Research ArticleHUMAN GENETICS

DNA methylation as a mediator of the association between prenatal adversity and risk factors for metabolic disease in adulthood

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Science Advances  31 Jan 2018:
Vol. 4, no. 1, eaao4364
DOI: 10.1126/sciadv.aao4364
  • Fig. 1 Manhattan plots: Outcome genome-wide screens for potential mediators.

    The −log(P value) is shown (y axis) for each CpG relative to its genomic locations (x axis) on the 22 autosomal chromosomes tested for (A) an EWAS on both famine exposure and BMI and (B) an EWAS on both famine exposure and serum TG.

  • Fig. 2 Manhattan plot: Outcome genome-wide screen for potential mediators.

    The −log(P value) (y axis) for each CpG relative to its genomic locations (x axis) on the 22 autosomal chromosomes for the EWAS for both early famine exposure and serum TG.

  • Table 1 Phenotypic differences and famine exposure.
    ControlsFamine exposure
    N463348
    Age (years) [SD]+58.0 [5.4]58.9 [0.5]***
    Male (%)43.046.0
    BMI1 [SD]27.0 [4.2]28.5 [5.0]***
    LDL-C2 [SD]3.42 [0.96]3.45 [0.97]
    Triglycerides2 [SD]1.48 [0.86]1.68 [1.30]**
    Glucose baseline3 [SD]5.32 [0.93]5.52 [1.19]*

    Nominal P value either *P < 0.05, **P < 0.01 or ***P < 0.001 from a linear mixed-effects model with the denoted variable as the dependent variable and family identifier as random effect.

    +Model included an additional random effect for exposure status to control for the difference in variance in age between groups.

    1Model-applied correction for age and gender.

    2Model-applied correction for age, gender, and statin used, and individuals who were nonfasting at examination were excluded (excluding two controls and five famine-exposed individuals).

    3Model-applied correction for age and gender. Individuals who were nonfasting and had prediagnosed diabetes (thus receiving treatment) before the clinical examination were excluded (excluding 19 controls and 32 famine-exposed individuals).

    • Table 2 Genome-wide screen for potential mediators: famine exposure and BMI.
      CpG characteristicsMediation EWASAssociations with either famine exposure or BMI*
      CpGLocation (hg19)Nearest gene
      (expression)
      Methylation (SD)RankEWAS P§EWAS PFDRβfaminePfamineβBMIPBMIPrevious EWAS
      cg00574958chr11:68607622CPT1A13.6 (2.6)16.7 × 10−142.3 × 10−8−0.20.19−4.01.7 × 10−16(33, 56, 72, 73)
      cg06500161chr21:43656587ABCG165.9 (3.0)22.0 × 10−123.3 × 10−7−0.10.754.32.5 × 10−13(33, 43, 56, 73)
      cg26950531chr19:38704515DPF132.5 (6.1)32.2 × 10−104.3 × 10−50.30.50−8.91.3 × 10−11(56)
      cg11024682chr17:17730094SREBF153.2 (3.2)42.2 × 10−81.9 × 10−3−0.10.703.31.2 × 10−9(33, 43, 56)
      cg09349128chr22:50327986CRELD239.0 (3.8)51.3 × 10−78.3 × 10−3−0.71.5 × 10−3−3.56.5 × 10−8(3336, 56)
      cg09737197chr11:68607675CPT1A20.4 (4.6)61.5 × 10−78.3 × 10−3−0.40.093−4.43.2 × 10−9(33, 73)
      cg23032421chr3:3152038IL5RA73.9 (4.1)72.1 × 10−70.01−0.30.18−3.45.8 × 10−9(33)
      cg17058475chr11:68607737CPT1A16.1 (4.1)87.4 × 10−70.032−0.10.66−4.22.3 × 10−8(30, 56, 7274)
      cg15659713chr8:38586183TACC124.6 (3.9)91.7 × 10−70.0641.31.7 × 10−7−0.40.63(28)
      cg26199857chr12:54764265ZNF385A68.9 (5.7)145.2 × 10−70.132.03.1 × 10−71.30.28(28)

      *The estimate and (nominal) P value belonging to the EWAS for famine exposure (β = exposed − unexposed) or BMI (β/log(BMI)).

      †Nearest gene within 100 kb.

      ‡The Illumina 450k array β value (ranging from 0 to 1) multiplied by 100 for easy interpretation. This is done throughout the presented work.

      §The P value belonging to an analysis of variance (ANOVA) test (χ2, df = 2) between a generalized estimating equations (GEE) model with and without both famine exposure and BMI.

      ¶The two CpGs identified in a previous EWAS on famine exposure (28).

      • Table 3 Mediation analysis: DNAm and the association between famine exposure and triglycerides.
        CpGLocation
        (hg19)
        Nearest
        gene*
        Methylation
        (SD)
        RankEWAS
        PFDR
        PfaminePTGPrevious
        studies
        βmediationP
        mediation
        Proportion
        mediated (%)
        [95% CI]§
        Pproportion
        cg19693031chr1:145441552TXNIP77.5 (4.3)62.6 × 10−54.8 × 10−32.3 × 10−11(4145)2.6 [0.7–4.8]0.00528.0 [5.7–100]0.026
        cg18120259chr6:43894639LOC10013235460.4 (4.7)101.8 × 10−36.6 × 10−46.4 × 10−8(44)2.3 [0.8–4.1]0.00124.9 [7.5–100]0.021
        cg15020801chr17:46022809PNPO36.1 (3.4)123.5 × 10−37.1 × 10−46.0 × 10−8(30)2.3 [0.9–4.2]0.00125 [7.0–100]0.022
        cg06983052chr1:90288099LRRC8D64.8 (3.8)134.2 × 10−31.0 × 10−55.3 × 10−62.6 [1.1–4.5]<0.00128.0 [8.8–100]0.024
        cg07397296chr21:43655316ABCG126.9 (3.8)140.0215.1 × 10−31.9 × 10−7(49)1.9 [0.6–3.6]0.00520.5 [4.6–97.4]0.027
        cg20496314chr22:39759864SYNGR140.2 (4.3)150.0323.9 × 10−31.5 × 10−7(45, 46)1.8 [0.5–3.5]0.00719.6 [3.6–88.3]0.026

        *Nearest gene within 100 kb.

        †The Illumina 450k array β value (ranging from 0 to 1) multiplied by 100 for easy interpretation.

        ‡This is the estimate and CI based on 10K Monte Carlo simulations of the indirect effect or mediation effect, which is often referred to as the “a × b” effect.

        §The percentage of the total exposure-phenotype relationship explained by the indirect (mediated) effect as based on 10K Monte Carlo simulations.

        Supplementary Materials

        • Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/4/1/eaao4364/DC1

          fig. S1. Quantile-quantile (QQ) plots for EWAS on famine exposure and phenotypes.

          fig. S2. QQ plots for EWAS on early exposure and phenotypes.

          fig. S3. Correlation between tissues for the nine mediating CpG dinucleotides.

          table S1. Associations with gene expression and phenotypes.

          table S2. Genome-wide screen for potential mediators: famine exposure and TG.

          table S3. Early exposure.

          table S4. Genome-wide screen for potential mediators: early exposure and triglycerides.

          Reference (75)

        • Supplementary Materials

          This PDF file includes:

          • fig. S1. Quantile-quantile (QQ) plots for EWAS on famine exposure and phenotypes.
          • fig. S2. QQ plots for EWAS on early exposure and phenotypes.
          • fig. S3. Correlation between tissues for the nine mediating CpG dinucleotides.
          • table S1. Associations with gene expression and phenotypes.
          • table S2. Genome-wide screen for potential mediators: famine exposure and TG.
          • table S3. Early exposure.
          • table S4. Genome-wide screen for potential mediators: early exposure and triglycerides.
          • Reference (75)

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