<strong>Bi-directional Mendelian randomization and multi-phenotype GWAS show causality and shared pathophysiology between depression and type 2 diabetes</strong>

Abstract

<p>OBJECTIVE. Depression is a common co-morbidity of type 2 diabetes. We assessed the causal relationships and shared genetics between them.</p> <p>RESEARCH DESIGN AND METHODS. We applied two-sample bi-directional 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) GWAS, separately, and 2) multi-phenotype GWAS (MP-GWAS) of type 2 diabetes (cases=19,344, controls=463,641) and depression, using major depressive disorder (MDD, cases=5,262, controls=86,275) and self-reported depressive symptoms (n=153,079) in UK biobank. We analyzed expression quantitative trait loci (eQTL) data from public databases to identify target genes in relevant tissues.</p> <p>RESULTS. MR demonstrated a significant causal effect of depression on type 2 diabetes (OR=1.26[1.11-1.44], <em>p</em>=5.46×10-4), but not in the reverse direction. Mediation analysis indicated that 36.5% [12.4-57.6%, <em>p</em>=0.0499] of the effect from depression to 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 <em>TCF7L2, CDKAL1, IGF2BP2, SPRY2, CCND2-AS1, IRS1, CDKN2B-AS1</em>. MDD was insignificant in both GWAS and MP-GWAS. Most MP-GWAS loci had an eQTL, including SNPs implicating the cell cycle gene <em>CCND2</em> in pancreatic islets and brain, and insulin signaling gene <em>IRS1</em> in adipose tissue, suggesting a multi-tissue and pleiotropic underlying mechanism.</p> <p>CONCLUSION. 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 co-morbidity.</p>