Type II diabetes mellitus and amyotrophic lateral sclerosis: genetic overlap, causality, and mediation

J Clin Endocrinol Metab. 2021 Jun 25:dgab465. doi: 10.1210/clinem/dgab465. Online ahead of print.


OBJECTIVE: To disentangle the nature of the inverse relationship between type II diabetes (T2D) mellitus and amyotrophic lateral sclerosis (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 eQTL weighted integrative analysis and the ccFDR method. We implemented Mendelian randomization (MR) analyses to evaluate the causal relationship between the two 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 common genetic foundation between T2D and ALS (rg=-0.223, p=0.004), and identified eight pleiotropic genes (ccFDR<0.10). The MR analysis confirmed that T2D exhibited a neuroprotective effect on ALS, leading to an approximately 5% (95% confidence intervals 0~9.6%, p=0.038) 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, obesity class 2, with the mediation effect estimated to be 0.024, -0.022, -0.041, -0.016, and -0.012, respectively.

CONCLUSION: We provided new evidence supporting the observed inverse link between T2D and ALS, and revealed that shared genetic component and causal association commonly drove such relationship. We also demonstrated the mediating role of T2D standing in the pathway from T2D-related glycemic/anthropometric traits to ALS.

PMID:34171091 | DOI:10.1210/clinem/dgab465