In addition, we evaluated whether the list of historical candidate genes, as a whole, were making a significant contribution to risk of SCZ by evaluating the polygenic score profile. This approach has provided support for an important polygenic contribution to SCZ (Purcell et al., 2009). We created a polygenic score profile for SNPs which mapped to historical candidate genes using the ISC data. We then applied this score to an independent dataset (SCZ GAIN, N=1230 cases and 1136 controls). Independent SCZ cases did not have greater risk scores than controls based on these historical candidate genes (p=0.92). Many hypothesis-driven candidate genes were selected from two over-arching hypotheses, schizophrenia as a synaptic or neurodevelopmental disorder (Table 1). These hypotheses have been incompletely assessed. We used pathway analysis of the ISC data to assess these hypotheses far more completely than has been done previously. The set of 4,808 genes that comprise the synaptic cluster 1 from DAVID did not show over-representation of lower ISC p-values (p-value ~1). This list may be over-inclusive and the candidate genes actually studied might be more refined
