Abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of upper and lower motor neurons, resulting in muscle weakness and spasticity, eventually leading to death due to respiratory failure. Analyses by our group of a case-control cohort from an isolated island population have found that genetics plays a significant role in disease etiology (Farrugia Wismayer et al., 2023). In addition to rare variants that cause familial monogenic forms of the disease, genetic variants that are commonly found in the population have also been associated with disease risk. To this end, the latest landmark cross-ancestry genome-wide association study (GWAS) identified multiple risk loci in patients with sporadic ALS or those without a family history of the disease (van Rheenen et al., 2021). Top-ranking loci identified in this study included the Sec1 Family Domain Containing 1 (SCFD1) gene and the uncoordinated 13 homolog A (UNC13A) gene based on association with the rs229195 and rs12608932 variants, respectively. Interestingly, although proteins encoded by SCFD1 and UNC13A have similar functions in vesicle transport and disruption of this pathway is well known to induce motor neuron degeneration (Mead et al., 2022), establishing a relationship between these risk genes and ALS pathophysiology has been challenging. This is nonetheless imperative because risk loci can be therapeutically targeted in a broad spectrum of ALS patients in addition to pre-symptomatic individuals with a higher ALS risk. Notably, recent studies have attempted to discover a potential link between major GWAS-identified risk loci and disease mechanism (Brown et al., 2022; Ma et al., 2022; Borg et al., 2023). For UNC13A, mis-splicing of its messenger RNA (mRNA) transcript in ALS patients was found to result in lower protein levels with serious consequences for synaptic maintenance (Brown et al., 2022; Ma et al., 2022). Making use of a pre-clinical model, we have shown that synaptic deficits and the resulting decline in neuromuscular function can also result from reduced levels of SCFD1 (Borg et al., 2023; Figure 1). Importantly, disease predisposition from loss of UNC13A or SCFD1 function may be intimately linked to protein misfolding and aggregation which remains a hallmark feature of ALS (Mead et al., 2022). Risk variants in the UNC13A locus are thought to be consequential in the absence of functional nuclear TDP-43 (Brown et al., 2022; Ma et al., 2022), a main constituent of cytoplasmic protein aggregates in ALS patients (Mead et al., 2022). A general downregulation of protein folding pathways may explain why the loss of SCFD1 leads to a decline in neuromuscular function (Borg et al., 2023).