Non-coding genome contribution to ALS.

The majority of amyotrophic lateral sclerosis (ALS) is caused by a complex gene-environment interaction. Despite high estimates of heritability, the genetic basis of disease in the majority of ALS patients are unknown. This limits the development of targeted genetic therapies which require an understanding of patient-specific genetic drivers. There is good evidence that the majority of these missing genetic risk factors are likely to be found within the non-coding genome. However, a major challenge in the discovery of non-coding risk variants is determining which variants are functional in which specific CNS cell type. We summarise current discoveries of ALS-associated genetic drivers within the non-coding genome and we make the case that improved cell-specific annotation of genomic function is required to advance this field, particularly via single-cell epigenetic profiling and spatial transcriptomics. We highlight the example of TBK1 where an apparent paradox exists between pathogenic coding variants which cause loss of protein function, and protective non-coding variants which cause reduced gene expression; the paradox is resolved when it is understood that the non-coding variants are acting primarily via change in gene expression within microglia, and the effect of coding variants is most prominent in neurons. We propose that cell-specific functional annotation of ALS-associated genetic variants will accelerate discovery of the genetic architecture underpinning disease in the vast majority of patients.