Atrial fibrillation (AF) is one of the most common arrhythmias in clinic. It is characterized by rapid and disordered atrial electrical activity. AF can be divided into first diagnosed AF, paroxysmal AF, persistent AF, and permanent AF (1). AF can make people experience a variety of uncomfortable symptoms such as panic, fatigue, sweating, which seriously affect their quality of life (2). The purpose of AF treatment is to prevent thromboembolic complications, restore and maintain sinus rhythm, and control ventricular rate during AF (3). The most important thing in the treatment of AF is to actively search for the primary disease and inducing factors, and make corresponding treatment. Studies have shown that male sex, advancing age, and Caucasian ancestry are important risk factors for developing AF (4). Controllable risk factors for AF include smoking (5), alcohol use (6), high blood pressure (7), diabetes (8), obesity (9), obstructive sleep apnea (10), and a sedentary lifestyle (11), among other factors. Previous studies have shown that AF and psychiatric disorders are inextricably linked. It is important to note that patients with AF often exhibit one or more negative emotions, such as anxiety, depression, reactive instability, and high neuroticism under the influence of severe stressors (12). It has been demonstrated that depression significantly increases the cumulative incidence of atrial fibrillation (from 1.92% to 4.44% at 10 years), and 20-40% of AF patients are found to have high levels of depression (13). Similarly, Kim et al. found that depression was associated with a significantly increased risk and cumulative incidence of new-onset AF (14). A meta-analysis of cohort studies demonstrated that anxiety was independently associated with an increased risk of recurrence of AF after catheter ablation (adjusted relative risk, 2.3; 95%CI, 1.710-3.260; P < 0.001) (15). One study demonstrated that the level of anxiety before coronary artery bypass surgery is an important factor in the development of AF after surgery (16). Studies have shown that severe psychological distress (35%) and suicidal ideation (20%) were prevalent in the tertiary population with AF (17).

Mental illness causes serious social and economic burden, and it is difficult to accurately identify its pathogenesis and risk factors (18). Due to the complex pathogenesis of mental diseases, the reverse causality between risk factors and mental diseases is easily confused, which makes MR analysis become an important tool in the study of mental diseases. A previous review of 50 MR articles showed a causal relationship between a particular psychiatric disorder and its causative factors (19). This review is divided into four groups based on the mental disorders assessed: schizophrenia, major depressive disorder, attention deficit and hyperactivity disorder, and autism spectrum disorder or other mental disorders. BPD, though one of the screening criteria in this review, was not included in the target article. It can also be seen that the number of MR articles on BPD is relatively small. To some extent, our paper can fill the gap in the study of MR of BPD. Borderline personality disorder (BPD), also known as emotionally unstable personality disorder, is characterized by widespread instability in interpersonal relationships, emotional regulation, impulse control, and self-image management (20). Patients with BPD often suffer from depression, anxiety, impulsivity, anger and other negative emotions, and even have self-harm and suicidal tendencies (21). Emotional instability is the main characteristic of BPD. BPD is a serious mental disorder that can have a significant impact on an individual’s quality of life, mental health and social interactions. We hypothesize that there may be a causal relationship between BPD and AF.

Mendelian Randomization (MR) is a data analysis technique used to evaluate causal inference in epidemiological studies. In MR analysis, genetic variants are used as Instrumental Variables (IVs) to estimate the causal relationship between the exposure factor of interest and the outcome of concern (22). We conducted a two-sample bidirectional MR study to estimate the causal relationship between BPD and AF. This paper expounds the causal relationship between BPD and AF, and provides the basis for early prevention and detection of arrhythmia in patients with BPD.

To our knowledge, this is the first MR analysis to assess the causal relationship between BPD and the risk of AF. We have two new findings in European populations. On the one hand, our study suggests a causal relationship between genetic susceptibility to BPD and an increased risk of AF. On the other hand, there is no evidence to support a causal relationship between AF and the risk of BPD. However, due to certain limitations of MR studies, these results must be interpreted with caution.

AF is one of the most common persistent arrhythmia. Mental disorders such as anxiety, depression and stress may activate the autonomic nervous system, which may be closely related to the development of AF. Previous studies have systematically and prospectively revealed that negative emotions such as stress, sadness, anger, and anxiety can induce AF, while happiness has a protective effect on AF (28). A systematic review noted that AF imposes significant psychosocial burdens on individuals, including depression and anxiety, as well as impaired quality of life in people with AF (29). A meta-analysis of 2017,276 participants (222,253 with anxiety disorders) from 46 cohorts showed that anxiety was not associated with AF [relative risk(RR), 1.27; 95%CI, 0.90-1.80] (30). Studies have confirmed that 20-40% of AF patients are found to have high levels of depression. Depression significantly increased the 10-year cumulative incidence of AF (from 1.92% to 4.44%) (13). A descriptive study involving 126 patients undergoing coronary artery bypass grafting (CABG) found that the mean trait anxiety scale score of patients with postoperative atrial fibrillation was 40.2 ± 7.8, with a statistically significant difference (16). A meta-analysis involving 5,329,908 participants clearly indicated that anxiety increased the risk of AF by 10% [hazard ratios(HRs) 1.10; 95%CI, 1.02-1.19; P = 0.013; N = 235,599 in 6 studies]. Anger increased the risk of AF by 15% (HR, 1.15; 95%CI 1.04-1.26; P = 0.04, N = 21,791 in 3 studies). Depression increased the risk of AF by 25% (HR, 1.25; 95%CI, 1.12-1.39; P < 0.001; N = 5,160,247 in 6 studies). Work stress increased the risk of AF by 18% (HR, 1.18; 95%CI,1.05-1.32; P = 0.004; N = 51,664 in 4 studies) (31). At the same time, many studies have shown how to influence the negative emotions of patients with AF to improve the prognosis and improve the quality of life of patients. Randomized studies in Australia have reported that improvement in psychological symptoms of anxiety and depression can be observed in patients with symptomatic AF treated with catheter ablation (32). Lakkireddy et al. have shown that yoga therapy improves depression, anxiety, blood pressure and resting heart rate, as well as quality of life in patients with paroxysmal AF (33). While several past observational studies have found a link between mental disorders and AF, the findings have been inconsistent. A large population survey suggests otherwise, that symptoms of depression and anxiety are not associated with an increased incidence of AF (34).

As mentioned above, there have been numerous studies that have linked AF to negative emotions such as depression and anxiety or psychiatric disorders, but the specific nature of their relationship is unclear. The current study also could not shed light on a key question: whether the mental disorder occurred before or after AF, or whether they affected each other at the same time. BPD, centered on emotional dysregulation, can be composed of many symptoms such as depression, anxiety, stress, and suicidal tendencies (20, 35, 36). The multiple manifestations of these unstable personality traits are similar to many mental disorders of AF. Our study specifically identified BPD as an exposure factor and concluded that BPD may predate and lead to AF.

Several studies have shown that patients with BPD exhibit fewer Respiratory sinus arrhythmia (RSA) than healthy individuals, a result that can be explained by reduced parasympathetic activity in BPD patients (37–39). We found that no experts had conducted systematic studies on the relationship between BPD and other arrhythmias. Our study was a MR study of the causal relationship between BPD and AF at the genetic level. It has been documented that inflammation is a driver of AF (40). Similarly, some experts believe that BPD may exhibit a pro-inflammatory state (41). Inflammation may be a mediating factor between BPD and AF. The TSMR analysis we performed was sufficient to validate the most direct causal relationship between BPD and AF, without further exploring how this causal relationship is affected step by step.

Finally, it should be noted that in the course of our study, we used a more relaxed threshold (P < 5×10^-6) to select instrumental variables for BPD. Although this improves the statistical efficiency, it is more likely to introduce multi-effect instrumental variables. Although we performed multiple sensitivity analyses, each SNP independently affected BPD and AF, which reduced the reliability of the results.

To our knowledge, our study is the first to use MR Analysis to explore the causal relationship between BPD and AF. TSMR analysis has several advantages (1): Compared with traditional observational studies, MR Method reduces the influence of confounding factors and reverse causality (2); We have strictly identified the SNPs selection to reduce the sampling bias; (3) The data we used are all from European populations, which reduces the influence of population stratification to a certain extent.

Our study also has some limitations: (1) Due to the lack of individual information in the samples, we could not stratify the analysis of age, and AF subtypes; (2) BPD is more common in women, and we did not stratify our study subjects by gender;(3) The samples we studied were all of European ancestry, and the conclusions cannot be generalized to all populations; (4) Not all data employed in the GWAS diagnosed BPD patients according to Diagnostic and Statistical Manual of Mental Disorders (DSM) or International Classification of Diseases (ICD) criteria, together with the lack of adjustment for comorbidities, it is difficult to be sure that the results are specific to BPD and not just common to psychiatric disorders in general.

Our TSMR analysis provides genetic evidence of a causal relationship between BPD and an increased risk of AF. On the contrary, no causal relationship of AF on BPD risk was observed. Our study enhances the current understanding of the role of psychiatric disorders in AF. Our study provides evidence to support early prevention of arrhythmias in patients with BPD. Further research is now needed to explore strategies for detecting and treating BPD.

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/ Supplementary Material .

WZ: Methodology, Supervision, Writing – review & editing, Validation. ZW: Conceptualization, Data curation, Methodology, Writing – original draft. HH: Formal analysis, Investigation, Project administration, Writing – review & editing. YS: Resources, Software, Writing - original draft. QW: Project administration, Supervision, Validation, Writing – original draft. MX: Supervision, Validation, Visualization, Writing – review & editing.