TCF7L2 functionally relevant genetic variation with clinical implications in bipolar disorder with impaired glucose metabolism

Impaired glucose metabolism (IGM) and type 2 diabetes (T2DM) are common in bipolar disorder (BD). Genome-wide association studies have identified variation (rs7903146) in the gene encoding transcription factor 7-like 2 ( TCF7L2 ) as a well-established risk factor for T2DM in the general population and variation (rs12772424) showing a significant association with BD when accounting for BMI. Evaluating T2DM- and BD-associated TCF7L2 SNPs within bipolar IGM groups, along with their clinical correlates, could provide translational insights for future clinical practice. IGM was operationalized as evidence of prediabetes (fasting glucose of 100-125 mg/dL or glycated hemoglobin of 5.7%-6.4%) or T2DM. We compared sociodemographic, genetic, clinical characteristics, and course of illness measures between BD groups with and without IGM, then within BD subgroups (prediabetes, T2DM, and no IGM). Out of 850 BD patients included (mean age 49, SD = 13, 57% female, 8% non-White) 280 (33%) individuals had IGM. Compared to BD patients without IGM, those with IGM were older (p < 0.001), more likely to be non-White (p = 0.005), and obese (p < 0.001). The minor allele for the rs7903146 SNP (T2DM-associated SNP) was significantly greater in the IGM group compared to the group without IGM (11% vs. 5%, p = 0.009). There was no significant association between rs12772424 SNP (BD-associated SNP) with bipolar course of illness measures. Further investigation examining the complex interactions between functional genetic variants, molecular markers, environmental influence, and clinical phenotypes in BD is needed to better understand the mechanistic underpinnings to the high rate of T2DM bipolar comorbidity and identify early targets for treatment of both disorders.