Extended Data Table 8. Testing for synthetic associations across GWAS-identified T2D loci.
Gene names refer to protein-coding transcript(s) closest to the index SNV. Reported index SNVs are the previously-reported GWAS variants (in European populations) with the strongest association signal in the GoT2D sequencing data (n=2,657). Relative likelihoods are based on causal models with only the chosen low-frequency and rare missense variants, relative to models with only the GWAS index SNV, assessed using the Akaike Information content (AIC) of each regression model, calculated as exp[(AICindex–AIClow-frequency or rare)/2]. n1 provides the number of low-frequency or rare variants required for the residual odds ratio at the GWAS index SNV, after joint conditioning on the low-frequency and rare variants, to switch direction of effect. n2 provides the number of low-frequency or rare variants required for the association p-value remaining at the GWAS index SNV, after joint conditioning on the low-frequency and rare variants, to exceed 0.05.
| Index SNV association signal |
Synthetic association by
missense variants |
Synthetic association by all
low- frequency and rare variants across 5Mb region |
||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Index SNV association signal before inclusion of missense variants |
Index SNV association signal after inclusion of missense variants |
Index SNV association after inclusion of single best variant |
Testing groups of low- frequency and rare variants |
|||||||||||
| Gene | Index SNV | MAF | OR [95% interval] |
p-value | Number Missense Variants |
OR [95% interval] |
p-value | Relative likelihood of LF model |
Best LF Variant |
MAF | OR [95% interval] |
p-value | n1 | n2 |
| TCF7L2 | 10:114758349 | 0.27 | 1.75 [1.54-1.99] | 2.80×10−18 | 6 | 1.73 [1.52-1.97] | 2.33×10−17 | 1.8×10−17 | 10:114787948 | 1.6% | 1.72 [1.51-1.95] | 1.62×10−16 | >50 | 35 |
| ADCY5 | 3:123065778 | 0.19 | 0.69 [0.60-0.79] | 1.12×10−7 | 13 | 0.70 [0.61-0.81] | 9.00×10−7 | 9.7×10−8 | 3:123096056 | 2.5% | 0.71 [0.61-0.82] | 3.04×10−6 | 13 | 6 |
| IRS1 | 2:227093745 | 0.36 | 0.76 [0.68-0.86] | 2.80×10−6 | 5 | 0.77 [0.69-0.86] | 4.30×10−6 | 4.5×10−7 | 2:226993370 | 1.7% | 0.78 [0.70-0.88] | 2.19×10−5 | 12 | 6 |
| KCNQ1 | 11:2847069 | 0.45 | 0.78 [0.70-0.87] | 1.22×10−5 | >50 | 0.84 [0.75-0.94] | 2.07×10−3 | 1.0×10−7 | 11:2825279 | 4.7% | 0.81 [0.71-0.91] | 3.19×10−4 | 16 | 6 |
| CDC 123-CAMK1D | 10:12307894 | 0.25 | 1.33 [1.17-1.52] | 1.19×10−5 | 4 | 1.30 [1.13-1.50] | 2.06×10−4 | 7.1×10−5 | 10:12325477 | 3.8% | 1.29 [1.12-1.48] | 3.03×10−4 | 10 | 5 |
| CDKN2A-CDKN2B | 9:22137685 | 0.28 | 1.28 [1.14-1.45] | 4.52×10−5 | 4 | 1.27 [1.13-1.43] | 9.28×10−5 | 4.3×10−5 | 9:22133773 | 3.5% | 1.25 [1.10-1.41] | 5.98×10−4 | 22 | 7 |
| IGF2BP2 | 3:185511687 | 0.32 | 1.25 [1.11-1.41] | 1.65×10−4 | 14 | 1.21 [1.07-1.36] | 2.12×10−3 | 3.0×10−4 | 3:185550500 | 4.1% | 1.20 [1.07-1.36] | 2.91×10−3 | 8 | 3 |
| KLHDC5 | 12:27965150 | 0.17 | 0.76 [0.66-0.88] | 2.19×10−4 | 3 | 0.77 [0.66-0.89] | 4.45×10−4 | 1.2×10−3 | 12:27832062 | 2.0% | 0.80 [0.68-0.92] | 3.04×10−3 | 10 | 4 |
| SLC30A8 | 8:118184783 | 0.33 | 0.81 [0.72-0.91] | 2.95×10−4 | 2 | 0.81 [0.72-0.91] | 3.73×10−4 | 0.02 | 8:117964024 | 2.2% | 0.83 [0.73-0.93] | 1.23×10−3 | 17 | 6 |
| CDKAL1 | 6:20694884 | 0.18 | 1.28 [1.11-1.48] | 6.05×10−4 | 1 | 1.28 [1.11-1.48] | 7.57×10−4 | 0.007 | 6:20718780 | 2.8% | 1.23 [1.06-1.43] | 7.71×10−3 | 9 | 3 |