There is a strong genetic contribution to Amyotrophic lateral sclerosis (ALS) risk, with heritability estimates of up to 60%. Both Mendelian and small effect variants have been identified, but in common with other conditions, such variants only explain a little of the heritability. Genomic structural variation might account for some of this otherwise unexplained heritability. We therefore investigated association between structural variation in a set of 25 ALS genes, and ALS risk and phenotype. As expected, the repeat expansion in the C9orf72 gene was identified as associated with ALS. Two other ALS-associated structural variants were identified: inversion in the VCP gene and insertion in the ERBB4 gene. All three variants were associated both with increased risk of ALS and specific phenotypic patterns of disease expression. More than 70% of people with respiratory onset ALS harboured ERBB4 insertion compared with 25% of the general population, suggesting respiratory onset ALS may be a distinct genetic subtype.
There is increasing evidence that endogenous retroviruses (ERVs) play a significant role in central nervous system diseases, including amyotrophic lateral sclerosis (ALS). Studies of ALS have consistently identified retroviral enzyme reverse transcriptase activity in patients. Evidence indicates that ERVs are the cause of reverse transcriptase activity in ALS, but it is currently unclear whether this is due to a specific ERV locus or a family of ERVs. We employed a combination of bioinformatic methods to identify whether specific ERVs or ERV families are associated with ALS. Using the largest post-mortem RNA-sequence datasets available we selectively identified ERVs that closely resembled full-length proviruses. In the discovery dataset there was one ERV locus (HML6_3p21.31c) that showed significant increased expression in post-mortem motor cortex tissue after multiple-testing correction. Using six replication post-mortem datasets we found HML6_3p21.31c was consistently upregulated in ALS in motor cortex and cerebellum tissue. In addition, HML6_3p21.31c showed significant co-expression with cytokine binding and genes involved in EBV, HTLV-1 and HIV type-1 infections. There were no significant differences in ERV family expression between ALS and controls. Our results support the hypothesis that specific ERV loci are involved in ALS pathology.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.