Systematic Functional Characterization of Candidate Causal Genes for Type 2 Diabetes Risk Variants
Article Figures & Tables
Figures
- 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).
- 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.
- 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
- Table 1
Effects of significant hits identified in a primary screen for β-cell dysfunction
Gene Locus Low glucose High glucose IBMX Tolbutamide Cell count ABCC8 KCNJ11 48.2* 24.0 26.7* 1.8 −1.4 ADAMTS9 ADAMTS9 6.3 −4.8 2.8 −8.0 12.2* ADIPOQ ST64GAL1 87.0* 23.2 23.1 8.8 −7.3 ARL15 ARL15 −5.5 −25.9* −2.1 −15.5 −1.5 BCAR1 BCAR1 5.9 25.2 28.5* 9.5 −7.0 BCL6 LPP −20.7* −8.9 −1.0 −12.0 5.6 BMP8B MACF1 7.8 16.5 9.5 26.9* −1.0 CCNT2 TMEM163 −32.6* 1.8 4.7 5.0 −2.8 CDKAL1 CDKAL1 2.4 1.7 −10.6 −23.5* 7.5 DGKQ MAEA 3.3 17.5 20.4 33.6* −9.8 DMRTA2 FAF1 32.3* 24.5 13.1 22.7 −0.3 ELAVL4 FAF1 −3.6 9.1 21.2 22.8 −11.4* ETV5 IGF2BP2 −12.4 −25.6* −10.9 −12.6 −2.5 FAH ZFAND6 −23.1* −20.6* −16.9 −27.2 −2.3 FBXW7 TMEM154 45.2* 9.6 8.7 11.7 9.9* GINS4 ANK1 −16.1 −14.2 −9.5 −17.0 8.7* GLIS3 GLIS3 −13.0 −10.6 6.4 −9.3 −10.3* HEYL MACF1 29.2 29.2* 0.4 20.0 −7.2 HMGA2 HMGA2 16.5 4.1 14.2 24.1* −1.2 HNF1A HNF1A 21.7 38.3* 23.1 25.5* 5.2 HNF4A HNF4A 36.7* 66.9* 74.9 92.9* −8.8 IGF2 DUSP8 −26.3* −10.4 1.2 0.1 −1.3 INS DUSP8 −53.5* −44.8* −48.7 −38.7* 0.9 KCNK17 KCNK16 −9.4 −17.3 −2.5 −1.2 9.8* KCTD15 PEPD 21.7 9.4 12.5 0.8 −10.9* KIF11 HHEX/IDE 45.4* 35.0* 26.9 55.4* −40.1* LINGO1 HMG20A 0 19.1 −12.4 −14.9 7.9* MFGE8 AP3S2 30.0* 3.4 2.8 −1.7 −5.7 MIER3 ANKRD55 5.9 36.5* 5.8 18.2 1.9 NDUFS4 ARL15 1.6 −4.9 3.9 −1.7 10.8* PABPC1L HNF4A −9.7 −12.3 −10.4 −28.8* −1.2 PHF23 SLC16A11 −25.6* −1.7 −5.9 3.5 −0.9 PLA2R1 RBMS1 8.6 1.6 10.8 1.6 9.1* PRDX3 GRK5 24.0 31.7* 23.4 9.6 16.6* PTHLH KLHDC5 −2.8 −6.5 −0.5 −25.0* −5.9 RND3 RND3 −8.7 −6.1 0 −3.0 −14.9* SLC2A4 SLC16A11 14.5 0 27.2* 18.2 −1.6 SOCS7 HNF1B 3.9 −18.5* 11.2 −14.7 −1.6 SPPL3 HNF1A −11.9 −21.9* −6.1 −10.0 −10.8* STK38L KLHDC5 15.2 40.9* 4.7 25.2* −3.0 THADA THADA −1.9 6.5 27.5 24.8* −10.3 TLE1 TLE1 4.3 −5.0 −23.0* 16.2 4.6 TM6SF2 CILP2 −22.6* −8.3 −0.8 −12.0 −8.7 UPF2 CDC123 7.5 −12.5 4.7 −24.9* −3.2 ZMIZ1 ZMIZ1 −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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