The second most pleiotropic locus in our analysis was identified in an intron of RBFOX1 (RNA Binding Fox-1 Homolog 1) on 16p13.3 (lead SNP rs7193263; Pmeta = 5.59 × 10−11). The lead SNP showed association with all of the disorders except AN (Fig. 3b). RBFOX1 (also called A2BP1) encodes a splicing regulator mainly expressed in neurons and known to target several genes important to neuronal development, including NMDA receptor 1 and voltage-gated calcium channels (Gandal, 2018; Gehman, 2011; Hamada et al., 2015). Knock-down and silencing of RBFOX1 during mouse corticogenesis impairs neuronal migration and synapse formation (Hamada et al., 2015; Hamada et al., 2016), implying its pivotal role in early cortical maturation. In contrast to DCC, however, developmental gene-expression of RBFOX1 showed gradually increasing gene expression throughout the prenatal period (Fig. S3). Animal models and association studies have implicated RBFOX1 in aggressive behaviors, a trait observed in several of the disorders in our analysis (Fernandez-Castillo et al., 2017).
