For MS, the GeneNetwork55 identified 257 unique genes that showed significant co-regulation with genes inside MS-associated loci (Fig. 7d and Supplementary Table 29), many of which were immunity genes, which is also expected for this disease. However, when we used the brain co-regulation networks, we identified a much smaller set of genes that showed strong enrichment for the neurotrophin signaling pathway (Fig. 7e,f). Neurotrophins are polypeptides secreted by immunological cell types and promote the survival and proliferation of neurons as well as synaptic transmission (Supplementary Note). The identified genes showed high expression in immunity-related tissues when using the GeneNetwork55 (Supplementary Fig. 31a) and high expression in the spinal cord but low expression in cortex samples (Supplementary Fig. 31b). This could implicate specific brain regions with MS development: for instance, the cerebellum is involved in muscle coordination and ataxia occurs in approximately 80% of patients with symptoms of MS63. But this could also implicate the ‘outside-in hypothesis’ that suggests the immune system may be a potential trigger for MS29,64.
