Oxidative stress and neurodegenerative diseases: a bidirectional Mendelian randomization study

ABSTRACT

Introduction

Oxidative stress (OS) has been linked to neurodegenerative diseases in numerous epidemiological studies; however, whether it is a pathogenesis or a downstream factor remains controversial.

Methods

A two-sample bidirectional Mendelian randomization (MR) analysis was implemented to examine evidence of causality of 15 OS injury markers with 3 major neurodegenerative diseases using available genome-wide association studies statistics. As a main approach, inverse-variance weighted (IVW) analysis was performed. The weighted-median (WM) analysis was used to validate the relationship. In order to investigate the existence of horizontal pleiotropy and correct the IVW estimate, the Radial MR approach was applied. To gauge the consistency and robustness of the findings, several sensitivity and pleiotropy analyses were used. For this analysis, p < 0.05 indicates a nominally causal association; according to the Bonferroni correction test, p < 0.0011 indicates a statistically significant causal association.

Results

Via IVW and WM, in directional MR, it was genetically predicted that zinc was nominally causally correlated with the risk of Parkinson’s disease but not after Bonferroni correction test; alpha-tocopherol was nominally causally correlated with the risk of Amyotrophic lateral sclerosis (ALS) but not after Bonferroni correction test; furthermore, in reverse MR, it was genetically predicted that Alzheimer’s disease was causally correlated with uric acid but not after Bonferroni correction test. These above findings were stable across sensitivity and pleiotropy analyses.

Conclusions

Based on the current study, there is no authentic genetic causal association between OS biomarkers and neurodegenerative diseases. The complex relationship is required to be confirmed in future experimental research.

KEYWORDS:

• Oxidative stress
• neurodegenerative diseases
• Alzheimer's disease
• Parkinson's disease
• Amyotrophic lateral sclerosis
• zinc
• alpha-tocopherol
• uric acid‌
• Mendelian randomization

Acknowledgments

We would like to thank Editage (www.editage.cn) for English language editing. Zihan Yin and Fanrong Liang conceptualized the whole article; Zihan Yin rendered support in data curation; Zihan Yin rendered support in formal analysis; Ling Zhao and Fanrong Liang rendered support in funding acquisition; Zihan Yin investigated the article; Zuoqin Yang developed the methodology; Yiwei Liu supervised the article; Zihan Yin, Zuoqin Yang and Yiwei Liu wrote the original draft; Ling Zhao and Fanrong Liang wrote the review and edited. All authors read and approved the final manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability

All statistics used in this study are from the publicly available datasets and can be obtained in https://gwas.mrcieu.ac.uk/datasets/.

Ethics statement

GWAS data of the study were publicly available. We did not collect additional raw data, and therefore approval from the medical ethical committee is not required. Each original GWAS is approved by the corresponding ethical approval board. And informed consent is procured from each participant.

Additional information

Funding

This work was financially supported by the National Natural Science Foundation of China (nos. 81590951, 82004486, 81722050, 81973961), State Administration of Traditional Chinese Medicine of the People's Republic of China .

Notes on contributors

Zihan Yin

Zihan Yin holds a Doctor's degree in acupuncture. He mainly studies the relationship between acupuncture and neurodegenerative disease.

Zuoqin Yang

Zuoqin Yang has higher education in acupuncture and holds a Master's degree in acupuncture.

Yiwei Liu

Yiwei Liu has higher education in acupuncture and holds a Master's degree in acupuncture.

Ling Zhao

Ling Zhao holds a doctor's degree in acupuncture. She is a professor at the School of acu-mox and tuina at Chengdu University of Traditional Chinese Medicine. She uses clinical and mechanistic studies bridging basic and clinical aspects of acupuncture, neurodegenerative disease, and nutrition to investigate the concept of the link among them.

Fanrong Liang

Fanrong Liang holds a master's degree in acupuncture. He is a professor at the School of acu-mox and tuina at Chengdu University of Traditional Chinese Medicine. He uses clinical and mechanistic studies bridging basic and clinical aspects of acupoint, neuroscience, and nutrition to investigate the concept of the link among them.