Identifying Clinical Screening for Major Depressive Disorder in Patients with Pulmonary Arterial Hypertension and the Role of SESTD1 in Pathogenic Process: Mendelian Randomization and Bioinformatics Analyses

Abstract

Abstract Interpretation: Our findings enhance the understanding of the causal link between PAH and ten major mental illnesses, firmly establishing PAH as a distinct risk factor for MDD. Furthermore, our study highlights the potential pivotal role of SESTD1 in this pathophysiological process, offering valuable insights for drug intervention targets. Background: Evidence from clinical studies suggests that pulmonary arterial hypertension (PAH) is associated with psychiatric disorders. However, the causal association between PAH and major psychiatric disorders (MPD) remains unknown. Therefore, we aimed to elucidate the causal relationship between PAH and MPD from a genetic perspective. Method: We used summary data about PAH, MPD, eQTL from genome-wide association studies (GWAS) of mostly European adults from Psychiatric Genomics Consortium, GWAS catalog and IEU OpenGWAS. We conducted bidirectional mendelian randomization (MR) analyses to explore whether PAH could be causally associated with ten MPD which include attention deficit hyperactivity disorder, Tourette syndrome, Alzheimer’s disease, anxiety disorder, autism spectrum disorder, bipolar disorder, eating disorders, major depressive disorder (MDD), post-traumatic stress disorder, and schizophrenia. We conducted sensitivity analyses to examine the MR assumptions. Bonferroni correction was also adopted to account for multiple comparisons. We obtained differentially expressed genes (DEGs) of PAH and conduct enrichment analyses from GSE113439 and GSE117261. We performed MR between DEGs of PAH and MDD. Findings: Our study identified PAH as a risk factor for MDD (OR=1.003; 95% CI, 1.001-0.005; P=0.021), showing a consistent association without horizontal pleiotropy and heterogeneity. Additionally, we found that SESTD1, upregulated in the context of PAH, acts as a risk gene for MDD (OR=1.002; 95% CI, 1.000-1.004; P=0.03). Gene set enrichment analysis revealed enrichment in steroid biosynthesis, a hallmark of MDD.