Unraveling the missing heritability of amyotrophic lateral sclerosis: should we focus more on copy number variations?

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive degeneration of upper and lower motor neurons in the brainstem and spinal cord, leading to muscle weakness, paralysis, and respiratory failure (Morgan and Orrell, 2016). Despite identifying many genes associated with ALS risk and pathogenesis, a discrepancy exists between heritability estimates based on familial studies (40%–60%) (Al-Chalabi et al., 2010) and heritability estimates derived from genetic data (5%–10%) (Megat et al., 2023), such as those obtained through Genome- Wide Association Studies. This discrepancy, termed “missing heritability,” fuels ongoing debate and likely stems from ALS’s complex genetic architecture, limitations of current genetic research, unidentified genetic and epigenetic factors, environmental influences, random chance, and potential biases in family and twin study heritability estimates (Van Damme, 2018).