Integrative genetic analyses illuminates ALS heritability and identifies novel risk genes

<p>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 (<em>C9ORF72, SCFD1, SLC9A8</em>) and 3 novel loci including <em>NUP50 </em>encoding for the nucleopore basket protein NUP50 In our meta-analysis of TWAS cohorts, <em>NUP50 </em>common variant was associated with ALS and to decreased expression of <em>NUP50 </em>in the central nervous system. Independently, we further show association of rare variants in <em>NUP50</em> with ALS risk (<em>P</em> = 3.71.10^-03; odds ratio&nbsp; = 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 <em>NUP50 </em>frameshift mutation displayed a decreased levels of NUP50. Loss of NUP50 leads to neuronal death in cultured neurons, and motor defects in <em>Drosophila </em>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.</p>