Novel TCF7L2 familial linkage and association with Type 2 diabetes, depression, and their comorbidity

OBJECTIVE: Alterations in the activity of the transcription factor 7-like 2 (TCF7L2) generate defects previously associated with neuropsychiatric disorders. We investigated the role of the TCF7L2 gene in major depressive disorder (MDD), type 2 diabetes (T2D), and MDD-T2D comorbidity. We tested whether TCF7L2 is in linkage to and/or in linkage disequilibrium (LD, namely association) with MDD, T2D, and MDD-T2D. PATIENTS AND METHODS: In 212 families with T2D and MDD in the Italian population, we analyzed 80 microarray-based SNPs using Pseudomarker software for linkage to and LD with T2D and MDD under the recessive model with complete penetrance (R1). In a secondary analysis, we tested the variants under the dominant models with complete penetrance (D1), recessive with incomplete penetrance (R2), and recessive with incomplete penetrance (R2). RESULTS: We found several novel linkage signals and genetic associations. In addition, we found two new transcription-factor (TF) binding sites created by two risk variants found: the MDD-risk variant rs12255179 creates a new TF-binding site for the CCAAT/enhancer-binding protein α (C/EBPα), and the T2D-risk variant rs61872794 creates a new TF-binding site for the organic cation-uptake transporter (OCT1). Both new binding sites are related to insulin metabolism. CONCLUSIONS: These results highlight the cross-interactivity between T2D and MDD. Further replication is needed in diverse ethnic groups.