Bidirectional Mendelian Randomization and Multiphenotype GWAS Show Causality and Shared Pathophysiology Between Depression and Type 2 Diabetes

• Published in: Diabetes care Vol. 46; no. 9; pp. 1707 - 1714
• Main Authors: Maina, Jared G., Balkhiyarova, Zhanna, Nouwen, Arie, Pupko, Igor, Ulrich, Anna, Boissel, Mathilde, Bonnefond, Amélie, Froguel, Philippe, Khamis, Amna, Prokopenko, Inga, Kaakinen, Marika
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.09.2023
• Subjects: Adipose tissue; Cell cycle; Comorbidity; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Gene mapping; Genetics; Genome-wide association studies; Genomes; Insulin; Life Sciences; Mental depression; Nucleotides; Original; Quantitative trait loci; Randomization; Single-nucleotide polymorphism; Target recognition
• ISSN: 0149-5992; 1935-5548; 1935-5548; 0149-5992
• DOI: 10.2337/dc22-2373

Depression is a common comorbidity of type 2 diabetes. We assessed the causal relationships and shared genetics between them. We applied two-sample, bidirectional Mendelian randomization (MR) to assess causality between type 2 diabetes and depression. We investigated potential mediation using two-step MR. To identify shared genetics, we performed 1) genome-wide association studies (GWAS) separately and 2) multiphenotype GWAS (MP-GWAS) of type 2 diabetes (19,344 case subjects, 463,641 control subjects) and depression using major depressive disorder (MDD) (5,262 case subjects, 86,275 control subjects) and self-reported depressive symptoms (n = 153,079) in the UK Biobank. We analyzed expression quantitative trait loci (eQTL) data from public databases to identify target genes in relevant tissues. MR demonstrated a significant causal effect of depression on type 2 diabetes (odds ratio 1.26 [95% CI 1.11-1.44], P = 5.46 × 10-4) but not in the reverse direction. Mediation analysis indicated that 36.5% (12.4-57.6%, P = 0.0499) of the effect from depression on type 2 diabetes was mediated by BMI. GWAS of type 2 diabetes and depressive symptoms did not identify shared loci. MP-GWAS identified seven shared loci mapped to TCF7L2, CDKAL1, IGF2BP2, SPRY2, CCND2-AS1, IRS1, CDKN2B-AS1. MDD has not brought any significant association in either GWAS or MP-GWAS. Most MP-GWAS loci had an eQTL, including single nucleotide polymorphisms implicating the cell cycle gene CCND2 in pancreatic islets and brain and the insulin signaling gene IRS1 in adipose tissue, suggesting a multitissue and pleiotropic underlying mechanism. Our results highlight the importance to prevent type 2 diabetes at the onset of depressive symptoms and the need to maintain a healthy weight in the context of its effect on depression and type 2 diabetes comorbidity.