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Genetics/Genomes/Proteomics/Metabolomics

Type 1 Diabetes Genetic Risk Score: A Novel Tool to Discriminate Monogenic and Type 1 Diabetes

  1. Kashyap A. Patel1,2,
  2. Richard A. Oram1,2,
  3. Sarah E. Flanagan1,
  4. Elisa De Franco1,
  5. Kevin Colclough3,
  6. Maggie Shepherd1,2,
  7. Sian Ellard1,3,
  8. Michael N. Weedon1 and
  9. Andrew T. Hattersley1,2⇑
  1. 1Institute for Biomedical & Clinical Science, University of Exeter Medical School, Exeter, U.K.
  2. 2National Institute for Health Research Exeter Clinical Research Facility, Exeter, U.K.
  3. 3Department of Molecular Genetics, Royal Devon and Exeter National Health Service Foundation Trust, Exeter, U.K.
  1. Corresponding author: Andrew T. Hattersley, a.t.hattersley{at}exeter.ac.uk.
  1. M.N.W. and A.T.H. contributed equally to this study.

Diabetes 2016 Jul; 65(7): 2094-2099. https://doi.org/10.2337/db15-1690
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    Figure 1

    T1D-GRS is higher in T1D patients than in confirmed MODY patients and control subjects without diabetes. A: Dot plot of T1D-GRS from 1,963 T1D patients, 805 MODY (subtype of monogenic diabetes) patients, and 2,938 control subjects without diabetes. The blue bar highlights the median T1D-GRS for each group. The upper red horizontal line shows a GRS equivalent to 50th centile for the T1D cohort, and the lower red horizontal line shows a GRS equivalent to 5th centile for the T1D cohort. The control subjects and T1D patients came from WTCCC (11). B: ROC curve (area under the curve 0.87) for T1D-GRS to discriminate MODY (n = 805) and T1D (n = 1,963).

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    Figure 2

    T1D-GRS identified proven and probable monogenic NDM. A: T1D-GRS identified proven monogenic NDM. A total of 242 white European patients with NDM (diagnosed before 6 months of age) who had comprehensive genetic testing for all 23 NDM genes were grouped by their T1D-GRS (12). The subgroups of T1D-GRS are based on centiles of the T1D cohort: low to high score groups (left to right). The bar chart shows the proportion of proven monogenic NDM (total n = 194, patients with positive genetic test, black bar) and NDM with unknown etiology (total n = 48, NDMX patients, white bar) for each score category. The total number of patients is also shown for each category. B: T1D-GRS identified probable monogenic NDM and probable T1D in NDMX patients. The T1D-GRS distribution of NDMX patients (n = 48) showed bimodal distribution with peaks at <5th T1D centile and >75th T1D centile with the nadir around 50th T1D centile. T1D-GRS 50th T1D centile categorized this group as probable T1D (T1D-GRS >50th T1D centile, n = 21) and probable monogenic diabetes due to mutations in as-yet undiscovered disease genes (T1D-GRS ≤50th T1D centile, n = 27).

Tables

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  • Table 1

    T1D-GRS is discriminatory for T1D and MODY

    Categories based on GRS centiles of T1D cohort (actual score value)T1D, n (%)Confirmed MODY, n (%)TotalOdds ratio for T1D (95% CI)
    <5th centile (<0.234)98 (5)423 (53)5211
    5–25th centile (0.234–0.262)392 (20)242 (30)6347 (5–9)
    26–50th centile (0.263–0.280)492 (25)89 (11)58124 (16–36)
    51–75th centile (0.281–0.299)491 (25)42 (5)53350 (29–89)
    >75th centile (>0.299)490 (25)9 (1)499235 (73–755)
    Total1,963 (100)805 (100)2,768
    • The groups were categorized by GRS centiles of the T1D cohort. The odds ratios are relative to <5th centile of T1D-GRS category.

  • Table 2

    Clinical characteristics of patients with proven and probable monogenic NDM and probable T1D

    Proven monogenic NDM <6 months, n = 194Probable monogenic NDM <6 months (T1D-GRS ≤50th T1D centile), n = 27Probable T1D <6 months (T1D-GRS >50th T1D centile), n = 21P value (proven monogenic vs. probable monogenic)P value (proven monogenic vs. probable T1D)
    T1D-GRS, median (IQR)0.231 (0.206–0.251)0.237 (0.210–0.250)0.299 (0.295–0.313)0.86<0.001
    Age at diagnosis in weeks, median (IQR)5 (1–12)1 (0.6–6)12 (3–20)0.130.04
    Male, n (%)111 (57)17 (63)15 (71)0.680.25
    Presence of other autoimmune disorders, n (%)1 (1)1 (4)3 (14)0.230.003
    Syndromic presentation, n (%)77 (40)9 (33)2 (10)0.670.007
    Consanguineous parents, n (%)3 (2)001.001.00
    • NDMX patients were categorized into probable T1D and probable monogenic NDM by T1D-GRS equivalent to 50th centile of T1D cohort. Fisher exact test was used to compare proportions, and Mann-Whitney U test was used to compare continuous variables. IQR, interquartile range.

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Type 1 Diabetes Genetic Risk Score: A Novel Tool to Discriminate Monogenic and Type 1 Diabetes
Kashyap A. Patel, Richard A. Oram, Sarah E. Flanagan, Elisa De Franco, Kevin Colclough, Maggie Shepherd, Sian Ellard, Michael N. Weedon, Andrew T. Hattersley
Diabetes Jul 2016, 65 (7) 2094-2099; DOI: 10.2337/db15-1690

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Type 1 Diabetes Genetic Risk Score: A Novel Tool to Discriminate Monogenic and Type 1 Diabetes
Kashyap A. Patel, Richard A. Oram, Sarah E. Flanagan, Elisa De Franco, Kevin Colclough, Maggie Shepherd, Sian Ellard, Michael N. Weedon, Andrew T. Hattersley
Diabetes Jul 2016, 65 (7) 2094-2099; DOI: 10.2337/db15-1690
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