Abstract Body (Do not enter title and authors here): Introduction: Several glycemic traits indicate risk for type 2 diabetes (T2D). Although previous studies have identified many genes associated with glycemic traits, the underlying molecular mechanisms remain unclear. Identifying gene expression signatures, both protein-coding mRNAs and long non-coding RNAs (lncRNAs), associated with glycemic traits may provide insight into the biological pathways that contribute to glycemic regulation and the development of T2D.

Methods: Whole blood RNA-seq data were analyzed from Framingham Heart Study (FHS, N=3,469; 55% female, discovery cohort) and Women’s Health Initiative (WHI, N=1,699; female only, replication cohort) participants. Glycemic traits examined included fasting glucose, fasting insulin, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), and glycosylated hemoglobin. Associations between gene expression (mRNAs and lncRNAs) and glycemic traits were assessed using linear mixed models, excluding participants with prevalent T2D and adjusting for age, age squared, body mass index, batch effects, family structure, and sex. Sex-specific analyses were also conducted. Two-sample Mendelian Randomization (MR) was used to infer putative causal relations between gene expression and glycemic traits. Gene ontology analysis was performed to identify enriched biological functions and pathways.

Results: In the discovery cohort we identified 2,022 protein-coding mRNA and 172 lncRNA associated with glycemic traits (FDR<0.01), of which 129 protein-coding mRNAs and 11 lncRNA replicated (FDR< 0.05). When limiting the discovery sample to women (N=1,929), 140 mRNAs and 8 lncRNAs were significant in discovery, and 51 mRNAs and 6 lncRNAs replicated. Glycemic signatures were significantly enriched for genes involving mitochondrial synthesis, immune function, and protein synthesis. MR further identified 87 of the 144 replicated genes as causal for the corresponding glycemic trait (P_MR<0.05). ADM, which encodes for adrenomedullin, was associated with insulin and identified as the top mRNA in MR analysis. AL357033.4, which is associated with immune-related functions and cancer, was associated with HOMA-IR and identified as the top lncRNA in the MR analysis.

Conclusion: These findings reveal mRNAs and lncRNA associations with glycemic traits that may provide insights into molecular mechanism underlying diabetes risk and highlight promising therapeutic targets for treatment and prevention of T2D.