking | phenotype |
| SNP | cohort |
| social consequences | phenotype |
| socio-economic deprivation | phenotype |
| South Asian | cohort |
| South Asian American local | cohort |
| South Asian Americans local | cohort |
| South Asian American (SAA) local | cohort |
| South Asians local | cohort |
| South Asian (SAS) local | cohort |
| TBCK local | gene |
| tobacco dependence | phenotype |
| tobacco use | phenotype |
| Triglyceride concentration local | phenotype |
| TRMT10A local | gene |
| TSPAN5 | gene |
| type 2 diabetes | phenotype |
| UKBB | cohort |
| UK Biobank | cohort |
| U.S. Department of Veterans Affairs | cohort |
| VA EHR local | cohort |
| veterans | cohort |
| Veterans Aging Cohort Study | cohort |
| Veterans Health Administration | cohort |
| Veterans Health Administration Electronic Health Record local | cohort |
| VRK2 | gene |
| Yale-Penn | cohort |
| Yale-Penn sample | cohort |
| Yale-Penn study sample local | cohort |
| years of education | phenotype |
| ZNF512 | gene |
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| Alcohol consumption and telomere length: Mendelian randomization clarifies alcohol's effects. | Topiwala A et al. | β | 2022 | β |
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| An exploratory study of pro-inflammatory cytokines in individuals with alcohol use disorder: MCP-1 and IL-8 associated with alcohol consumption, sleep quality, anxiety, depression, and liver biomarkers. | Kazmi N et al. | β | 2022 | β |
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