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The genetic basis of sporadic amyotrophic lateral sclerosis (ALS) is not well understood. Using large genome-wide association studies and validated tools to quantify genetic overlap, we systematically identified single nucleotide polymorphisms (SNPs) associated with ALS conditional on genetic data from 65 different traits and diseases from >3 million people. We found strong genetic enrichment between ALS and a number of disparate traits including frontotemporal dementia, coronary artery disease, C-reactive protein, celiac disease and memory function. Beyond C9ORF72, we detected novel genetic signal within numerous loci including GIPC1, ELMO1 and COL16A and confirmed previously reported variants, such as ATXN2, KIF5A, UNC13A and MOBP. We found that ALS variants form a small-world co-expression network characterized by highly inter-connected 'hub' genes. This network clustered into smaller sub-networks, each with a unique function. Altered gene expression of several sub-networks and hubs was over-represented in neuropathological samples from ALS patients and SOD1 G93A mice. Our collective findings indicate that the genetic architecture of ALS can be partitioned into distinct components where some genes are highly important for developing disease. These findings have implications for stratification and enrichment strategies for ALS clinical trials.

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