Differential associations of depression‐related phenotypes with cardiometabolic risks: Polygenic analyses and exploring shared genetic variants and pathways

Abstract

Background: Numerous studies have suggested associations between depression and cardiometabolic (CM) diseases. However, little is known about the mechanism underlying this comorbidity, and whether the relationship differs by depression subtypes.Methods: Using polygenic risk scores (PRS) and linkage disequilibrium (LD) score regression, we investigated the genetic overlap of various depression-related phenotypes with a comprehensive panel of 20 CM 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 identified the shared genetic variants and inferred enriched pathways. We also looked for drugs overrepresented among the top-shared genes, with an aim to finding repositioning opportunities for comorbidities. Results:We found significant genetic overlap between MDD, DS, and neuroticism with cardiometabolic traits. In general, positive polygenic associations with CM abnormalities were observed except for MDD-CONVERGE. Counterintuitively, PRS representing severe melancholic depression was associated with reduced CM risks. Enrichment analyses of shared SNPs revealed many interesting pathways such as those related to inflammation that underlie the comorbidity of depressive and CM traits. Using a gene-set analysis approach, we also revealed several repositioning candidates with literature support (e.g., bupropion). Conclusions:Our study highlights shared genetic bases of depression with CM traits, and suggests the associations vary by depression subtypes, which may have implications in targeted prevention of cardiovascular events for patients. Identification of shared genetic factors may also guide drug discovery for the comorbidities. K E Y W O R D Sbiological markers, cardiovascular/cardiac/heart disease, depression, epidemiology, genetics 330

Genetic comorbidity between major depression and cardio‐metabolic traits, stratified by age at onset of major depression

“…Twin studies have previously shown genetic overlap between MDD and type 2 diabetes, but evidence from genetic studies has been weaker. The current study, however, does show evidence for a shared genetic etiology between MDD and type 2 diabetes based on both PRS and genetic correlations (Clarke et al, 2016;Kan et al, 2016;Wong et al, 2019).…”

“…Studies using twin data also showed that the phenotypic association between MDD and type 2 diabetes was partly due to genetic effects (Kan et al, 2016). This finding has been replicated using a polygenic risk score approach (Wong et al, 2019), but not using genetic correlations (Clarke et al, 2016;Wong et al, 2019). The Brainstorm Consortium did not find a significant genetic correlation between MDD and stroke (Anttila et al, 2018), while Wassentheil-Smoller et al (Wassertheil-Smoller et al, 2018) showed that higher polygenic risk for MDD was associated with increased risk for stroke, in particular small vessel disease.…”

“…Findings for other cardio-metabolic traits have been inconsistent. Previous studies have identified genetic overlap between MDD and BMI using polygenic risk scores (PRS) (Milaneschi et al, 2017), but not based on genetic correlations (Wong et al, 2018). However, more recent GWAS studies now have the power to detect a genetic correlation between MDD and BMI (Wray et al, 2018).…”

Genetic comorbidity between major depression and cardio-metabolic disease, stratified by age at onset of major depression

“…Findings for other cardio-metabolic traits have been inconsistent. Previous studies have identified genetic overlap between MDD and BMI using polygenic risk scores (19), but not based on genetic correlations (20). However, more recent GWAS studies now have the power to detect a genetic correlation between MDD and BMI (14).…”

Uncovering bi-directional causal relationships between plasma proteins and psychiatric disorders: A proteome-wide study and directed network analysis

“…In addition to the above, sometimes a protein whose level changes as a result of a disease may yet be a risk factor for another condition. For example, depression is associated with increased risk of cardiometabolic disorders 9 , and some have postulated inflammatory pathways and proteins as mediating factors 10,11 .…”