This PhD thesis of Azmeraw Amare leveraged advanced genomic and bioinformatic techniques to explore the genetic architecture of depression and cardiometabolic conditions and their overlap. The study focused on identifying genetic factors, pleiotropic genes, and shared biological pathways underlying depression, type 2 diabetes (T2D), heart rate variability (HRV), and other cardiometabolic traits and diseases.
The first study identified 24 pleiotropic genes and common biological pathways for mood disorders and cardiometabolic diseases, such as corticotropin-releasing hormone signaling, AMPK signaling, and serotonin receptor signaling, providing valuable insights into the shared genetic mechanisms of these complex conditions.
The second study estimated the genetic correlation between depressive symptoms and T2D, revealing pleiotropic genes that mediate their relationship. Common biological pathways, including immune function, insulin signaling, glucose metabolism, and neurotransmitter regulation, were implicated in the bidirectional link between depression and T2D, suggesting that shared genetic factors contribute to their comorbidity.
Two subsequent studies identified nine novel genetic loci associated with depression. A meta-analysis of genome-wide association study data on depressive symptoms and major depressive disorder revealed a significant locus in the FHIT gene. Further meta-analysis across depression, bipolar disorder, and schizophrenia revealed 20 genetic loci, including eight novel for depression, underscoring the importance of cross-disorder analyses in advancing genetic discovery.
The final study identified 17 genome-wide significant variants across eight loci related to HRV, providing further evidence on the potential links between HRV and cardiovascular diseases.
In conclusion, this PhD research contributes new insights into the (shared) genetic architecture of mental and cardiometabolic disorders, highlighting pleiotropic genes and shared biological pathways that could inform future therapeutic strategies for complex multimorbid conditions.
