ALS-Specific GWAS Challenges

Amyotrophic Lateral Sclerosis (ALS) is the most common late-onset motor neuron disorder, but our current knowledge of the molecular mechanisms and pathways underlying this disease remains elusive. Genome-Wide Association Studies (GWAS) aim to identify Single Nucleotide Polymorphisms (SNPs) and other types of genetic variation that are more frequent in patients than in people without the disease, using a variety of statistical tests. Despite the rapid recent technological advances and great efforts in the GWAS field that have led to the genomic profiling of large ALS cohorts, the identified associations have been able to explain only a very small fraction of the ALS heritability and aetiology. Here, we outline ALS-Specific GWAS Challenges, explaining the limitations of traditional GWAS analyses, considering known features of the ALS genetic architecture and hypotheses about ALS pathology (e.g., multilocus interactions, rare variations with low effect size). Future advances in the genomic and machine learning fields may bring about a better understanding of ALS genetic architecture and enable improved personalized approaches to this and other devastating and complex diseases.