For large-scale genomics studies, the level of investment that is often required can cast doubt over their justification, particularly in diseases for which only a minority of patients exhibit a clear family history. One such disease is amyotrophic lateral sclerosis (ALS), which has a discernible family history in 5% to 15% of cases with the remainder termed sporadic ALS. Nevertheless, genetic risk factors are widely considered to contribute to sporadic ALS, a tenet that is reinforced by the observation that familial ALS mutations often cause sporadic forms of the disease. However, despite increasingly large genome-wide association studies aimed at identifying risk loci, a substantial proportion of sporadic and familial ALS cases remain to be explained by genetic risk factors and the question of the “missing heritability” of ALS is therefore an ongoing focus of intensive international research.