Bi-directional causal association between 17 neurosurgical diseases and three emotional disorders: perspective from Mendelian randomization analysis

doi:10.21203/rs.3.rs-4869584/v1

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Bi-directional causal association between 17 neurosurgical diseases and three emotional disorders: perspective from Mendelian randomization analysis

https://doi.org/10.21203/rs.3.rs-4869584/v1

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Background

Although numerous studies have reported correlations between emotional disorders and neurosurgical conditions, their causal relationships is not convincing. Therefore, we seek to comprehensively investigate the connection between the two using bidirectional Mendelian randomization studies.

Methods The GWAS aggregated data encompassed 17 types of neurosurgical diseases (including cerebrovascular diseases, functional disorders, central nervous system neoplasms, spinal and spinal cord diseases, and other brain conditions) and 3 emotional disorders (anxiety, mania, and depression), sourced from IEU and FINNGEN. The primary analysis method applied was inverse variance-weighted (IVW) analysis, supplemented by MR-Egger and weighted median methods to ensure robust estimates. A series of sensitivity analyses, including Cochran’s Q test, MR-Egger regression, and leave-one-out analysis, were conducted to detect pleiotropy or heterogeneity.

Results IVW estimates indicated that trigeminal neuralgia significantly associated with the risk of mania (p=0.002, odds ratio [OR]=1.008, 95 % confidence interval [CI] = 1.003 to 1.014), a higher genetic predisposition to congenital malformations of nervous system may reduce the development of depression (p=0.002, OR= 0.996; 95 %CI = 0.992 to 0.998) and the causal effect of depression on transient ischemic attack (IVW, P=0.004, odds ratio (p=0.004, OR = 4.141; 95 %CI = 1.560 to 10.988). The results of comprehensive sensitivity analyses were consistent with the main causality estimate. No pleiotropy and heterogeneity were detected in our MR study.

Conclusions Our large-scaled MR analysis indicated that trigeminal neuralgia and congenital malformations of the nervous system predispose patients to emotional disorders, while depression, in particular, increases vulnerability to transient ischemic stroke.

neurosurgical diseases

emotional disorders

Mendelian randomization

causality.

A causal relationship was established between trigeminal neuralgia and manifestations of mania or irritability. This suggests that the neural pathways involved in trigeminal neuralgia may also play a role in triggering manic episodes.
MR analysis indicated that congenital malformations of the nervous system predispose patients to emotional disorders.
MR analysis indicated that depression, in particular, increases vulnerability to transient ischemic stroke.

Neurosurgical disorders are notorious of their complexity and variant nature, encompassing a vast array of conditions such as cerebrovascular diseases, functional neurological disorders, and central nervous system tumors. The incidence of neurosurgical diseases climbs up as the inclined aging of the global population. Cerebrovascular diseases, including ischemic stroke, hemorrhagic stroke, and vascular malformations, are leading causes of morbidity and mortality worldwide(Liu et al., 2024).

Cerebral infarction, one manifestation of ischemic stroke, particularly affects the elders and signifies the occlusion of major cerebral arteries like the middle cerebral artery (MCA), leading to significant brain damage. Its mortality rate can reach as high as 80% if untreated(Huttner and Schwab, 2009). Functional neurological disorders, such as Parkinson's disease, are more frequent in the male and the elders(Ben-Shlomo et al., 2024), characterized by the degeneration of dopamine-producing neurons in the substantia nigra (De Virgilio et al., 2016; Tolosa et al., 2006).These disorders, while not so tremendously fatal as cerebrovascular diseases, still severely impact the quality of life and result in physical, psychological, and social agony (Coukos and Krainc, 2024). Central nervous system tumors, including meningiomas, gliomas, and acoustic neuromas, also pose significant health risks, in which gliomas have extreme mortality rate in particular. Malignant primary brain tumors cause over 15,000 deaths annually in the United States alone. The incidence of primary malignant brain tumors is approximately 7 cases per 100,000 people per year and increases with age, with a five-year survival rate of about 36%(Schaff and Mellinghoff, 2023). The aggravating global burden of neurosurgical diseases brings significant challenges to public health and medical systems.

It is not rare to observe the concurrence of emotional disorders in patients with neurosurgical diseases. More epidemiological evidence suggests a close link between neurosurgical conditions and emotional abnormalities. Neurosurgical diseases display a tendency of mutual reinforcement with emotional disturbances. Studies had shown that patients with arachnoid cysts exhibited higher levels of anxiety and depression compared to the general population, while these symptoms usually normalized after cyst decompression surgery. A hemispheric asymmetry in anxiety-like behavior induced by arachnoid cysts was also reported, with right temporal lobe cysts yielding higher anxiety and depression scores than left-sided cysts(Gjerde et al., 2019). Epileptic patients, particularly those with temporal lobe epilepsy (TLE), frequently experience psychiatric disorders(de Oliveira et al., 2010; Schmitz, 2005). Between 11–44% of epilepsy patients suffer from depression, whereas about half of TLE patients experience emotional disorders. Additionally, more than one-third of patients with cervical spondylotic myelopathy (CSM) report depressive or anxious feelings; these negative emotions closely linked to decreased activity levels(de Oliveira et al., 2010). Brain lesions can also result in secondary mania, with acute brain injuries, chronic neurological diseases, and neurosurgical interventions all associated with manic symptoms.

Conversely, there is evidence suggesting that emotional disorders might predispose individuals to neurological diseases. A study on cerebrospinal fluid biomarkers in patients with major depression identified 11 characteristic proteins and 144 peptides consisting a signature atlas expressed alternatively from those in healthy controls. These biomarkers linked substantially to brain metabolism or central nervous system diseases. A meta-analysis also found increased total protein levels in patients with affective disorders, indicating blood-brain barrier dysfunction and central nervous system inflammation, suggesting rising prevalence of neurological diseases caused by depression(de Oliveira et al., 2010).

Nevertheless, research evidence regarding the causal relationship between various neurological disorders and common emotional disorders are scattered and inconclusive. Using Mendelian randomization, we therefore performed this bidirectional two-sample MR analysis to reveal their causal relationships respectively.

2.1 | Data sources

The GWAS data involved 17 types of neurosurgical diseases, including cerebrovascular diseases, functional diseases, central nervous system neoplasms, spinal and spinal cord disease and other brain diseases alike. Three principal emotional disorders (anxiety, mania and depression) with their subtypes were from two modern independent cohorts, IEU open GWAS and FinnGen. The detailed information was presented in Table 1. Their data could be obtained from the websites (IEU open GWAS https://gwas.mrcieu.ac.uk; FinnGen https://www.finngen.fi/en/access_results ). In each MR analysis, no overlap was identified in the exposure and the outcome. We report the analysis following strobe-mr guideline.

Table 1

Summary of genetic data information utilized in the study.
Category	Disease	Number of case	Number of controls	Population	Year	Consortium	p
Functional diseases	severe traumatic brain injury, does not include concussion	7430	404751	European	2023	finngen	5e-8
	Parkinson's disease	4681	407500	European	2023	finngen	5e-8
	Epilepsy	12891	312803	European	2023	finngen	5e-8
	Trigeminal neuralgia	1777	360538	European	2023	finngen	5e-8
Cerebrovascular diseases	Transient ischemic attack	19930	374310	European	2023	finngen	5e-8
	Cerebral infarction	1420	461590	European	2018	ukb-b-19350	5e-6
	Aneurysms, operations, SAH	5754	374631	European	2023	finngen	5e-8
	Cerebral aneurysm, nonruptured	2784	374631	European	2023	finngen	5e-8
	Intracerebral hemorrhage	1935	471578	European	2021	ebi-a-GCST90018870	5e-6
Central nervous system neoplasms	Malignant neoplasm of brain and other parts of CNS	816	314193	European	2023	finngen	5e-8
	Benign neoplasm of brain and other parts of central nervous system	1917	410264	European	2023	finngen	5e-8
	Benign neoplasm: Pituitary gland, craniopharyngeal duct	1508	410673	European	2023	finngen	5e-8
	Brain meningioma (controls excluding all cancers)	1316	313392	European	2023	finngen	5e-8
	Brain glioblastoma (controls excluding all cancers)	253	314393	European	2023	finngen	5e-8
Other brain diseases	Hydrocephalus	2455	382198	European	2023	finngen	5e-8
Other brain diseases	Congenital malforma tions of the nervous system	637	411544	European	2023	finngen	5e-6
Spinal and spinal cord disease	Cervical spondylosis	3352	481256	European	2021	ebi-a-GCST90038693	5e-8
Emotional disorders	anxious	255812	194953	European	2018	ukb-b-6519	5e-8
	Depression (broad)	113769	208811	European	2018	ebi-a-GCS005902	5e-8
	Manifestations of mania or irritability: I was more restless than usual	12876	101546	European	2018	ukb-d-205482	5e-8
	Non-cancer illness code self-reported: mania/bipolar disorder/manic depression	902	336,257	European	2017	ukb-a-83	5e-8
	depression	2149	246352	European	2023	finngen	5e-8
	anxious	27664	368054	European	2023	finngen	5e-8
	mania	992	359290	European	2023	finngen	5e-8

2.2 | Instrumental variable 2.2 IVS selection

We utilized the “extract_instruments” function from the R package “TwoSampleMR” to interpret the exposure factors and IVs were determined by the relevance of SNPs to those factors (p < 5×10 − 8 ). If no corresponding SNP be present in either disease category, we adjusted the P-value threshold to p < 5× 10 − 5. The exclusion of SNPs relied on the exhibition of linkage disequilibrium regardless of the p value threshold (clump = TRUE, r2 = 0.001, kb = 10,000). We also eliminated those with strong associations with the outcomes from the identification of genome-wide association study (GWAS) data. In the forward MR analysis, the exposure factor was Neurosurgical diseases, and the outcome was Emotional disorders; whereas they were reciprocated in the reverse analysis. To endorse the robustness of our method, we computed the F-statistics for each genetic instrument. An F-value exceeding 10 was regarded as indicative of a minimal likelihood of bias resulting from weak instruments. The F-statistics were calculated as F=\(\:\frac{R2}{1-R2}\) \(\:\times\:\)(N-2) and R2=\(\:\frac{\beta\:2}{\beta\:2+se2\times\:\text{N}}\), R2 means variance of exposure explained by instrument variable; N indicates sample size;βindicated effect size for the genetic variant of interest; se indicated a standard error for b; N indicated sample size(Luo et al., 2023).

2.3 | MR analysis

Three MR methods were used to provide robust MR estimates: Inverse-Variance Weighted (IVW) (Burgess et al., 2013), MR‐Egger(Fujii et al., 2024), Weighted Median(Bowden et al., 2015). The IVW method was chosen as the primary analytical approach due to its distinguished recommendation and the remaining three were to enhance the robustness of the estimates. In the IVW analysis, the MR estimates was derived from the weighted regression slope reflecting the effect of neurosurgical disease-related SNP on those corresponded to emotional disorder, with the intercept fixed at zero to ensure accuracy. Even in senarios of up to 50% of invalidity presented in the instrumental variables, weighted median still sustained consistency on the estimate of causality. The MR-Egger method was predicated on the assumption of no directed pleiotropy in the SNP-exposure effects (Bowden et al., 2015). The MR‐PRESSO method detected potential horizontal pleiotropic effects of SNPs for the correction of possible outliers (Verbanck et al., 2018). All results were presented as odds ratio (OR) and 95% confidence interval (95% CI), representing the risks of emotional disorders for patients with neurological disorders compared to those without them. Since our data included 17 neurosurgical diseases, we used Bonferroni correction to adjust the significance threshold and set it to 0.05/17 for multiple analyses.

2.4 | Sensitivity analysis

In an MR study, three main assumptions must be met to generate robust causal estimates: (1) the selected genetic variant is strongly associated with exposure, (2) the genetic variant is not associated with any confounding factors for exposure and outcome, and (3) the genetic variant should independently affect the outcome through exposure only but not by any other causal pathway (Boef et al., 2015). The robustness of instrumental variables satisfied the fist assumption, while the second one was fulfied by the random and environment-independent assignment of SNPs during pregnancy. The performance of a sensitivity analysis using MR-Steiger acted as the assessment of the third assumption and the possible effect of horizontal pleiotropy. Scatter plots were utilized to offer a intuitive interpretation of the data from a two-sample MR study. We also conducted several rigorous tests, including the MR-Egger regression intercept test, MR-PRESSO, leave-one-out analysis, and funnel plots, each contributing to a thorough examination of the data's integrity. The implementation of Cochran's Q test next aimed to filter heterogeneity (Burgess and Thompson, 2017). Following the exclusion of SNPs associated with potential confounders of genome-wide significance, the ascertainment of solid causal effects were verified by reperforming the MR analyses.

2.5 | Statistics analysis

All analyses were conducted using the TwoSampleMR (version 0.4.25) and MR-PRESSO (version 1.0) packages in R (version 3.6.1). Two‐sided p < 0.05 was considered significant. In this study it was not the goal to set a particular threshold of p-value but rather find the causal relationship between different neurosurgical and emotional disorders.

We conducted bidirectional Mendelian randomization between 17 common Neurosurgical diseases and 3 Emotional disorders. Following filtration, 3 to 25 independent SNPs of neurosurgical diseases and 1 to 12 independent SNPs of emotional disorders were identified as IVs (Supplementary Table S1&S5). Our research results showed a significant correlation between trigeminal neuralgia and mania, congenital malformations of nervous system and depression(broad), depression and transient ischemic stroke in the circumstance of no correction. No causal relationship was found in other studies (Supplementary Table S2-S4, S6-S8).

3.1 |Association between Trigeminal neuralgia and mania

The IVW method established causality of trigeminal neuralgia with manifestations of mania or irritability (p = 0.002) (odds ratio [OR] = 1.008, 95% confidence interval [CI] = 1.003 to 1.014). The results weighted median and MR-egger purported insignificant tendency of the same causal effect, suggesting trigeminal neuralgia as a risk factor for mania with a positive slope based on the IVW method. Cochrane’s Q test identified no heterogeneity in the data (P = 0.711), the MR-Egger intercept revealed no evidence of directional pleiotropy regarding trigeminal neuralgia and mania (P = 0.371) (Table 2, Table 3, Fig. 2A, Supplementary Fig. 1A).

TABLE 2. MR analyses of the effect of Neurosurgical diseases on Emotional disorders and Emotional disorders on Neurosurgical diseases.

TABLE 3. Tests of heterogeneity, pleiotropy

The P value of reverse Wald Ratio estimates was greater than 0.05, indicating no statistical significance in the reverse MR of mania and trigeminal neuralgia (p = 0.613) (Table 2). Given that only one SNP was associated with exposure, there was no heterogeneity, directional pleiotropy or point of severe bias detected. In summary, our results unraveled that trigeminal neuralgia was a risk factor for mania whereas no causal effect of mania on trigeminal neuralgia was found.

3.2 | Association between congenital malformations of nervous system and

depression(broad)

The results of IVW method indicated that a higher genetic predisposition to congenital malformations of nervous system might reduce the development of depression (odds ratio (OR) = 0.996; 95% confidence interval [CI] = 0.992 to 0.998; P = 0.002). Cochrane’s Q test showed no heterogeneity in the data (P = 0.574). Moreover, the MR-Egger intercept revealed no evidence of directional pleiotropy between congenital malformations of nervous system and depression (broad) (P = 0.120). Since "congenital malformations of nervous system" represented a neurological manifestation and should not be considered as an outcome, we did not perform a Mendelian analysis for depression and congenital malformations of nervous system (Table 2, Table 3, Fig. 2B, Supplementary Fig. 1B).

3.3 | Association between depression and transient ischemic attack

The primary MR using IVW estimated no statistically significant effect of transient ischemic attack on depression (P = 0.398, odds ratio [OR] = 0.995, 95% confidence interval [CI] 0.984 to 1.006) (Table 2). No horizontal pleiotropy (P = 0.237) or point of severe bias was detected (Table 3), neither did any evidence of directional pleiotropy revealed in the MR-Egger intercept regarding transient ischemic stroke and depression(P = 0.990) (Table 2, Table 3, Fig. 2C, Supplementary Fig. 1C)

However, the reverse MR analysis denoted the causal effect of depression on transient ischemic attack (IVW, P = 0.004, odds ratio (OR) = 4.141; 95% confidence interval [CI] = 1.560 to 10.988; P = 0.004), although the P value did not meet the Bonferroni correction for multiple tests. No horizontal pleiotropy (P = 0.724) or point of severe bias was detected. The MR-Egger intercept revealed no evidence of directional pleiotropy concerning depression and ischemic stroke (P = 0.973). In summary, our results inclined to increased risk of transient ischemic attack by depression.(Table 2, Table 3, Fig. 2D, Supplementary Fig. 1D)

In this study, the MR analysis was used to assess whether there is a bidirectional causal association between 17 neurosurgical diseases and 3 emotional disorders. The results showed that there were causal associations between trigeminal neuralgia and mania, depression and transient ischemic attack, and congenital malformations of nervous system and depression(broad). Trigeminal neuralgia particularly increased the risk of mania; and likewise, similar circumstance applied to depression on transient ischemic attack.

In clinical practice, it is a common observation that patients suffering from trigeminal neuralgia (TN) frequently exhibit symptoms of depression and anxiety (Stubbs et al., 2017). However, the exploration into whether trigeminal neuralgia can precipitate manic episodes has been notably sparse. Additionally, in cases where patients do experience manic episodes, trigeminal neuralgia is rarely considered as the principal trigger. As a chronic neurological disorder, trigeminal neuralgia is intricately linked to neurovascular compression (NVC) of the trigeminal nerve near its entry site into the spine(Cheshire, 2007; Truini et al., 2005). Carbamazepine, a traditional medication widely used in the treatment of trigeminal neuralgia(Peterson-Houle et al., 2021), has also demonstrated efficacy in the treatment of various psychiatric disorders, such as both acute and chronic management of bipolar disorder. This dual utility hints at a potential connection between trigeminal neuralgia and the occurrence of manic episodes (Denicoff et al., 1994). The amygdala, being a crucial hub within the emotion-related network, plays a crucial role in stress regulation. Research has shown that in patients suffering from depression, there is a marked reduction in the functional connectivity (FC) of the right lateral amygdala with the right anterior and right posterior hippocampus. Conversely, in patients experiencing manic episodes, there is an increase in connectivity within the left medial amygdala and the left nucleus accumbens shell. Another groundbreaking study employing ultra-high-field MRI techniques revealed significant structural changes in the trigeminal nerve, hippocampus, amygdala, and thalamic subregions in TN patients(Zhang et al., 2018); specifically, the basal nuclei of the amygdala on the symptomatic side were smaller in patients with classic paroxysmal trigeminal neuralgia compared to the control group (Alper et al., 2021). Further research into the dysregulation of pain and emotion-related networks in trigeminal neuralgia has uncovered a reduction in gray matter volume within the bilateral amygdala, periaqueductal gray (PAG), and right insula of TN patients. These discoveries underscore the presence of profound structural and functional deficiencies within the emotion-related networks of those afflicted with TN. Such evidence implies the notion that the neurobiological underpinnings of TN encompass a complex interplay between local structural alterations within the trigeminal nerve and subnuclear changes in limbic structures, collectively suggesting that the amygdala may serve as a critical bridge linking trigeminal neuralgia with emotional disorders.

Furthermore, extensive cerebral changes of structure in patients with classic trigeminal neuralgia (CTN) had also been reported (Liu et al., 2022). One study that evaluated MRI changes in trigeminal neuralgia (TN) patients found cortex thinning in the bilateral temporal lobes, frontal lobes, cingulate gyrus, somatosensory and occipital regions (Liu et al., 2022). Patients with bipolar disorder often experience alternatively manic and depressive episodes. Research indicates that bipolar disorder is primarily associated with structural abnormalities in the brain, particularly in the prefrontal and temporal cortices, cingulate gyrus, and subcortical regions. Manic episodes are linked to increased cortical volume and reduced thickness in certain brain regions, especially in the prefrontal cortex(Abé et al., 2023). This was further supported by the largest longitudinal MRI study on bipolar disorder to date, which analyzed extensive imaging data and found that abnormal thinning of the frontal cortex associated with frequent manic episodes. These findings suggest that long-term trigeminal neuralgia patients may experience changes in the prefrontal cortex, leading to the influence of the emotion regulation network and uncontrollable manic reactions. In addition, a recent study in mice identified a dedicated neural circuit from the ventral hippocampus (vHPC) to the medial prefrontal cortex (mPFC) that mediates TN-related emotional changes. Although blocking this pathway primarily inhibited depressive and anxiety-like behaviors in mice (Lv et al., 2024), the involvement of the prefrontal cortex suggested that this neural circuit might also play a role in manic episodes.

Central nervous system (CNS) malformations can be broadly classified into cranial nervous system malformations and brain developmental abnormalities. Cranial nervous system malformations encompass conditions such as spina bifida, hydrocephalus, anencephaly, and encephalocele. Brain developmental abnormalities include holoprosencephaly, brain dysplasia, Dandy-Walker syndrome, and agenesis of the corpus callosum(Verity et al., 2003). These malformations often result from a variety of factors, including genetic, environmental, and pharmaceutical influences(Poe et al., 1989), they impact the embryo during its developmental stages, leading to CNS abnormalities. Such impact on intellectual abilities is profound, often complicating the administration of emotional assessment questionnaires. As a result, there is a paucity of research exploring the link between nervous system malformations and emotional disorders. Our study has denoted an insight that nervous system malformations may reduce the incidence of depression. However, the underlying mechanisms remain elusive and warrant further investigation.

The classic definition of TIA is a sudden, focal neu-rologic deficit that lasts for less than 24 hours, is pre-sumed to be of vascular origin, and is confined to an area of the brain or eye perfused by a specific artery(Albers et al., 2002), affecting 46 000 people forhe first time in the UK every year(The, 2014). A comprehensive population-based cohort study investigated the effect of emotional stress on the incidence of cardiovascular events using standard psychological questionnaires, with follow-up periods up to 8.5 years. It revealed that higher levels of stress, hostility, and depressive symptoms were significantly associated with an increased risk of stroke or TIA in middle-aged and older adults (Everson-Rose et al., 2014; Hering et al., 2015). Another prospective population study on stroke incidence indicated that depression could increase the likelihood of stroke by up to 35% (Wadley et al., 2007). Many patients with TIA generally exhibit a spectrum of anxiety or depression-like behaviors(El Husseini et al., 2012; Luijendijk et al., 2011), as TIA can lead to long-term neurological issues due to increased nitrosative stress (Tomas-Sanchez et al., 2024). However, there is a lack of sufficient prospective research to support whether depression can directly cause TIA. Our research indicated that while depression indeed heightened the risk of TIA, the occurrence of TIA did not reciprocally increase the risk of depression. This discrepancy might be attributed to the brief duration of TIA episodes and the insufficient intensity and duration of nitrosative stress to provoke depression. To thoroughly understand the intricate relationship between depression and TIA, larger and more comprehensive prospective studies are essential. Such studies would be instrumental in verifying their causal associations.

Mendelian randomization offers an alternative to traditional randomized controlled trials to evaluate causal relationships by bypassing ethical constraints. This approach bolsters the hypothesis of a causal link between neurological disorders and emotional diseases, potentially paving the way for innovative preventive strategies for both conditions. However, our study is not without its limitations. Primarily, our research was restricted to individuals of European ancestry. While this minimized bias from population stratification, it also limited the applicability of our findings to other racial and ethnic groups. Furthermore, like all Mendelian randomization studies, we could not entirely address unobserved pleiotropy, which might likely introduce bias into our results. Therefore, extensive randomized controlled trials remain essential to further investigate the intricate relationship between neurological disorders and psychiatric conditions.

In summary, our study identified causal relationships between neurological diseases (trigeminal neuralgia, CNS malformation and transient ischemic stroke) and emotional disorders (mania and depression); trigeminal neuralgia and congenital malformation of the nervous system predispose patients to emotional disorders, whereas depression in particular causes vulnerability to transient ischemic stroke. Proactive intervention in managing physical and emotional conditions potentially reduces their likelihoods of occurrence. This highlights the necessity for an integrated and holistic approach to patient care so to achieve ideal outcomes in healthcare.

Ethics approval and consent to participate

No applicable.

Consent for publication

No applicable.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

CRediT authorship contribution statement

Haonan Chen: Resources, Project administration, Methodology, Investigation, Formal analysis, Data curation. Renhao Zhang : Resources, Data curation. Xinjie Wen: Methodology, Investigation, Data curation. Dongqi Shao:Methodology, Investigation. Qiang Fu: Resources, Project administration, Shichao Yin: Data curation, Software. Yifan Lv: Formal analysis, Supervision. Tao Sun: Writing – review & editing, Writing – original draft, Conceptualization.

Declaration of competing interest

The authors declare no conflicts of interest related to this study.

Acknowledgement

I would first like to thank my supervisors, Tao Sun, whose expertise was invaluable in formulating the research questions and methodology. I would particularly like to appreciate my groupmates for their wonderful collaboration and patient support.

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No competing interests reported.

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Bi-directional causal association between 17 neurosurgical diseases and three emotional disorders: perspective from Mendelian randomization analysis

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Version 1

Abstract

Figures

Highlights

1 Introduction

2 Methods

2.1 | Data sources

2.2 | Instrumental variable 2.2 IVS selection

2.3 | MR analysis

2.4 | Sensitivity analysis

2.5 | Statistics analysis

3 RESULTS

3.1 |Association between Trigeminal neuralgia and mania

3.2 | Association between congenital malformations of nervous system and

3.3 | Association between depression and transient ischemic attack

4 Discussion

5 Conclusion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1