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. 2024 Mar 5:18:1333782.
doi: 10.3389/fnins.2024.1333782. eCollection 2024.

Evidence based on Mendelian randomization and colocalization analysis strengthens causal relationships between structural changes in specific brain regions and risk of amyotrophic lateral sclerosis

Jiaying Shi #  1 , Zhaokun Wang #  1 , Ming Yi  1 , Shengyu Xie  1 , Xinyue Zhang  1 , Dachang Tao  1 , Yunqiang Liu  1 , Yuan Yang  1
Affiliations

Evidence based on Mendelian randomization and colocalization analysis strengthens causal relationships between structural changes in specific brain regions and risk of amyotrophic lateral sclerosis

Jiaying Shi et al. Front Neurosci. .

Abstract

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the degeneration of motor neurons in the brain and spinal cord with a poor prognosis. Previous studies have observed cognitive decline and changes in brain morphometry in ALS patients. However, it remains unclear whether the brain structural alterations contribute to the risk of ALS. In this study, we conducted a bidirectional two-sample Mendelian randomization (MR) and colocalization analysis to investigate this causal relationship.

Methods: Summary data of genome-wide association study were obtained for ALS and the brain structures, including surface area (SA), thickness and volume of subcortical structures. Inverse-variance weighted (IVW) method was used as the main estimate approach. Sensitivity analysis was conducted detect heterogeneity and pleiotropy. Colocalization analysis was performed to calculate the posterior probability of causal variation and identify the common genes.

Results: In the forward MR analysis, we found positive associations between the SA in four cortical regions (lingual, parahippocampal, pericalcarine, and middle temporal) and the risk of ALS. Additionally, decreased thickness in nine cortical regions (caudal anterior cingulate, frontal pole, fusiform, inferior temporal, lateral occipital, lateral orbitofrontal, pars orbitalis, pars triangularis, and pericalcarine) was significantly associated with a higher risk of ALS. In the reverse MR analysis, genetically predicted ALS was associated with reduced thickness in the bankssts and increased thickness in the caudal middle frontal, inferior parietal, medial orbitofrontal, and superior temporal regions. Colocalization analysis revealed the presence of shared causal variants between the two traits.

Conclusion: Our results suggest that altered brain morphometry in individuals with high ALS risk may be genetically mediated. The causal associations of widespread multifocal extra-motor atrophy in frontal and temporal lobes with ALS risk support the notion of a continuum between ALS and frontotemporal dementia. These findings enhance our understanding of the cortical structural patterns in ALS and shed light on potentially viable therapeutic targets.

Keywords: Mendelian randomization; amyotrophic lateral sclerosis; brain structures; causality; colocalization; genome-wide association study.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Workflow of the causal inference between brain structures and ALS. ALS, amyotrophic lateral sclerosis; GWAS, genome-wide association study; SNP, single nucleotide polymorphisms.
Figure 2
Figure 2
Significant and nominally significant MR estimates for the causal relationship between brain structures and ALS using IVW method. Significant p-values after FDR correction (PFDR < 0.1) were marked in bold. (A) Forward MR analysis for the causal relationship between brain structures SA and ALS risk. (B) Forward MR analysis for the causal relationship between brain structures TH and ALS risk. (C) Reverse MR analysis for the causal relationship between ALS and brain structures TH. SNP, single nucleotide polymorphism; OR, odds ratio; 95% CI, 95% confidence interval; se, standard error. SA, surface area; TH, thickness; ALS, amyotrophic lateral sclerosis.
Figure 3
Figure 3
Scatterplots, funnel plots, and leave-one-out sensitivity analysis of the causal effect of brain structures SA on ALS risk. SA, surface area; TH, thickness.
Figure 4
Figure 4
Scatterplots, funnel plots, and leave-one-out sensitivity analysis of the causal effect of brain structures TH (not adjusted for the respective global measures) on ALS risk. SA, surface area; TH, thickness; ALS, amyotrophic lateral sclerosis.
Figure 5
Figure 5
Scatterplots, funnel plots, and leave-one-out sensitivity analysis of the causal effect of brain structures TH (adjusted for the respective global measures) on ALS risk. SA, surface area; TH, thickness; ALS, amyotrophic lateral sclerosis.
Figure 6
Figure 6
Scatterplots, funnel plots, and leave-one-out sensitivity analysis of the causal effect of ALS on brain structures. SA, surface area; TH, thickness; ALS, amyotrophic lateral sclerosis.
Figure 7
Figure 7
Colocalization analysis results for the association between brain structures and ALS. SA, surface area; TH, thickness; ALS, amyotrophic lateral sclerosis.
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Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the National Natural Science Foundation of China (No. 81871203).
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