Mendelian randomization study supports relative carbohydrate intake as an independent risk factor for amyotrophic lateral sclerosis

ABSTRACT

Objectives

Observational studies suggested a potential correlation between dietary intake and amyotrophic lateral sclerosis (ALS), but conflicting findings exist and causality remains unclear. Here, we performed a Mendelian randomization (MR) analysis to evaluate the causal impact of relative intake of (i) carbohydrate, (ii) fat, and (iii) protein on ALS risk.

Methods

The genome-wide association summary statistics of three dietary macronutrient intake traits and ALS were obtained. Initially, forward and reverse univariable MR (UVMR) analysis were conducted using the inverse variance weighted (IVW) method as the primary approach, supplemented by MR-Egger, weighted median, and maximum likelihood. Subsequently, multivariable MR (MVMR) analysis was performed to assess the independent causal effects of each dietary. Additionally, diverse sensitivity tests were conducted to evaluate the reliability of the MR analyses.

Results

The forward UVMR analysis conducted by IVW indicated that relative carbohydrate intake significantly increased ALS risk. Furthermore, results from three other MR methods paralleled those from IVW. However, the other two dietary intake traits did not have a causative impact on ALS risk. The reverse UVMR analysis indicated that ALS did not causatively influence the three dietary intake traits. The MVMR analysis showed that after adjusting for the effects of the other two dietary intake traits, relative carbohydrate intake independently and significantly increased ALS risk. Sensitivity tests indicated no significant heterogeneity or horizontal pleiotropy.

Discussion

MR analysis supported relative carbohydrate independently increasing ALS risk. Nevertheless, further validation of this finding in future large cohorts is required.

Abbreviations: ALS: amyotrophic lateral sclerosis; CI: confidence interval; GWAS: genome-wide association study; IV: instrumental variable; IVW: iverse variance weighted; MR: Mendelian randomization; MVMR: multivariable Mendelian randomization; OR: odds ratio; RCT: randomized controlled trial; SNPs: single-nucleotide polymorphisms; UVMR: univariable Mendelian randomization

KEYWORDS:

• Dietary composition
• amyotrophic lateral sclerosis
• Mendelian randomization analysis
• independent risk factors
• incidence risk
• disease prevention
• neurodegenerative diseases
• neurodegenerative disorders‌

Acknowledgements

We are grateful to the NHGRI-EBI GWAS Catalog database and the SSGAC Data Portal for providing GWAS summary-level statistics.

Ethics approval and consent to participate

Publicly available de-identified data from participant studies approved by an ethical standards committee were used in this study. Therefore, no additional separate ethical approval or patient consent was required for this study.

Disclosure statement

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

Authors’ contributions

Youjie Zeng: Conceptualization, Formal analysis, Methodology, Investigation, Writing – Original Draft, Visualization; Ren Guo: Validation, Formal analysis, Data Curation; Si Cao: Software, Validation, Formal analysis; Sarel Chavarria Gonzalez: Resources, Data Curation; Ke Pang: Investigation, Formal analysis; Chunxia Liu: Investigation, Formal analysis; Heng Yang: Supervision, Project administration, Funding acquisition, Writing – Review & Editing.

Data availability statement

The data used for this study are available in the Supplementary Tables.

Additional information

Funding

This research was funded by the Natural Science Foundation of Hunan Province (2022JJ70069).

Notes on contributors

Youjie Zeng

Youjie Zeng is a PhD candidate in the Third Xiangya Hospital of Central South University. He is a medical researcher specializing in computational analysis methods, including Mendelian randomization and bioinformatics analysis. His work focuses on identifying potential risk factors and understanding the disease mechanisms in cardiovascular and neurological disorders.

Ren Guo

Ren Guo is an Associate Professor in the Department of Pharmacy at Third Xiangya Hospital of Central South University.

Si Cao

Si Cao is a physician at the Reproductive and Genetic Hospital of CITIC-XIANGYA.

Sarel Chavarria Gonzalez

Sarel Chavarria Gonzalez is a master's student in the Xiangya Hospital of Central South University

Ke Pang

Ke Pang is a research assistant in the Department of Anesthesiology at Third Xiangya Hospital of Central South University.

Chunxia Liu

Chunxia Liu is a master's student in the Third Xiangya Hospital of Central South University

Heng Yang

Heng Yang is an Associate Professor in the Department of Neurology at Third Xiangya Hospital of Central South University.