Table 1.
Cardiometabolic profile, example loci and physiological effect of index SNVs at T2D association signals allocated to eight mechanistic clusters
| Mechanistic cluster | Cardiometabolic profile | Number of T2D associations | Example loci | Physiological effect | |
|---|---|---|---|---|---|
| Insulin secretion | Insulin sensitivity | ||||
| Beta cell +PI | +FG*, +2hG*, +HbA1c, +PI* | 91 | TCF7L2, KCNQ1, CDKAL1, CDKN2A–CDKN2B, SLC30A8 | − | + |
| Beta cell −PI | +FG*, +2hG*, +HbA1c, −PI* | 89 | CDC123–CAMK1D, HNF1B, KCNJ11–ABCC8, HNF4A, HNF1A | − | + |
| Residual glycaemic | +FG*, +HbA1c | 389 | GCC1–PAX4–LEP, ANKRD55, GCKR, UBE2E2 | − | − |
| Body fat | +Body fat, +ASAT* | 273 | ZMIZ1, HMGA2, CTBP1 | + | − |
| Metabolic syndrome | +FG*, +FI*, +WHR, +VAT*, −GFAT*, +TG, −HDL, +BP | 166 | IGF2BP2, CCND2, HHEX–IDE, JAZF1, GPSM1 | + | − |
| Obesity | +BMI, +WHR, +body fat, +BMR, +TG, −HDL | 233 | FTO, MC4R, MACF1, TMEM18 | + | − |
| Lipodystrophy | +FI*, +WHR, −body fat, −GFAT*, +TG, −HDL, +BP | 45 | IRS1, GRB14–COBLL1, PPARG | + | − |
| Liver and lipid metabolism | −LDL, −TC, +liver fat, +liver biomarkers | 3 | TOMM40–APOE–GIPR, TM6SF2, PNPLA3 | − | − |
+/−: T2D risk alleles associated with increased or decreased phenotype values.
ASAT, abdominal subcutaneous adipose tissue volume; BMI, body mass index; BMR, basal metabolic rate; BP, blood pressure; FG, fasting glucose; FI, fasting insulin; GFAT, gluteofemoral adipose tissue volume; HbA1c, glycated haemoglobin; HDL, high-density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol; PI, proinsulin; TC, total cholesterol; TG, triglycerides; VAT, visceral adipose tissue volume; WHR, waist–hip ratio; 2hG, two-hour glucose.
*Adjusted for BMI.