For ALS, we applied Downstreamer to summary statistics from individuals with EUR ancestry (Supplementary Table 30) and a trans-ancestry meta-analysis including individuals with EUR and Asian ancestry60 (EUR + ASN; Supplementary Table 25). In contrast, whereas Downstreamer did not identify genes using GeneNetwork55 (n = 31,499), we identified a set of 27 unique co-regulated genes when applied to the smaller brain co-regulation networks (EUR + ASN summary statistics; Fig. 7a and Supplementary Table 25). Of the identified genes, HUWE1 was shared between the results from all brain regions and separate results from cortex, whereas UBR4 was shared between the cortex and cerebellum results. UBR4 encodes a ubiquitin ligase protein expressed throughout the body, which interacts with calmodulin, a protein regulating Ca2+—a process which has been linked to ALS disease-associated genes and motor-neuron vulnerability61. Furthermore, a previously discovered private mutation in UBR4 implicates its role in muscle coordination62. Many of the genes prioritized by Downstreamer are co-regulated with each other (Fig. 7b) and were enriched for genes implicated in causing gait disturbances (Fig. 7c). Our analysis identified genes that show strong co-regulation with positional candidate genes inside ALS-associated loci, suggesting that they must have a shared biological function.
