Increasing statistical power through a gene-based GWAS of the gSEM summary statistics identified two novel GWS genes for OA: PPP6C and FURIN. PPP6C (Protein Phosphatase 6 Catalytic subunit gene) is a component of a signaling pathway that regulates cell cycle progression known to be involved with the immune system and cancer (https://www.uniprot.org/uniprot/O00743#function). However, the gene is also strongly expressed in a variety of adult human brain tissues (Supplementary Fig. 17c) and is linked to abnormal locomotor behavior in mice (http://www.informatics.jax.org/diseasePortal/genoCluster/view/2062856). Predicted biological processes for PPP6C include G-protein coupled purinergic nucleotide receptor signaling pathway (GO:0035589) (https://maayanlab.cloud/archs4/gene/PPP6C), which affects regulation of neurons, microglia and astrocytes57. Predicted genetically driven differential expression of PPP6C by OA was significant across several brain regions, and colocalization analysis of PPP6C cis-eQTLs and the OA-variant association signal at this locus also showed a high probability of being driven by a shared single variant. Because the PPP6C-centered association locus extends into the nearby genes SCAI and RABEPK, and significant predicted genetically driven differential expression of SCAI was also observed, we cannot exclude the possibility that these other genes play
