Table 1.
Overview of multi-ancestry T2D genetic clusters. Refer to Supplementary Table 3 for trait abbreviations legend.
| Cluster (# Variants) | Expected physiological impact | Key top-weighted traits | Key top-weighted loci | Suspected mechanism | Note |
|---|---|---|---|---|---|
| Beta Cell 1 (82) | Insulin deficiency | CIR (−), disposition index (−) | CDKAL1, C2CD4A, HHEX, ST6GAL1, LDHB, TET2 | Beta cell function, glucose homeostasis | Recaptures part of Beta Cell cluster from Udler et al 2018 [3] and Beta Cell 1 from Kim et al 2022 [4] |
| Beta Cell 2 (40) | Insulin deficiency | HbA1c female (+), FGadjBMI (+), glucose male (+), proinsulin (+) | GCK, TCF7L2, SLC30A8, SLC2A2, ADCY5, DGKB | Beta cell function, insulin processing | Recaptures part of Beta Cell cluster from Udler et al 2018 [3] and Beta Cell 2 from Kim et al 2022 [4] |
| Proinsulin (16) | Insulin deficiency | PI (−), VAT (−) | ARAP1/STARD1, LINC01512 | Insulin synthesis | Recaptures Proinsulin cluster from Udler et al 2018 [3] and Kim et al 2022 [4] |
| Obesity (76) | Insulin resistance | BMI male (+), SAT (+), waist C female (+), Trunk fat % female (+) | FTO, MC4R, TMEM18, BDNF | Obesity-mediated insulin resistance | Recaptures Obesity cluster from Udler et al 2018 [3] and Kim et al 2022 [4] |
| Hyper Insulin (41) | Insulin resistance | DI (+), CIR (+) | PDE3A, RBM6, TRAF3, CNTN2 | Insulin secretion, inflammation | Recaptures Hyper Insulin cluster from Kim et al 2022 [4] |
| Cholesterol (5) | Insulin resistance | CRP male (+), Cholesterol (−), Apolipoprotein A (+) | APOE, NECTIN2, TM6SF2, POLK/HMGCR | HMGCR expression | New cluster in this study |
| Lipodystrophy 1 (47) | Insulin resistance | GFATAdjBMI (−), VAT/GFAT (+), adiponectin (−) | VEGFA, CCFC92, LINC01625/CITED2, GRB14/COBLL1, FAM13A | Fat distribution-mediated insulin resistance | Recaptures Lipodystrophy cluster from Udler et al 2018 [3] and Kim et al 2022 [4] |
| Lipodystrophy 2 (29) | Insulin resistance | ALT (+), ISIadjAgeSexBMI (−), AST (+), GGT (+) | PNPLA3, PPARG, LOC646736/IRS1, PEPD, ANKRD55, ERLIN1 | Hepatic steatosis | New cluster in this study; split from previous Lipodystrophy cluster |
| Liver-Lipid (7) | Insulin resistance | TG female (−), SHBG male (+), IGF female (+), Albumin male (−) | GCKR, FADS1, PPIP5K1 | Liver/lipid metabolism | Recaptures Liver-Lipid cluster from Udler et al 2018 [3] and Kim et al 2022 [4] |
| Bilirubin (2) | Unclear | Bilirubin (+) | UGT1A3 | Bilirubin metabolism | New cluster in this study |
| SHBG-LpA (3) | Unclear | SHBG male (−), Lp(a) female (+), oestradiol female (−) | SHBG, SLC22A3, STAG1 | SHBG and Lp(a) metabolism | Merged from LpA and SHBG clusters from Kim et al 2022 [4] |
| ALP Negative (6) | Insulin resistance | ALP (−), RBC count (−), Hgb concentration (−) | ABO, FADS1 | ALP activity levels | Recaptures ALP Neg cluster from Kim et al 2022 [4] |