Integrative genetic analyses illuminates ALS heritability and identifies novel risk genes

Amyotrophic lateral sclerosis (ALS), the major adult onset motor neuron disease, has substantial heritability, in part shared with fronto-temporal dementia (FTD). We show here that ALS heritability is enriched in splicing variants and in binding sites of 6 RNA binding proteins including TDP-43 and FUS. A discovery and replication transcriptome wide association study (TWAS) identified 6 loci associated with ALS, 3 in known ALS loci (C9ORF72, SCFD1, SLC9A8) and 3 novel loci including NUP50 encoding for the nucleopore basket protein NUP50 In our meta-analysis of TWAS cohorts, NUP50 common variant was associated with ALS and to decreased expression of NUP50 in the central nervous system. Independently, we further show association of rare variants in NUP50 with ALS risk (P = 3.71.10-03; odds ratio  = 3.29; 95%CI, 1.37 to 7.87) in a cohort of 9,390 ALS/FTD patients and 4,594 controls. Cells from one patient carrying a NUP50 frameshift mutation displayed a decreased levels of NUP50. Loss of NUP50 leads to neuronal death in cultured neurons, and motor defects in Drosophila and zebrafish models. Thus, our study identifies alterations in splicing in neurons as a critical pathogenic process in ALS, uncovers several new loci potentially contributing to ALS, and provides genetic evidence linking nuclear pore defects to ALS.