Differential associations of various depression-related phenotypes with cardiometabolic risks: Identification of shared genetic factors and implications for drug repositioning

作者：Brian Chi‐Fung Wong, Carlos Kwan‐Long Chau, Fu‐Kiu Ao, Cheuk‐Hei Mo, Sze‐Yung Wong, Yui Hang Wong, Hon‐Cheong So · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2017 · DOI：10.1101/140590 · 被引用次数：2 · 研究领域：Genetic Associations and Epidemiology、Tryptophan and brain disorders、Hormonal Regulation and Hypertension

Abstract Numerous studies have suggested associations between depression and cardiometabolic abnormalities or diseases, such as coronary artery disease and type 2 diabetes. However, little is known about the mechanism underlying this comorbidity, and whether the relationship differs by depression subtypes. Using the polygenic risk score (PRS) approach and linkage disequilibrium (LD) score regression, we investigated the genetic overlap of various depression-related phenotypes with a comprehensive panel of 20 cardiometabolic traits. GWAS results for major depressive disorder (MDD) were taken from the PGC and CONVERGE studies, with the latter focusing on severe melancholic depression. GWAS results on general depressive symptoms (DS) and neuroticism were also included. We also identified the shared genetic variants and inferred enriched pathways. In addition, we looked for drugs over-represented among the top shared genes, with an aim to finding repositioning opportunities for comorbidities. We found significant polygenic sharing between MDD, DS and neuroticism with various cardiometabolic traits. In general, positive polygenic associations with CV risks were observed for most depression phenotypes except MDD-CONVERGE. Counterintuitively, PRS representing severe melancholic depression was associated with reduced CV risks. Enrichment analyses of shared SNPs revealed many interesting pathways, such as those related to inflammation, that underlie the comorbidity of depressive and c...