Quantitative trait loci mapping identifies genetic loci modifying MafAS64F-mediated dysglycemia

Increasing evidence has shown the role of genetic background on the penetrance of monogenic diabetes. A missense mutation of the pancreatic β-cell-enriched transcription factor MafA co-segregates with diabetes (MafA-MODY) and non-syndromic insulinomatosis. We recently investigated the effects of genetic background on MafAS64F-driven dysglycemia in genetically diverse mice harboring this mutation. Here we leveraged the effects of genetic background on phenotypic penetrance to map quantitative trait loci (QTL) potentially modifying glycemia in response to this variant. We investigated MafaS64F/+ mice from an F2 intercross of the C57BL/6J and SJL/J genetic backgrounds through oral glucose tolerance testing at 4, 5, 6, and 8 weeks of age to evaluate glucose tolerance and glycemic trajectory. All F2 mice were genetically monitored for single nucleotide polymorphisms (SNPs) between the C57BL/6J and SJL/J backgrounds, allowing us to identify modifying loci on 6 chromosomes (2, 126 Mbp; 3, 59 Mbp and 103 Mbp; 7, 47 Mbp; 11 45 Mbp; 13, 4 Mbp; and 16, 85-97 Mbp), containing 172 candidate genes. For example, known MODY genes Abcc8 (Sur1) and Kcnj11 (Kir6.2) are within the QTL region on chromosome 7 and contain polymorphisms between backgrounds that may impart combinatorial effects on the phenotypic penetrance of MafAS64F-mediated dysglycemia