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Genetics/Genomes/Proteomics/Metabolomics

Systematic Functional Characterization of Candidate Causal Genes for Type 2 Diabetes Risk Variants

  1. Soren K. Thomsen1,
  2. Alessandro Ceroni2,
  3. Martijn van de Bunt1,3,
  4. Carla Burrows1,
  5. Amy Barrett1,
  6. Raphael Scharfmann4,
  7. Daniel Ebner2,
  8. Mark I. McCarthy1,3,5 and
  9. Anna L. Gloyn1,3,5⇑
  1. 1Oxford Centre for Diabetes, Endocrinology & Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K.
  2. 2Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, U.K.
  3. 3Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, U.K.
  4. 4INSERM U1016, Institut Cochin, Université Paris Descartes, Paris, France
  5. 5National Institute for Health Research Oxford Biomedical Research Centre, Churchill Hospital, Oxford, U.K.
  1. Corresponding author: Anna L. Gloyn, anna.gloyn{at}drl.ox.ac.uk.
Diabetes 2016 Dec; 65(12): 3805-3811. https://doi.org/10.2337/db16-0361
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    Figure 1

    Comparing mean absolute effect sizes for MODY and non-MODY genes. Box plots of mean absolute effect sizes for MODY genes and non-MODY genes (excluding controls) across the five phenotypes measured. Effect sizes were calculated as described for Table 1, and the absolute values were then averaged for the two categories of genes. Among 14 identified MODY genes, 8 fulfilled criteria for inclusion in the screen: HNF4A, GCK, HNF1A, HNF1B, PAX4, INS, ABCC8, and KCNJ11. Tol, tolbutamide. Box plots show median and interquartile ranges for groups of n = 8 and 292 data points. ***q value <0.001 by Student t test (FDR-adjusted).

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    Figure 2

    Comparison of insulin secretion data for high and low glucose. Normalized insulin secretion responses under high glucose vs. low glucose, with selected hits annotated. The blue circle indicates the 95% confidence contour for NT control, and the orange circle indicates the 95% confidence contour for INS-positive controls. All measurements were normalized on a per-well basis to cell counts, and averages for each condition were then subsequently normalized to the mean of NT control. Data points are mean of n = 3 and shown as percentage of NT control.

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    Figure 3

    Insulin secretion data for selected genes in a follow-up validation experiment. Insulin secretion for ARL15 (A), ZMIZ1 (B), THADA (C), and HNF4A (D) (white bars) vs. NT (black bars) negative control under the indicated conditions. Measurements were processed as described for Fig. 2 and shown as percentage of NT control. Tol, tolbutamide. Data points are the mean of n = 6 for NT and n = 3 for other genes, and error bars are SEM. +q value <0.1, *q value <0.05, **q value <0.01, ***q value <0.001 by Student t test (FDR-adjusted).

Tables

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  • Table 1

    Effects of significant hits identified in a primary screen for β-cell dysfunction

    GeneLocusLow glucoseHigh glucoseIBMXTolbutamideCell count
    ABCC8KCNJ1148.2*24.026.7*1.8−1.4
    ADAMTS9ADAMTS96.3−4.82.8−8.012.2*
    ADIPOQST64GAL187.0*23.223.18.8−7.3
    ARL15ARL15−5.5−25.9*−2.1−15.5−1.5
    BCAR1BCAR15.925.228.5*9.5−7.0
    BCL6LPP−20.7*−8.9−1.0−12.05.6
    BMP8BMACF17.816.59.526.9*−1.0
    CCNT2TMEM163−32.6*1.84.75.0−2.8
    CDKAL1CDKAL12.41.7−10.6−23.5*7.5
    DGKQMAEA3.317.520.433.6*−9.8
    DMRTA2FAF132.3*24.513.122.7−0.3
    ELAVL4FAF1−3.69.121.222.8−11.4*
    ETV5IGF2BP2−12.4−25.6*−10.9−12.6−2.5
    FAHZFAND6−23.1*−20.6*−16.9−27.2−2.3
    FBXW7TMEM15445.2*9.68.711.79.9*
    GINS4ANK1−16.1−14.2−9.5−17.08.7*
    GLIS3GLIS3−13.0−10.66.4−9.3−10.3*
    HEYLMACF129.229.2*0.420.0−7.2
    HMGA2HMGA216.54.114.224.1*−1.2
    HNF1AHNF1A21.738.3*23.125.5*5.2
    HNF4AHNF4A36.7*66.9*74.992.9*−8.8
    IGF2DUSP8−26.3*−10.41.20.1−1.3
    INSDUSP8−53.5*−44.8*−48.7−38.7*0.9
    KCNK17KCNK16−9.4−17.3−2.5−1.29.8*
    KCTD15PEPD21.79.412.50.8−10.9*
    KIF11HHEX/IDE45.4*35.0*26.955.4*−40.1*
    LINGO1HMG20A019.1−12.4−14.97.9*
    MFGE8AP3S230.0*3.42.8−1.7−5.7
    MIER3ANKRD555.936.5*5.818.21.9
    NDUFS4ARL151.6−4.93.9−1.710.8*
    PABPC1LHNF4A−9.7−12.3−10.4−28.8*−1.2
    PHF23SLC16A11−25.6*−1.7−5.93.5−0.9
    PLA2R1RBMS18.61.610.81.69.1*
    PRDX3GRK524.031.7*23.49.616.6*
    PTHLHKLHDC5−2.8−6.5−0.5−25.0*−5.9
    RND3RND3−8.7−6.10−3.0−14.9*
    SLC2A4SLC16A1114.5027.2*18.2−1.6
    SOCS7HNF1B3.9−18.5*11.2−14.7−1.6
    SPPL3HNF1A−11.9−21.9*−6.1−10.0−10.8*
    STK38LKLHDC515.240.9*4.725.2*−3.0
    THADATHADA−1.96.527.524.8*−10.3
    TLE1TLE14.3−5.0−23.0*16.24.6
    TM6SF2CILP2−22.6*−8.3−0.8−12.0−8.7
    UPF2CDC1237.5−12.54.7−24.9*−3.2
    ZMIZ1ZMIZ1−29.5*−21.4*−19.8−16.8−15.2*
    • The table lists effect sizes (% deviation from NT control) for each gene with a least one significant effect across the five phenotypes measured. All insulin secretion measurements were normalized on a per-well basis to cell counts, and the mean percentage deviations from NT control were then calculated for each condition. For cell counts, values were median-normalized for interplate differences, and the mean percentage deviations from NT control were calculated across conditions.

    • *q < 0.05 by Student t test (FDR-adjusted).

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Systematic Functional Characterization of Candidate Causal Genes for Type 2 Diabetes Risk Variants
Soren K. Thomsen, Alessandro Ceroni, Martijn van de Bunt, Carla Burrows, Amy Barrett, Raphael Scharfmann, Daniel Ebner, Mark I. McCarthy, Anna L. Gloyn
Diabetes Dec 2016, 65 (12) 3805-3811; DOI: 10.2337/db16-0361

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Systematic Functional Characterization of Candidate Causal Genes for Type 2 Diabetes Risk Variants
Soren K. Thomsen, Alessandro Ceroni, Martijn van de Bunt, Carla Burrows, Amy Barrett, Raphael Scharfmann, Daniel Ebner, Mark I. McCarthy, Anna L. Gloyn
Diabetes Dec 2016, 65 (12) 3805-3811; DOI: 10.2337/db16-0361
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