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

Abstract

OBJECTIVE. Depression is a common co-morbidity of type 2 diabetes. However, the causality and underlying mechanisms remain unclear. RESEARCH DESIGN AND METHODS. We applied bi-directional Mendelian randomization (MR) to assess causality between type 2 diabetes and self-reported depression. Using the UK biobank, 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 two depression definitions–clinically diagnosed major depressive disorder (MDD, cases=5,262, controls=86,275) and self–reported depressive symptoms (PHQ-9, n=153,079). The FinnGen study was used for replication for MDD (n=23,424) and type 2 diabetes (n=32,469). Based on the results, we analyzed expression quantitative trait loci (eQTL) data from public databases to identify target genes in relevant tissues. RESULTS. MR demonstrated a significant causal effect of depression on type 2 diabetes (OR=1.18[1.06–1.32], p=0.0024), but not in the reverse direction. GWAS of type 2 diabetes and depressive symptoms did not identify any shared loci between them, whereas MP-GWAS identified seven shared loci mapped toTCF7L2, CDKAL1, IGF2BP2, SPRY2, CCND2-AS1, IRS1, CDKN2B-AS1. MDD did not yield genome-wide significant loci in either GWAS or MP-GWAS. We found that most MP-GWAS loci had an eQTL, including SNPs implicating the cell cycle gene CCND2 in pancreatic islets and brain, and key insulin signaling gene IRS1 in adipose tissue, suggesting a multi-tissue and pleiotropic underlying mechanism. CONCLUSION. Our study reveals the complexity in the depression-diabetes relationship and our results have important implications for a more efficient prevention of type 2 diabetes from early adulthood when depressive symptoms usually occur.

GWAS advancements to investigate disease associations and biological mechanisms

“…It also extends to unveiling shared pathophysiology between two diseases. For instance, these include depression and type 2 diabetes, 72 rheumatoid arthritis and myocardial infarction, 73 and AF and HF 74 . Statistically, it is depicted that nearly two‐third of people living with AF, irrespective of its aetiology, will subsequently develop HF as their condition progresses, whereas AF arises in only one‐third of those with pre‐existing HF 75,76 …”

Causal relationship analysis between 35 blood/urine metabolites and gastroesophageal reflux disease: A Mendelian randomization combined meta-analysis study

“…[19,20] Bidirectional MR offers advantages such as reducing reverse causality bias and strengthening the credibility of causal inference. [21,22] Therefore, this study employs a bidirectional 2-sample MR analysis to explore the causal relationship between 35 blood/urine metabolites and GERD. Finally, a meta-analysis of the inverse variance weighted (IVW) results from the MR analyses of GERD data derived from different databases was conducted, and multiple corrections were applied to the meta-analysis results to ensure data accuracy.…”