Pulmonary Arterial Hypertension (PAH) is a rare and severe condition characterized by progressive pulmonary vascular remodeling, leading to life-threatening right-sided heart failure with a resting mean pulmonary arterial pressure exceeding 25 mmHg, as determined by right heart catheterization (1). According to data from the US-based REVEAL registry, a multicenter prospective cohort study involving 54 centers and spanning from 2006 to 2007, the incidence of PAH is reported as 2.0 cases per 1 million per year, with a prevalence of 10.6 cases per 1 million adults (2). Individuals with PAH often experience a spectrum of complications, including cardiac arrhythmias, renal dysfunction, neurohumoral overactivation, skeletal muscle dysfunction, metabolic dysfunctions, and congestive hepatopathy (3). It is noteworthy that psychiatric disorders are also likely to be the significant complications of PAH. A study conducted at two German referral centers, involving 217 PAH patients, revealed that more than one-third of them exhibited psychological disorders, including current or past adjustment disorders (38.2%), current major depressive disorder (23.0%), and panic disorder (15.2%) (4). Another study by Madelaine-Rachel Dering et al. found that 31.8% of 107 chronic thromboembolic pulmonary hypertension patients had current psychological disorders, encompassing panic disorder (8.4%), specific phobia (8.4%), and Major Depressive Disorder (MDD) (6.5%) (5). Additionally, a cross-sectional study conducted by Juxia Zhang et al. reported particularly high levels of depressive symptoms (70.09%) among 106 PAH patients, with anxiety affecting 17.55% of them (6). The clinical symptoms of PAH, such as shortness of breath, excessive fatigue, and chest pain, significantly limit patients' daily lives and social activities. Consequently, it is unsurprising that individuals with PAH may be prone to a range of mental health disorders, with depression being especially prevalent.
Psychiatric disorders stand as the most enigmatic and intricate maladies within the realm of medicine. Despite their existence being recognized for millennia, remarkably little is known about their causal risk factors and fundamental neurobiology, notwithstanding a substantial body of research (7). This paper endeavors to elucidate the causal relationship between PAH and the following ten major mental illnesses, with a particular focus on MDD. The objective is to offer insights that can guide recommendations for the treatment and management of patients grappling with PAH. Attention Deficit Hyperactivity Disorder (ADHD) is marked by pervasive and impairing symptoms of inattention, hyperactivity, and impulsivity (8). It afflicts approximately 5% of children and adolescents (9) and 2.5% of adults (10). Tourette syndrome, a chronic neurodevelopmental disorder, is characterized by motor and vocal disorders that significantly diminish the quality of life for those affected (11). Alzheimer's disease, the leading cause of dementia, has swiftly emerged as one of the most costly, deadly, and burdensome diseases of the present century (12). Anxiety disorder, with symptoms encompassing worry, social and expressive fear, unexpected or triggered panic attacks, expected anxiety, and avoidance behavior, boasts a lifetime prevalence of approximately 34% in America (13). Autism Spectrum Disorder (ASD) manifests as insufficient social communication, restrictive repetitive behaviors or interests, with a prevalence of around 2.3% among 8-year-old children and 2.2% among adults in the United States (14). Bipolar disorder, a psychiatric ailment, reveals itself through recurrent episodes of elevated mood and depression, accompanied by changes in activity levels (15). Eating disorders, constituting a group of disabling, deadly, and expensive conditions, significantly impair physical health and disrupt psychosocial functioning (16). PTSD is a mental disorder that may develop after exposure to abnormal threats or terrorist events, and it is proved to increase the risk of suicide (17). MDD is a debilitating mental illness typically associated with low mood, lack of pleasure, and a range of comorbidities (18). Schizophrenia is described as the following symptoms—including hallucinations, cognitive dysfunction, loss of motivation and of social engagement (19).
MDD is widely recognized as one of the most urgent mental health issues. Over the past 30 years, the number of global cases of MDD has increased by nearly 50% (20). It is estimated that over 300 million people in the world suffer from depression, which is listed by the World Health Organization (WHO) as the largest cause of global disability (21). In addition, depression also brings great economic burden. In the past 10 years, the economic costs of the United States alone have increased by 48%, and now exceed $325 billion annually (22). It is expected that the global economic costs associated with depression will nearly double by 2030 (23), however, research has indicated that for every $1 spent on depression care, a return of $4 can be obtained (24). Terre L et al declared that early screening in patients who have risk factor for depression could be useful to prevent the development of depression and decrease the burden of disease (25).
Mendelian Randomization (MR) stands out as an innovative study design that offers a genetic epidemiological approach to exploring the causal relationship between exposure and outcome, utilizing Single Nucleotide Polymorphisms (SNPs) as Instrumental Variables (IVs) (26). Diverging from traditional observational studies, the random allocation of these instrumental variants during conception significantly mitigates susceptibility to reverse causation and confounding in MR studies (27). In comparison to randomized controlled trials, MR is more accessible to implement. However, it is crucial for researchers to acknowledge specific limitations associated with MR to interpret its results comprehensively and judiciously. Employing SNPs as IVs does not entirely circumvent biases arising from weak instruments, population stratification, and developmental compensation (28). It is worth noting that a substantial portion of existing research in this domain is cross-sectional (4–6), thereby lacking the ability to definitively establish causality between PAH and the specified outcome MPD. This limitation stems from the potential presence of confounders and residual confounding in cross-sectional studies. A nuanced understanding of these limitations is crucial for a balanced interpretation of MR results in the context of investigating complex relationships between genetic factors, exposure, and outcomes.
Our current research endeavors to clarify the causal relationship between PAH and ten types of MPD through a comprehensive approach, including MR analyses, bioinformatic analyses and an extensive literature review. Our research identified the causal relationship between PAH and MDD. Furthermore, we found that SESTD1, an upregulated expression gene in PAH, is a risk gene for depression. And steroid biosynthesis pathway is enriched in high SESTD1 group. Based on our work, we proposed a hypothesis that the upregulation of SESTD1 expression leads to an increase in cortisol levels in patients with PAH, thereby increasing the likelihood of depression. The anticipated outcomes of our study are poised to offer valuable insights, potentially supporting the inclusion of clinical screening for MDD in patients diagnosed with PAH and a new intervention target SESTD1 for patients with concomitant PAH and MDD.