Research ArticleHUMAN GENETICS

Functional validity, role, and implications of heavy alcohol consumption genetic loci

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Science Advances  15 Jan 2020:
Vol. 6, no. 3, eaay5034
DOI: 10.1126/sciadv.aay5034
  • Fig. 1 Manhattan plot of the GWAS outcomes for alcohol consumption phenotype using the entire UKB cohort (n = 125,249).

    Inset: QQ plot of expected versus observed GWAS results from UKB, demonstrating modest deviation from the null, λGC = 1.09.

  • Fig. 2 Genetic correlation between alcohol phenotype and other traits using LD score regression from LDHub.

  • Fig. 3 Genetic targets identified by GWAS have conserved roles in alcohol phenotypes.

    C. elegans with loss-of-function mutations in worm orthologs to ADH (sodh-1), glucokinase (hxk-1), solute carrier family 39 member 8 (zipt-15), and β-Klotho protein (klo-2;klo-1) were exposed to ethanol, and the resultant effect on locomotion rate was determined. Results are presented normalized to locomotion of untreated worms [basal locomotion rate: 99.03 ± 1.47 (Bristol N2 controls), 103.13 ± 3.66 (sodh-1), 87.37 ± 1.91 (hxk-1), 31.43 ± 2.97 (zipt-15), and 99.90 ± 21.7 (klo-2;klo-1)]. *P < 0.05.

  • Fig. 4 RNAi of genetic targets.

    RNAi knockdown of worm orthologs to glucokinase (hxk-1) and solute carrier family 39 member 8 (zipt-15) phenocopies the loss-of-function mutations. Results are presented as locomotion of worms treated with ethanol normalized to untreated worms [basal locomotion rate: 87.63 ± 21.6 (empty vector control), 94.17 ± 2.91 (sodh-1), 77.60 ± 2.34 (hxk-1), 60.0 ± 2.34 (zipt-15), 90.97 ± 3.56 (klo-1), 99.13 ± 2.78 (klo-2), and 110.0 ± 3.40 (klo-2;klo-1)]. *P < 0.05; n.s., not significant.

  • Table 1 Summary of validated associations that meet genome-wide significance in the meta-analysis of UKB and GERA, which also demonstrate nominal association with the same direction of effect in GERA.

    OR, odds ratio; CI, confidence interval.

    UKB heavy alcohol drinker status (cases versus controls)GERA (replication)
    drinks/week (among
    drinkers)
    Meta-
    analysis
    ChrPositionLead SNPLocusRisk alleleOther alleleRAFOR
    (95% CI)
    Pβ (SE)PP
    227730940rs1260326GCKRCT0.6121.06
    (1.04–1.08)
    2.6 × 10−80.033
    (0.029)
    1.1 × 10−61.5 × 10−13
    439422242rs13130794KLBTC0.6321.07
    (1.05–1.09)
    2.6 × 10−100.035
    (0.007)
    4.2 × 10−75.7 × 10−16
    499713350rs144198753BTF3P13CT0.9911.66
    (1.48–1.85)
    2.70 × 10−180.156
    (0.023)
    2.1 × 10−114.1 × 10−29
    4100239319rs1229984ADH1BCT0.9801.58
    (1.48–1.70)
    3.30 × 10−360.187
    (0.016)
    2.9 × 10−322.3 × 10−66
    4103188709rs13107325SLC39A8CT0.9281.12
    (1.08–1.16)
    1.60 × 10−80.029
    (0.013)
    0.02496.7 × 10−9
    11113316102rs11214609DRD2GC0.3951.06
    (1.04–1.08)
    2.10 × 10−70.021
    (0.007)
    0.00354.30 × 10−9
  • Table 2 Summary of conditional analysis using outcomes from UKB.

    Summary of conditional analysis using outcomes from UKB.. Joint models refer to the estimated joint effects of all selected SNPs in a region (i.e., all independent SNPs are fitted together).

    Primary signalChrSNPNearest
    gene
    PositionRef
    allele
    Ref allele
    frequency
    βSEPJoint βJoint SEJoint P
    rs131073254rs13107325SLC39A8103188709C0.9280.1110.0201.6 × 10−80.1120.0201.4 × 10−8
    rs131073254rs13116422NFKB1103387160T0.9160.0910.0191.9 × 10−60.0920.0191.7 × 10−6
    Extended analysis of 4.q23 region containing ADH1B (rs1229984) and BTF3P13 loci (rs144198753)
    4rs1229984ADH1B100239319T0.020−0.4550.0363.3 × 10−36−0.4670.0368.7 × 10−38
    4rs551676206ADH5100019089A0.9900.5140.0536.2 × 10−220.5280.0546.1 × 10−23
    4rs62307263ADH1A100167112C0.8990.0830.0171.1 × 10−60.1690.0231.9 × 10−13
    4rs140859990TSPAN599456373G0.937−0.1020.0212.0 × 10−6−0.1020.0211.9 × 10−6
    4rs182381822ADH4100179872T0.993−0.2740.0697.2 × 10−5−0.3440.0697.1 × 10−7
    4rs1800761ADH4100065593T0.183−0.0460.0130.00054−0.4010.0345.3 × 10−33
    4rs200411287ADH4100078163A0.851−0.0230.0150.12−0.5200.0384.4 × 10−42
    4rs150187763EIF4E99801016A0.9820.0100.0390.79−0.3130.0472.8 × 10−11

Supplementary Materials

  • Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/6/3/eaay5034/DC1

    Supplementary Methods

    Table S1. Summary of final multivariable logistic regression model.

    Table S2. Summary of genome-wide significant SNPs following distance-based clumping on the UKB cohort, and the replication cohort and meta-analysis outcomes.

    Table S3. eQTL analysis outcomes.

    Table S4. LD between the top eQTL SNP for any eQTL signal and the GWAS SNP.

    Table S5. Variant-trait significant outcomes from PheWAS.

    Table S6. Variants at 5 × 10−6 and submitted to the Reactome Knowledgebase.

    Table S7. Mendelian randomization results for nominally significant outcomes in the IVW analysis and FDR outcomes using the IVW method.

    Fig. S1. LocusZoom plots for lead SNPs from GWAS on alcohol phenotype in the entire cohort.

    Fig. S2. Constitutive signaling by aberrant PI3K in cancer.

    Fig. S3. Individual C. elegans b-Klotho genes outcomes.

    References (6171)

  • Supplementary Materials

    The PDFset includes:

    • Supplementary Methods
    • Table S1. Summary of final multivariable logistic regression model.
    • Table S2. Summary of genome-wide significant SNPs following distance-based clumping on the UKB cohort, and the replication cohort and meta-analysis outcomes.
    • Legend for table S3
    • Table S4. LD between the top eQTL SNP for any eQTL signal and the GWAS SNP.
    • Table S5. Variant-trait significant outcomes from PheWAS.
    • Table S6. Variants at 5 × 10−6 and submitted to the Reactome Knowledgebase.
    • Table S7. Mendelian randomization results for nominally significant outcomes in the IVW analysis and FDR outcomes using the IVW method.
    • Fig. S1. LocusZoom plots for lead SNPs from GWAS on alcohol phenotype in the entire cohort.
    • Fig. S2. Constitutive signaling by aberrant PI3K in cancer.
    • Fig. S3. Individual C. elegans β-Klotho genes outcomes.
    • References (6171)

    Download PDF

    Other Supplementary Material for this manuscript includes the following:

    • Table S3 (.csv format). eQTL analysis outcomes.

    Files in this Data Supplement:

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