in identification of functionally important SNPs. For single-GWAS analysis of BPD, GPA was able to identify SNPs located in the ANK3 gene. By using annotation data, the CACNA1C gene, which encodes an alpha-1 subunit of a voltage-dependent calcium channel, was identified by GPA. After incorporating pleiotropy information between SCZ and BPD, additional functionally relevant genes, such as PBRM1, C6orf136, DPCR1, SYNE1, were identified by GPA. For instance, SYNE1 encodes the synaptic nuclear envelope protein 1, and codes the protein Syne-1 that is found in many tissues and is especially critical in the brain. The Syne-1 protein is active (expressed) in Purkinje cells, which are located in the cerebellum and are involved in signaling between neurons. Mutations in the SYNE1 gene have been found to cause autosomal recessive cerebellar ataxia type 1 (ARCA1) and SYNE1 has recently been implicated as a susceptibility gene for BPD in a large collaborative GWAS study [35]. Clearly, the present results indicate that the statistical power to identify associated SNPs increased by making use of pleiotropy and functional annotation (in this real data example, pleiotropy played a more important role than functional annotation).
