In contrast to the differences in neuronal development and neuronal signaling pathways, pleiotropic and non-pleiotropic risk loci shared several characteristics related to genomic function. For instance, gene-set enrichment analyses indicated that both pleiotropic and non-pleiotropic risk loci were enriched for genes involved in the regulation of synaptic plasticity, neurotransmission, and synaptic cellular components. More than 41% of the genes associated with our genome-wide significant loci, both pleiotropic and non-pleiotropic, were intolerant of loss of function mutations (pLI score ≥ 0.9); this is highly unlikely to occur by chance (Fisher’s exact p=4.90×10−8). This finding was consistent when examining pleiotropic (p=2.85×10−11) and non-pleiotropic risk loci (p=1.56×10−3) separately.
