Second, variant-level analyses support the existence of substantial pleiotropy, with nearly 75% of the 146 genome-wide significant SNPs influencing more than one of the eight examined disorders. We also identified a set of 23 loci with particularly extensive pleiotropic profiles, affecting four or more disorders. The most highly pleiotropic locus in our analyses, with evidence of association with all eight disorders, maps within DCC, a gene fundamental to the early development of white matter connections in the brain (Bendriem and Ross, 2017). Prior studies showed that DCC is a master regulator of axon guidance (through its interactions with netrin-1 and draxin (Liu et al., 2018). Loss of function mutations in DCC cause severe neurodevelopmental syndromes involving loss of midline commissural tracts and diffuse disorganization of white matter tracts (Bendriem and Ross, 2017; Jamuar et al., 2017; Marsh et al., 2017). A highly pleiotropic effect of variation in DCC on diverse psychiatric disorders with childhood and adolescent onset would be consistent with its role in both early organization of neuronal circuits and the maturation of mesolimbic dopaminergic connections to the prefrontal cortex during adolescence (Hoops and Flores, 2017; Reynolds et al., 2018; Vosberg et al., 2018).
