Genetics of ALS

Abstract

The cause of ALS is unknown but it is thought that environmental exposures and genetic predisposition play a role in susceptibility to the disease. A family history of ALS is obtained in about 5% but the distinction between familial and apparently sporadic ALS is artificial and genetic factors play a role in all types. Large effect Mendelian genes account for 75% of inherited forms and about 10% of those with no obvious family history. It is not always possible to establish the mode of inheritance in each pedigree and not all familial cases may suffer from a genuine Mendelian disorder. Over ten different subtypes of familial ALS are distinguished of which the majority is inherited in an autosomal-dominant pattern: only mutations in SOD1, TARDBP, ANG, C9orf, VCP and FUS are associated with typical ALS the remainder are associated with unusual phenotypes or have been described in small numbers of kindreds. The clinical and pathological presenta tion of familial ALS is very similar to that of sporadic cases. Twin studies show that the heritability of apparently sporadic ALS is about 0.61 (0.38, 0.78). We are making great progress in the goal to identify all ALS genes, and the improvements in genetic, statistical, pathological and computing methods, and the willingness of the research community to collaborate and share large datasets have all contributed to the current successes. Future progress will require detailed phenotyping, population-based samples rather than clinic-based samples, and detailed epidemiological data to allow well-powered geneenvironment interaction studies.