Research ArticleGENETICS

Loss-of-function variants influence the human serum metabolome

See allHide authors and affiliations

Science Advances  31 Aug 2016:
Vol. 2, no. 8, e1600800
DOI: 10.1126/sciadv.1600800
  • Fig. 1 Distribution of metabolite levels among LoF mutation carriers in ARIC.

    The x axis indicates the number of LoF allele carried, and the y axis indicates the metabolite levels. (A) Octanoylcarnitine levels among CD36 (c.975T>G) LoF mutation carriers. (B) Decanoylcarnitine levels among CD36 (c.975T>G) LoF mutation carriers. (C) Hexadecanedioate levels among SLCO1B1 (c.481+1G>T) LoF mutation carriers. (D) Deoxycarnitine levels among LRRC69 (c.933+2T>A) LoF mutation carriers.

  • Table 1 Ten significant gene-metabolite associations identified among African-Americans in ARIC.

    Decanoylcarnitine and octanoylcarnitine were identified using the single-variant test, and the remains were identified using the gene-based burden test. Gene-related human pleiotropy was obtained through OMIM (Online Mendelian Inheritance in Man) (www.ncbi.nlm.nih.gov/omim) and the NHGRI GWAS catalog (www.genome.gov/gwastudies). NA, not applicable; LDL, low-density lipoprotein; MI, myocardial infarction; 5-HETE, 5-hydroxyicosatetraenoic acid; CHD, coronary heart disease; CVD, cardiovascular disease; MCAD, medium-chain acyl-CoA dehydrogenase.

    MetabolitePathwayGenePβ (SE)cMACGene-related human
    pleiotropy
    Metabolite-related
    human phenotypes
    Replication
    P
    DecanoylcarnitineLipidCD362.7 × 10−7−0.19 (0.04)221Platelet glycoprotein IV
    deficiency, CHD
    MCAD deficiency (7)0.03
    OctanoylcarnitineLipidCD363.9 × 10−8−0.20 (0.04)221Platelet glycoprotein IV
    deficiency, CHD
    MCAD deficiency (7)0.03
    HistidineAmino acidHAL2.3 × 10−130.23 (0.03)26HistidinemiaRheumatoid arthritis (23),
    CHD (24)
    0.05
    Methionine
    sulfoxide
    Amino acidC6orf251.3 × 10−8−0.45 (0.08)9Aging (25)NA
    MannoseCarbohydrateTEX157.9 × 10−9−0.70 (0.12)10NA
    CholesterolLipidPCSK95.4 × 10−9−0.21 (0.04)30LDL, CHD, MI, statin
    response, familial
    hypercholesterolemia
    Atherosclerosis (26),
    CVD (27)
    0.0002
    DeoxycarnitineLipidLRRC698.5 × 10−16−0.42 (0.05)170.6
    HexadecanedioateLipidSLCO1B12.2 × 10−90.38 (0.06)67Hexadecanedioate,
    tetradecanedioate,
    octadecanedioate,
    bilirubin,
    hyperbilirubinemia,
    statin-induced myopathy,
    statin response
    0.0001
    5-HETELipidFAM198B4.5 × 10−9−0.38 (0.07)14NA
    UrateNucleotideLRRC461.1 × 10−7−0.44 (0.08)10Gout (28), type 2
    diabetes (29), CVD (30)
    mortality (31)
    NA

Supplementary Materials

  • Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/2/8/e1600800/DC1

    table S1. Baseline characteristics of African-Americans in ARIC having metabolomic and exome sequence data.

    table S2. List of 308 named metabolites measured in ARIC.

    table S3. Eighteen significant LoF sites with metabolite associations identified among African-Americans in ARIC.

    table S4. Relationship between hexadecanedioate and blood pressure levels among European-Americans and African-Americans in ARIC.

    fig. S1. Distribution of the number of LoF sites per individual among ARIC African-Americans.

    fig. S2. QQ plots of the expected and observed −log P values for 10 identified metabolites.

    fig. S3. Pathways among genes, metabolites, and diseases identified among ARIC African-Americans.

  • Supplementary Materials

    This PDF file includes:

    • table S1. Baseline characteristics of African-Americans in ARIC having metabolomic and exome sequence data.
    • table S2. List of 308 named metabolites measured in ARIC.
    • table S3. Eighteen significant LoF sites with metabolite associations identified among African-Americans in ARIC.
    • table S4. Relationship between hexadecanedioate and blood pressure levels among European-Americans and African-Americans in ARIC.
    • fig. S1. Distribution of the number of LoF sites per individual among ARIC African-Americans.
    • fig. S2. QQ plots of the expected and observed −log P values for 10 identified metabolites.
    • fig. S3. Pathways among genes, metabolites, and diseases identified among ARIC African-Americans.

    Download PDF

    Files in this Data Supplement:

Navigate This Article