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Abstract

Background and objective:

Mitochondria are important organelles functioning in metabolic processes, inflammatory response and neurological disorders. Migraines are chronic and paroxysmal neurological disorders characterized by recurrent episodes of severe headache and other neurological symptoms. We explored whether mitochondria may be genetically and/or causally associated with migraine.

Methods:

Summary-level statistics of mitochondrial DNA copy number (mtDNA-CN), 69 mitochondria related exposures and migraine with aura, migraine without aura, migraine with aura and triptan purchases, migraine with aura, drug-induced, migraine without aura and triptan purchases and migraine without aura, drug-induced, were collected from genome-wide association studies (GWAS). The analysis employed two-sample Mendelian randomization, utilizing various methods including MR-Egger, inverse-variance weighted (IVW), MR-PRESSO (MR-pleiotropy residual sum and outlier), maximum likelihood, and weighted median.

Results:

We observed a potential association with decreased levels of mtDNA-CN with the risk of migraine without aura (Odds ratio (OR) 1.517, 95% Confidence interval (CI) 1.072–2.147, p = 0.019). Besides, for every 1 unit in NAD-dependent protein deacylase sirtuin-5 (SIRT5), relative risk of migraine without aura increased by 16.4%. For every 1 unit increase in Phenylalanine–transfer RNA (tRNA) ligase, relative risk of migraine without aura increased by 13.5%. For every 1 unit increase in Apoptosis-inducing factor 1, relative risk of migraine without aura increased by 27.4%.

Conclusion:

This study indicates fresh evidence of association between mtDNA-CN, mitochondrial related exposures and migraine especially migraine without aura. The findings may shed light on developing interventions targeting on the causal pathway from mitochondria to migraine.

Keywords

Mendelian randomization migraine neuroinflammation Sirtuin-5 mitochondria mitochondrial DNA copy number

Introduction

Migraines are chronic and paroxysmal neurological disorders characterized by recurrent episodes of severe headache and other neurological symptoms. The International Classification of Headache Disorders (ICHD) has defined specific diagnostic criteria for migraine types with and without auras. The understanding of these subtypes is essential for the diagnosis and research of the underlying pathophysiology of the disease.

Migraine without aura (MO) is the most prevalent form of migraine, which is characterized by recurrent and severe headaches, usually unilateral, throbbing and pulsating. Several concurrent symptoms may occur including nausea, vomiting and heightened sensitivity to light and sound (photophobia and phonophobia). MO is characterized by the absence of preceding sensory and visual impairments known as “auras” that accompany other subtypes. Neurological symptoms distinguish migraine with aura, called “auras,” that appear before or during headaches, causing visual impairments, sensory dysfunctions such as tingling or numbness and cognitive deficits.¹ Triptans are prescribed for migraines associated with migraine Triptans. Triptans constrict cranial blood vessels and are commonly prescribed to relieve migraine symptoms. This subtype of migraine may be studied to determine the effectiveness of triptan, side effects and patient outcomes with migraine.² Drugs for migraine can cause adverse events and severe complications, which involve migraine-related drug adverse reactions, comorbidities and other negative outcomes.³

Neuroinflammation in the central nervous system (CNS) is a notable characteristic of neurological diseases. Some inflammatory activities link infectious, neurodegenerative, and psychiatric conditions, disrupting intrinsic pathological processes and exacerbating the progress of CNS disorders.⁴ Recently published studies have provided invaluable insights into the relationships between neuroinflammation and migraine,⁵ indicating that migraine could be produced by the activation of trigeminal nociceptor related to neuroinflammation, which then produce the sensation of pain. What is more, several studies suggested that some pro-inflammatory cytokines such as TNF-α and IL-6 levels were higher in migraine patients than healthy ones.^5,6 It is noteworthy that the TNF-α-308 A allele, which has increased TNF-α production, was overrepresented in the migraine without aura group than the control group.⁷

Mitochondria are autonomous organelles that play a pivotal role in metabolic processes. Multiple mechanisms have been implicated in cerebral spreading depression (CSD) and fluctuations in cerebral blood flow. It is a neurovascular disorder that causes throbbing, pulsating, and headaches. Multiple studies have reported that higher mutation rates and environmental and biochemical factors have been the main areas of mitochondrial impairment in migraine research.⁸ P-nuclear magnetic resonance studies have revealed that migraineurs have deficits in supplying energy in the brain. Since glycolysis is the primary source of energy in the brain, mitochondria may be involved in the pathogenesis and progression of migraine.⁹ A pioneering study has revealed that migraines may alleviate oxidative stress and restore homeostasis in the brain.¹⁰ The researchers believe that mitochondrial impairments induce neuronal dysfunction, which further increases the susceptibility of migraines.¹¹

Studies into pathophysiology have been focused on mtDNA-CN. A variety of mtDNA polymorphisms can affect the generation and transmission of nerve impulses.⁸ The number of mitochondria and their functions consistently decreases with age in a variety of tissues.¹² Mutations affect only a fraction of the copy number of mammalian mtDNA. Filograna et al.¹³ report that recessive mutations in the human mtDNA cause OXPHOS defects. It has also been shown that mtDNA-CN and mitochondrial DNA transfer may further promote the progression of cancer.¹⁴ The quantification of mtDNA-CN in clinical and epidemiological research has become increasingly popular due to the availability of stored DNA materials and sequencing data.¹⁵ Healthy individuals and those with a variety of diseases, particularly neurodegenerative and age-related diseases, have different epigenetic statuses of mtDNA.¹⁶

To investigate the relationship between six different types of migraine and mtDNA-CN, we used Mendelian randomization (MR) which is a reliable method for analyzing the relationship between variables. MR facilitated the identification of potential targets and mechanism in the investigation of various complex neurological disorders, such as multiple sclerosis, epilepsy, and Alzheimer’s disease.^17–19 Compared to clinical studies in neurological disorders, which are reliable but often limited by the difficulty of obtaining sufficient sample sizes and potential harm to patients, Mendelian randomization (MR) studies offer a non-invasive and more efficient alternative by using existing large-scale genome-wide association study (GWAS) data. MR employs genetic variants as instrumental variables to establish causal relationships, capitalizing on their random assignment at conception. This approach mitigates bias from confounding factors, including lifestyle and environmental influences. With ongoing methodological advancements, Mendelian randomization (MR) can effectively utilize mitochondria-related biomarker statistics derived from GWAS, enhancing the power of research into dementia, stroke, and lung cancer.^20–22 However, to date, few MR studies have reported on the integration of mitochondria-related biomarkers and mtDNA copy number (mtDNA-CN) data from GWAS focused on complex migraine phenotypes. A MR approach offers a deeper understanding of migraine and mtDNA-CN than mere correlations. Furthermore, we validated the significant relationships between 69 mitochondria-related biomarkers retrieved from GWAS databases. The purpose of this step was to broaden the scope of our investigation and to understand the relationship between mitochondria and migraine, while also providing further insights into the pathogenesis of migraine.

This study aims to understand the relationship between mitochondria and migraine to provide valuable insights into the pathophysiology of disease, potentially leading to improved patient outcomes. Therefore, this research may benefit studies and clinical practices in related fields.

Methodology

Study design

Migraine may be associated with mitochondrial dysfunction. Several migraine subtypes were identified including migraine with aura. Migraines with aura and without aura are subdivided into triptans and adverse. The MR design was based on mtDNA-CN as a complex biomarker of mitochondrial disorders.²⁰ We investigated separately the relationship between mtDNA-CN and each migraine subtype. To assess the contributory role of mitochondrial protease, oxidase, ligases, etc., in mediating the association between mitochondrial exposure and migraine, we used a two-sample MR design (Additional file 1 Table S1). MR methodologies rest on three core premises: (1) the genetic instruments must have a strong correlation with the exposures; (2) there should be no link between the genetic instruments and any confounding variables; (3) the impact of the genetic instruments on the outcomes should be mediated exclusively through the exposures in question.²³ A variety of statistical methods are utilized to analyze the second and third assumptions of horizontal pleiotropy.²⁴ In this study, primary and replication analyses were performed using genetic information from publicly available GWAS consortia and FinnGen data from the European population. The consent to participate and ethical approval were obtained prior to the original publication. A brief overview of the Chong study is provided in Figure 1. Statistical analyses were performed using the “TwoSampleMR” package (Version 0.5.7) in the R program (Version 4.3.1).

Figure 1.

Mendelian randomization analysis design for assessing the causal relationship between mitochondrial DNA copy number (mtDNA-CN), 69 mitochondria-associated exposures, and migraine subtypes.

Data sources

GWAS data for mtDNA-CN

Data for mtDNA-CN was obtained from the OpenGWAS (https://gwas.mrcieu.ac.uk/). To improve the statistical power of our analysis, allowing us to detect even subtle genetic associations with greater confidence, we selected a well-conducted study of which the data set containing 395,718 samples and 22,679,963 Single-nucleotide polymorphisms (SNPs) in OpenGWAS from Chong et al.²⁰ The data set was originally used to analyze the association between mtDNA-CN and different neurologic diseases, which matched the purpose of our study.

GWAS data for mitochondria-associated exposure

To minimize biases in our analysis, the genetic information for each mitochondria-associated exposure was obtained from the OpenGWAS, two with rigorous quality control from Sun et al.²⁵ and Gilly et al.²⁶ separately, 4 groups altogether. Data comprised 3301, 1263, 1296, 1301 samples of European ancestry and 10,534,735, 18,093,722, 18,162,745, 18,166,693 SNPs. To guarantee the precision and relevance of our data, we carefully retrieved 82 mitochondria-associated exposures. Then, we obtained the instrumental variables for 69 exposures using the filter criteria (p-value – 5 × 10⁻⁶, cluster -KB – 10,000, cluster_r2 – 0.001) to ensure that all SNPs we selected are independent and strongly related to exposures.

GWAS and Finn data for migraine

To keep our analysis as general as possible, and improve the specificity of treatments to different types of migraine, we divided migraine into groups as migraine with aura and migraine without aura, of which the criteria is widely accepted by other researchers.^27,28 Based on the FinnGen public database, we obtained statistics of migraine with aura (3541 cases and 176,107 controls) and migraine without aura (3215 cases and 176,107 controls). These samples were of European ancestry, while males and females were both included. Moreover, we identified migraine with aura and triptan purchases (3541 cases and 164,098 controls), migraine with aura, drug-induced (192 cases and 218,600 controls), migraine without aura and triptan purchases (3215 cases and 164,098 controls) and migraine without aura, drug-induced (180 cases and 218,612 controls), with the purpose of confirming the results are coincide in different subgroups.

Instruments selection

We selected genetic variants associated with mtDNA-CN and mitochondria-associated exposure. To identify the independent SNPs, we reduced the association criterion to p< 5 × 10^–6 (pairwise linkage disequilibrium (LD) r2 < 0.001 within 10,000 kb). This method was used in the previous MR studies.²⁹ We also calculated F statistics for each SNP to avoid bias due to weak instruments. SNPs with F 10 were recognized as weak instruments for mitochondria-associated exposures and discarded. However, due to the lack of relevant data in the original study of mtDNA-CN, we could not calculated F statistics for SNPs of mtDNA-CN.¹⁶ We extracted the exposure SNPs from the outcome data and excluded those associated with the outcome (p < 5 × 10⁻⁶).

Primary analysis

We calculated the MR estimates for each risk factor based on an IVW analysis, which uses a random-effects meta-analysis approach to combine Wald ratio estimates of the significant effect.

Inverse-variance weighted

We performed a random-effect IVW to identify the associations between mitochondria-associated exposure and migraine. The IVW approach aggregates the Wald ratios from each SNP to derive a consolidated estimate for use in MR research. MR estimation can be performed using IDW by assuming that all genetic variations are valid. However, it is also subject to pleiotropic biases. In this study, IVW was used as a primary method to scan preliminary associations of mitochondria-associated exposure to migraines.

Sensitivity analysis for Mendelian randomization

We conducted multiple sensitivity analyses to verify the relationship between mitochondrial dysfunction and migraine. The MR-PRESSO were utilized to determine and exclude potential pleiotropic instruments. Further analyses were performed using the R package TwoSampleMR by conventional IVW, weighted median, simple median and MR-Egger. We further quantified the potential heterogeneity using Cochran’s IVW Q statistics and MR-Egger regression.

Results

Associations of mtDNA-CN levels with migraine

We investigated the relationship between migraine without aura risk and mtDNA-CN standard deviation (SD) decrease under the IVW model (OR 1.517, 95% CI 1.072–2.147, p = 0.019) based on the data from Chong et al.²⁰ Additionally, we examined migraine without aura and triptan purchase (OR 1.549, 95% CI 1.092–2.198, p = 0.014) and drug-induced migraine without aura (OR 5.132, 95% CI 1.266–20.800, p = 0.021; Additional file 1 Table S2). The scatter and forest plots visually represented the relationships between mtDNA-CN and three subtypes of migraine without aura (Additional file 2 Figures S1 and S2). Intriguingly, the data indicated that there were no statistically significant associations between mtDNA-CN and migraine with aura, migraine with aura and triptan purchase, and drug-induced migraine with aura (Additional file 3: Table S3). In addition, Cochran’s Q test and MR-Egger intercept analysis indicated no heterogeneity (Q-value = 70.864, PQ = 0.693; Q-value = 81.548, PQ = 0.645; Q-value = 84.363, PQ = 0.560, respectively) or horizontal pleiotropy (intercept = −0.004, intercept = −0.004, intercept = −0.025, respectively; Additional file 1 Table S4). The MR-PRESSO analysis revealed no significant pleiotropy (p = 0.520, 0.681, 0.541, respectively). The forest plots were generated for SNP conformity using a leave-one-out analysis (Figure 2). All SNPs of exposures in the MR analysis have F statistics higher than the conventional threshold of 10. R2 and F statistics for IVs are presented in the following Additional file 4: Table S5.

Figure 2.

Forest plot to visualize the causal effect of mtDNA-CN levels on the risk of three subtypes of migraine.

Associations of mitochondrial-related exposures with migraine

IVW analyses revealed that some mitochondrial exposures were closely associated with migraine without aura and its subgroups (Figures 3 –5, Additional file 1 Table S6–S8), migraine without aura and its subgroups (Additional file 2 Figures S3–S5, Additional file 1 Table S9–S11).

(a) Phenylalanine-tRNA ligase increases the risk of migraine without aura, triptan purchase and drug-induced migraine by 13.5%, 13.8%, and 90.0%, respectively (OR 1.135, 95% CI: 1.001–1.287, p = 0.047, OR 1.138, 95% CI: 1.004–1.291, p = 0.044, and OR 1.900, 95% CI: 1.136–3.176, p = 0.014).

(b) The relative risk of migraine without aura, without aura and triptan purchase and drug-induced increased by 16.4%, 18.0%, and 93.1% for every one-unit increment in NAD-dependent protein deacetylase sirtuin-5, respectively (OR 1.164, 95% CI: 1.037–1.306, p = 0.010, OR 1.180, 95% CI: 1.050–1.325, p = 0.005, and OR 1.931, 95% CI: 1.188–3.136, p = 0.008).

(c) The relative risk of migraine without aura and aura and triptan purchase increased by 24.6% (OR 1.246, 95% CI: 1.079–1.439, p = 0.003) and 24.9% (OR 1.249, 95% CI: 1.080–1.444, p = 0.003) for each unit increment in 39S ribosomal protein L32.

(d) The relative proportion of migraine without aura and triptan purchase reduced by 16.8% (OR 0.832 95% CI: 0.708–0.978, p = 0.026) and 16.9% (OR 0.831, 95% CI: 0.700–0.985, p = 0.033) for every 1 unit increase in NADH dehydrogenase (ubiquinone).

(e) Apoptosis-inducing factor 1 increased the risk of migraine with aura, migraine without aura and triptan purchase by 27.4% (OR 1.274, 95% CI: 1.056–1.538, p = 0.012), 27.4% (OR 1.274, 95% CI: 1.057–1.536, p = 0.011).

(f) The relative risk of migraines without aura and triptan purchase increased by 43.8% (OR 1.438, 95% CI: 1.136–1.819, p = 0.003) and 43.1% (OR 1.431, 95% CI: 1.129–1.813, p = 0.003) when (Pyruvate dehydrogenase (acetyl-transferring)) kinase isozyme 2 was increased by one unit.

(g) There was a 32.6% reduction in the relative risk of migraine without aura and drug-induced migraine with 1 unit increase in dihydrolipoyl dehydrogenase, hydroxymethylglutaryl-CoA synthase and ADP-ribose pyrophosphatase (OR 0.674, 95% CI: 0.476–0.956, p = 0.027). The ORs increased by 76.2% (OR 1.762, 95% CI: 1.117–2.778, p = 0.015) and 60.3% (OR 1.603, 95% CI: 1.088–2.360).

(h) The relative risk of migraine with aura, aura and triptan purchase increased by 20.9% for every unit increase in cytochrome c oxidase subunit 5B (OR 1.209, 95% CI: 1.079–1.354, p = 0.001).

(i) The relative risk of migraine with aura and triptan purchase increased by 6.2% for every 1 unit increase in cytochrome c oxidase subunit 8A (OR 0.938, 95% CI: 0.881–1.000, p = 0.049).

(j) The relative risk of migraine with aura and drug-induced migraine decreased by 43.4% (OR 0.566, 95% CI: 0.358–0.895, p = 0.015) for each unit increase in carbonic anhydrase 5A and histidine triad nucleotide-binding protein 2. Moreover, the relative risk rose by 64.4% (OR 1.644, 95% CI: 1.012–2.671, p = 0.045). The complete results including nonsignificant associations among all 69 mitochondria-related exposures is indicated in Additional file 5: Table S12.

Figure 3.

Forest plot to visualize the causal effect of mitochondria-related exposures on the risk of migraine without aura.

Figure 4.

Forest plot to visualize the causal effect of mitochondria-related exposures on the risk of migraine without aura, drug−induced.

Figure 5.

Forest plot to visualize the causal effect of mitochondria-related exposures on the risk of migraine without aura and triptan purchases.

The Cochran’s Q and MR-Egger intercept tests did not reveal heterogeneity or horizontal pleiotropy, the MR-PRESSO analysis showed no apparent outliers in the instrumental variables (Additional file 6: Table S13). Furthermore, the scatter plot, forest plot, and leave-one-out plot were all created and presented in the Additional file 7: Figure S4–S25.

Discussion

Migraine is a complex neurological disorder affecting millions of people worldwide. This discussion aims to explore the current state of research in this area, highlighting recent breakthroughs and existing gaps. Recent advances in neuroscience and molecular biology have provided valuable insights into the molecular mechanisms of migraine. Key findings include:

a. Neuroinflammation: Emerging evidence suggests that migraines may be caused by neuroinflammation.^30,31 Several immune cells are involved in neuroinflammation including mast cells, macrophages and glia. Activation of glial cells and release of several cytokines in the trigeminal ganglion and trigeminal nucleus caudalis promotes migraine without aura.³²

b. Cortical spreading depression (CSD): CSD is a phenomenon thought to underlie the aura phase of migraine.³³ A recent imaging study has provided insight into how CSD manifests throughout the cortex, contributing to our understanding of migraines with aura.

c. Neuropeptide calcitonin gene-related peptide (CGRP): Research has elucidated the significant role of CGRP in migraine, leading to the development of CGRP-targeted therapies such as monoclonal antibodies.^34,35

d. Genetics: GWAS have identified several genetic variants associated with migraine susceptibility. The understanding of the genetic basis of migraine can assist in personalizing treatment methods.³⁶

Migraines can be classified into two main subtypes: migraines with and without aura. Migraine with aura is characterized by neurological symptoms preceding or accompanying the headache. Studies have shown that migraine aura may result from CSD, which further induces visual and sensory impairments.^36,37 Migraine without aura is more common and its pathogenesis involves complex interactions between genetic, environmental and neurovascular factors. However, the identification of the specific mechanisms remains a challenge. Therefore, our research primarily concentrates on the relationship between mitochondrial dysfunction and migraines.

Accumulating studies have revealed that mutations in mt-DNA can result in mitochondrial dysfunction, affecting cellular energy production for a variety of diseases.^21,38,39 This can lead to the progression of mitochondrial disorders, metabolic syndrome, diabetes and neurodegenerative diseases. The mtDNA-CN can decrease or increase depending on the condition (mitochondrial depletion).^20,40

In this study, we found that the mt-DNA copy number was negatively associated with migraines without aura but not with migraines with aura. Our analysis was confirmed by several other studies.^41,42 It has been suggested that mitochondrial dysfunction may play a more complex role in the pathophysiology of migraine without aura.

Three migraine without aura subclasses share 69 mitochondrial-related exposures. All three subgroups showed that an increased sirtuin-5 level is associated with a higher risk of migraine without aura. While there is no significant relationship with migraine with aura. SIRT5, also called sirtuin-5, regulates metabolism and cellular hemostasis.⁴³ Earlier studies have shown that higher SIRT5 expression in microglia leads to the desuccinylation of annexin A1 (ANXA1), which elevates the production of proinflammatory cytokines and chemokines, ultimately leading to neuronal cell damage and neuroinflammation.⁴⁴ Neuroinflammation causes migraine attacks, while gilial cells trigger migraine without aura. Moreover, the upregulation of SIRT5 triggers the recruitment of pro-inflammatory macrophage into the neural microenvironment, leading to extensive inflammation in neurons and astrocytes.⁴⁵

We found that migraines without aura were associated with a higher level of the apoptosis-inducing factor 1. Research suggests that SIRT5 is upstream of Apoptosis-inducing factor 1, also known as AIFM1. Researchers found that reduced SIRT5 expression increased the succinylation of AIFM1, which reduced the level of AIFM1.⁴⁶ The CypA gene knockout mice (CypA(-/-)) lacking the AIF-dependent cell death were shown to have lower neuroinflammation after traumatic brain injury,⁴⁷ which indicates that AIFM-1 might contribute to migraines through triggering neuroinflammation. The tentative relationship between SIRT5 and migraine is depicted in Figure 6.

Figure 6.

The tentative relationship between SIRT5, AIFM1 and migraine. By Figdraw.

There are no significant relationships between migraine with aura and high levels of phenylalanine-tRNA ligase in three migraine without aura groups. Phenylalanine-tRNA ligase is also called FARS2, which facilitates phenylalanine transfer from its precursor to the tRNA.⁴⁸ Phenylalanine is converted to tyrosine in the body, which is then transformed into dopamine and norepinephrine. FARS2 decreases the levels of free phenylalanine, which results in a decrease in neurotransmitter production. A study found that migraines were associated with decreased phenylalanine in cerebrospinal fluid.⁴⁹ Current research suggests that migraine may be caused by abnormal neurotransmitter levels.^50,51 Some migraine patients may have sensitivity or impairments in the neurotransmitter system, leading to the progression of migraine attacks. We hypothesized that the disruption of phenylalanine metabolism and the mitochondrial protein translation system may be an important mechanism underlying migraine without aura. Evidence indicates that migraine is triggered by increased levels of free phenylalanine. An increase in phenylalanine may provide more substrates for neurotransmitter generation. It is possible that different subtypes of migraine have distinct pathogenic mechanisms, which require further investigation.⁵² Drug-induced migraine without aura was also found to be associated with ADP-ribose pyrophosphatase and superoxide dismutase.

The above findings indicate that NAD-dependent protein deacetylase sirtuin-5, apoptosis-inducing factor 1 and phenylalanine-tRNA ligase may be specific targets for migraine without aura therapy.

Conclusion

Migraine with aura has been associated with specific mechanisms, while migraine without aura has not yet been identified. The outcomes for the treatment of migraine without aura are poor and the mechanisms underlying migraine remain unclear. To address this research gap, we emphasized studying migraine without aura. Several studies have suggested a correlation between mitochondria and migraines. Therefore, we investigated mitochondrial disruptions using MR methods and found that mitochondria-related disruptions may provide potential pathophysiological mechanisms for migraine.

Supplemental Material

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Supplemental material, sj-docx-1-mpx-10.1177_17448069241298849 for Association between migraine and mitochondria: A Mendelian randomization study by Ming-Yang Hong, Yu-Xin Chen, Yi-Cheng Xiong, Yi-Han Sun, Abdullah Al Mamun and Jian Xiao in Molecular Pain

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Supplemental material, sj-docx-7-mpx-10.1177_17448069241298849 for Association between migraine and mitochondria: A Mendelian randomization study by Ming-Yang Hong, Yu-Xin Chen, Yi-Cheng Xiong, Yi-Han Sun, Abdullah Al Mamun and Jian Xiao in Molecular Pain

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Supplemental material, sj-xlsx-6-mpx-10.1177_17448069241298849 for Association between migraine and mitochondria: A Mendelian randomization study by Ming-Yang Hong, Yu-Xin Chen, Yi-Cheng Xiong, Yi-Han Sun, Abdullah Al Mamun and Jian Xiao in Molecular Pain

Footnotes

Acknowledgements

The authors express their gratitude to the investigators of the initial studies for providing the summary statistics of the GWAS.

Authors’ contributions

Ming-Yang Hong and Yu-Xin Chen designed and performed the experiments, analyzed the data, and wrote the manuscript. Abdullah Al Mamun edited the manuscript draft. Yi-Cheng Xiong and Jian Xiao assisted in the revising the manuscript. Yi-Han Sun analyzed the data. Ming-Yang Hong and Yu-Xin Chen confirmed the authenticity of all the raw data. All authors have read and approved the final manuscript.

Availability of data and materials

Data and materials supporting the findings of this study are available from the corresponding author upon reasonable request.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The study was supported by the Science and Technology Innovation Activity Plan for College Students of Zhejiang Province (2023R413042).

Ethics statement

Ethical approval and informed consent were not required for this study, as it utilized publicly available data. Both informed consent and ethical approval were secured in the original studies.

ORCID iD

Ming-Yang Hong

Supplemental material

Supplemental material for this article is available online.

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