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Published on: July 16, 2021
Type 2 Diabetes Mellitus and Amyotrophic Lateral Sclerosis: Genetic Overlap, Causality, and Mediation
Haimiao Chen1, Jinhui Zhang1, Ting Wang1
1Department of Biostatistics, School of Public Health, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China.
Context:
Understanding phenotypic connection between type II diabetes (T2D) mellitus and amyotrophic lateral sclerosis (ALS) can offer valuable sight into shared disease etiology and have important implication in drug repositioning and therapeutic intervention.
Objective:
This work aims to disentangle the nature of the inverse relationship between T2D mellitus and ALS.
Methods:
Depending on summary statistics of T2D (n = 898 130) and ALS (n = 80 610), we estimated the genetic correlation between them and prioritized pleiotropic genes through a multiple-tissue expression quantitative trait loci-weighted integrative analysis and the conjunction conditional false discovery rate (ccFDR) method. We implemented mendelian randomization (MR) analyses to evaluate the causal relationship between the 2 diseases. A mediation analysis was performed to assess the mediating role of T2D in the pathway from T2D-related glycemic/anthropometric traits to ALS.
Results:
We found supportive evidence of a common genetic foundation between T2D and ALS (rg = -0.223, P = .004) and identified 8 pleiotropic genes (ccFDR < 0.10). The MR analyses confirmed that T2D exhibited a neuroprotective effect on ALS, leading to an approximately 5% (95% CI, 0% ~ 9.6%, P = .038) reduction in disease risk. In contrast, no substantial evidence was observed that supported the causal influence of ALS on T2D. The mediation analysis revealed T2D can also serve as an active mediator for several glycemic/anthropometric traits, including high-density lipoprotein cholesterol, overweight, body mass index, obesity class 1, and obesity class 2, with the mediation effect estimated to be 0.024, -0.022, -0.041, -0.016, and -0.012, respectively.
Conclusion:
We provide new evidence supporting the observed inverse link between T2D and ALS, and revealed that a shared genetic component and causal association commonly drove such a relationship. We also demonstrate the mediating role of T2D standing in the pathway from T2D-related glycemic/anthropometric traits to ALS.
Insights
Type II diabetes (T2D) mellitus has a neuroprotective effect on amyotrophic lateral sclerosis (ALS), reducing disease risk by approximately 5%. This study reveals a shared genetic basis and causal link contributing to the inverse relationship between T2D and ALS.
Area of Science:
- Genetics
- Neuroscience
- Endocrinology
Background:
- Type II Diabetes Mellitus (T2D) and Amyotrophic Lateral Sclerosis (ALS) are complex diseases with potentially overlapping etiologies.
- Understanding the phenotypic connection between T2D and ALS can provide insights into shared disease mechanisms and inform therapeutic strategies.
- Investigating this relationship may reveal opportunities for drug repositioning and novel treatment interventions.
Purpose of the Study:
- To investigate the genetic correlation and causal relationship between Type II Diabetes Mellitus (T2D) and Amyotrophic Lateral Sclerosis (ALS).
- To identify pleiotropic genes that may contribute to the observed inverse association between T2D and ALS.
- To elucidate the mediating role of T2D in the pathway connecting glycemic/anthropometric traits to ALS.
Main Methods:
- Utilized summary statistics from large-scale genome-wide association studies for T2D (n=898,130) and ALS (n=80,610).
- Estimated genetic correlation and employed conjunction conditional false discovery rate (ccFDR) to identify pleiotropic genes.
- Performed Mendelian randomization (MR) analyses to assess causality and mediation analysis to evaluate T2D's role in trait-to-ALS pathways.
Main Results:
- Found significant genetic correlation (rg=-0.223, P=0.004) supporting a common genetic foundation between T2D and ALS.
- Identified 8 pleiotropic genes (ccFDR < 0.10) potentially linking the two diseases.
- MR analyses indicated a neuroprotective effect of T2D on ALS risk (approx. 5% reduction), with no evidence of causal influence from ALS to T2D.
- Mediation analysis showed T2D mediates effects of high-density lipoprotein cholesterol, overweight, BMI, and obesity classes on ALS.
Conclusions:
- Provided evidence for a shared genetic component and a causal association driving the inverse relationship between T2D and ALS.
- Confirmed a neuroprotective role of T2D in the context of ALS.
- Demonstrated T2D's mediating role in the pathway from glycemic/anthropometric traits to ALS, highlighting complex interconnections.
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