# Unveiling the Genetic Association Between Hemoglobin Concentration and Amyotrophic Lateral Sclerosis

## TL;DR

This study finds that higher hemoglobin levels may lower the risk of ALS, and identifies three genes that could be involved in this relationship.

## Contribution

The study establishes a causal link between hemoglobin concentration and ALS using genetic data and identifies potential genes involved.

## Key findings

- Genetically predicted hemoglobin concentration has a negative causal effect on ALS risk.
- BACH1, FLVCR1, and TRIM58 are potential genes involved in the hemoglobin-ALS association.
- RNA sequencing and qRT-PCR show altered gene expression in ALS motor neurons.

## Abstract

Although previous studies have suggested an association between hemoglobin (Hb) concentration and amyotrophic lateral sclerosis (ALS), the precise cause‐and‐effect relationship between them is still unclear. This study aims to investigate the causal correlation between Hb concentration and ALS, and explore the potential genes related to their association.

We extracted summary statistical data of Hb concentration and ALS from genome‐wide association studies (GWAS), performed Mendelian randomization (MR) analyses, and conducted RNA sequencing of motor neurons different from ALS patient‐derived induced pluripotent stem cells (iPSCs), followed by an intersection analysis between differentially expressed genes (DEGs) in ALS motor neurons and selected instrumental variables (IVs) associated with Hb concentration.

As a result, Hb concentration had a negative causal relationship with the risk of ALS, established through IVW (OR = 0.854; 95% CI: 0.767–0.951; p = 0.00418) of the univariable MR analysis. A multivariable MR further confirmed that this causal link remained robust, even when accounting for confounders including systolic blood pressure, total cholesterol levels, body mass index, LDL cholesterol, diastolic blood pressure, and smoking. Importantly, genetically predicted ALS did not show a causal connection to Hb concentration. Additionally, RNA sequencing analysis and qRT‐PCR results revealed that transcripts for BACH1 and FLVCR1 were upregulated, while those for TRIM58 were downregulated in SOD1
D90A ALS motor neurons, compared to the control. In motor neurons differentiated from a sporadic ALS patient‐derived iPSCs, qRT‐PCR showed increased transcript levels of BACH1, and decreased transcript levels of FLVCR1 and TRIM58. These three genes were intersected with harmonized SNPs between Hb concentration and ALS.

Our study concludes that genetically predicted Hb concentration exhibited an independent inverse causal association with the risk of developing ALS, with potential involvement of genes such as BACH1, FLVCR1, and TRIM58.

This study identified a causal relationship between genetically predicted hemoglobin (Hb) concentration and amyotrophic lateral sclerosis (ALS) through Mendelian randomization (MR), and integrated RNA‐seq and RT‐qPCR analyses to highlight BACH1, FLVCR1, and TRIM58 as potential genes involved in this association.