SCFD1 expression quantitative trait loci in amyotrophic lateral sclerosis are differentially expressed

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Genome-wide association studies (GWAS) identify common variants increasing disease risk.
• Gene regulation via expression Quantitative Trait Loci (eQTLs) is a key mechanism.
• Understanding eQTLs in Amyotrophic Lateral Sclerosis (ALS) is crucial for disease risk and progression insights.

Purpose of the Study:

• To investigate if Single Nucleotide Polymorphisms (SNPs) increase ALS risk through eQTLs.
• To determine if eQTL expression is consistent between ALS patients and controls.
• To identify specific genes and pathways involved in ALS pathogenesis via eQTLs.

Main Methods:

• Summary-data-based Mendelian Randomization (SMR) combining GWAS and eQTL data.
• Genome-wide analysis of eQTL differential expression in post-mortem motor cortex from ALS patients and controls.
• Gene-set analyses to explore correlations with eQTL hotspots and disease risk.

Main Results:

• SCFD1 was identified as the sole genome-wide significant gene mediating ALS risk via eQTLs (SMR P = 4.29 × 10⁻⁶).
• Differential expression of eQTLs was observed between ALS patients and controls, notably involving SCFD1 and VCP.
• SCFD1 eQTLs significantly impacted ALS survival (HR = 1.11, P = 2.06 × 10⁻⁴) and acted as a hotspot for ALS-related gene networks.

Conclusions:

• SCFD1 eQTLs are a major factor in ALS, influencing disease risk and showing differential expression in post-mortem tissue.
• Distinct SCFD1 eQTL profiles in ALS correlate with broader gene networks conferring disease risk and modifying duration.
• The study highlights the critical role of eQTLs in ALS pathogenesis and provides targets for further investigation.