The genetics of bipolar disorder with obesity and type 2 diabetes

Abstract

Background: Bipolar disorder (BD) presents with high obesity and type 2 diabetes (T2D) and pathophysiological and phenomenological abnormalities shared with cardiometabolic disorders. Genomic studies may help define if they share genetic liability. This selective review of BD with obesity and T2D will focus on genomic studies, stress their current limitations and guide future steps in developing the field.

Methods: We searched electronic databases (PubMed, Scopus) until December 2021 to identify genome-wide association studies, polygenic risk score analyses, and functional genomics of BD accounting for body mass index (BMI), obesity, or T2D.

Results: The first genome-wide association studies (GWAS) of BD accounting for obesity found a promising genome-wide association in an intronic gene variant of TCF7L2 that was further replicated. Polygenic risk scores of obesity and T2D have also been associated with BD, yet, no genetic correlations have been demonstrated. Finally, human-induced stem cell studies of the intronic variant in TCF7L2 show a potential biological impact of the products of this genetic variant in BD risk.

Limitations: The narrative nature of this review.

Conclusions: Findings from BD GWAS accounting for obesity and their functional testing, have prompted potential biological insights. Yet, BD, obesity, and T2D display high phenotypic, genetic, and population-related heterogeneity, limiting our ability to detect genetic associations. Further studies should refine cardiometabolic phenotypes, test gene-environmental interactions and add population diversity.

Keywords: Bipolar disorder; Diabetes type 2; Genome-wide association study; Genomics; Obesity; Polygenic risk score.

Fig. 1.

T2D pathophysiology and its interplay with obesity and BD. Defects at the early steps of insulin signaling such as INSR, IRS1, PI3K, and Akt activity (Caro et al., 1987; Cusi et al., 2000; Griffin et al., 2000), impair insulin ability to stimulate GLUT4 translocation and subsequent glycogen synthesis (Petersen and Shulman, 2018). Unlike starvation, compensatory hyperinsulinemia promotes insulin mitogenic effects (Wilcox, 2005). Furthermore, the liver increases free fatty acid delivery which results in rising circulating lipids which will accumulate in the liver and further compromise triglyceride content and VLDL secretion (Krauss and Siri, 2004). Expanded visceral adipose tissue (VAT) becomes inflamed leading to increased production of pro-inflammatory cytokines, leptin, RBP4 and PAI-I that impair further insulin signaling (Devaraj et al., 2004; Wilcox, 2005) in part related to the increased presence of pro-inflammatory macrophages, and cause systemic and brain inflammation (Goldstein et al., 2009; Sayana et al., 2017). Wnt signaling pathway regulates the development of mammalian nervous system (Muneer, 2017; Valvezan and Klein, 2012), as well as glucose homeostasis through the regulation of pro-glucagon gene expression, which encodes glucagon-like peptide 1 (GLP-1) in intestinal cells (Yi et al., 2005).

Fig. 2.

Possible models of obesity/T2D-gene interaction.