Mingrui Zou ^1,2,3 Jichun Yang ^2,3*

• ¹ School of Clinical Medicine, Peking University Health Science Center, Beijing, China
• ² Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
• ³ Key Laboratory of Molecular Cardiovascular Science of the Ministry of Education, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing, China

Background: Periodontitis is a common complication of type II diabetes (T2D). However, the existing research cannot fully elucidate the association between them, let alone identify therapeutic targets for precise treatment of diabetic periodontitis. Therefore, we employed integrated genetic approaches such as single-cell analysis, Mendelian randomization (MR) analysis and colocalization analysis to uncover novel therapeutic targets for T2D and periodontitis.This study integrated single-cell analysis, MR analysis, colocalization analysis, phenotype scanning, cell-cell communication analysis and metabolic pathway activity analysis to unveil novel therapeutic targets for periodontitis and T2D. We firstly identified core cell clusters of T2D and periodontitis, and important marker genes were selected. The causal associations between these genes and the two diseases were evaluated through MR analysis. Reverse MR analysis, colocalization analysis, additional validation and phenotype scanning further supported our findings. Finally, we further explored the function of identified genes Results: Through single-cell analysis, we identified classical monocytes and intermediate monocytes as core cell subclusters. Differential analysis identified 221 differentially expressed genes (DEGs). MR analysis identified 13 genes exhibiting causal associations with T2D, and 11 causal genes with periodontitis. Colocalization analysis, reverse MR analysis, additional validation and phenotype scanning further enhanced the robustness of our results. Finally, we identified NCF1 as the core therapeutic target for T2D (OR = 1.09, 95% CI: 1.03-1.14, p = 1.85 × 10 -3 ) and LRRC25 for T2D (OR = 0.96, 95% CI: 0.93-0.99, p = 3.44 × 10 -2 ) and periodontitis (OR = 0.92, 95% CI: 0.84-0.99, p = 4.45 × 10 -2 ). At last, cell-cell communication analysis indicated significant differences in functions and metabolic pathway activity between monocytes expressing or not expressing the core causal genes, which preliminarily interpreted the observed causal associations.This study integrated single-cell analysis, MR analysis and colocalization analysis to identified novel therapeutic targets for T2D and periodontitis. 13 causal genes were identified for T2D, and 11 for periodontitis. Among them, NCF1 and LRRC25 were regarded as core therapeutic targets. Our findings bridge the gap in the understanding of the association between T2D and periodontitis, and pave the way for targeted therapy of the two diseases.