Genome-wide association studies have identified 240 independent loci associated with type 2 diabetes (T2D) risk, but this knowledge has not advanced precision medicine. In contrast, the genetic diagnosis of monogenic forms of diabetes (including maturity-onset diabetes of the young (MODY)) are textbook cases of genomic medicine. Recent studies trying to bridge the gap between monogenic diabetes and T2D have been inconclusive. Here, we show a significant burden of pathogenic variants in genes linked with monogenic diabetes among people with common T2D, particularly in actionable MODY genes, thus implying that there should be a substantial change in care for carriers with T2D. We show that, among 74,629 individuals, this burden is probably driven by the pathogenic variants found in GCK, and to a lesser extent in HNF4A, KCNJ11, HNF1B and ABCC8. The carriers with T2D are leaner, which evidences a functional metabolic effect of these mutations. Pathogenic variants in actionable MODY genes are more frequent than was previously expected in common T2D. These results open avenues for future interventions assessing the clinical interest of these pathogenic mutations in precision medicine.

全基因组关联研究已经确定了 240 个与 2 型糖尿病 (T2D) 风险相关的独立基因座，但这些知识并没有促进精准医学。相比之下，单基因型糖尿病（包括青年成人型糖尿病（MODY））的基因诊断是基因组医学的教科书案例。最近试图弥合单基因糖尿病和 T2D 之间差距的研究尚无定论。在这里，我们展示了常见 T2D 患者中与单基因糖尿病相关的基因致病性变异的显着负担，特别是在可操作的 MODY 基因中，因此暗示应该对 T2D 携带者的护理进行重大改变。我们表明，在 74,629 人中，这种负担可能是由GCK中发现的致病变异驱动的，在HNF4A、KCNJ11、HNF1B和ABCC8中的影响较小。患有 T2D 的携带者更瘦，这证明了这些突变的功能代谢效应。可操作的 MODY 基因中的致病变异比以前在普通 T2D 中预期的更为频繁。这些结果为未来的干预措施开辟了途径，以评估这些致病突变在精准医学中的临床意义。