Molecule-Based Genetic Association Studies On Psychiatric Disorders

Background GWAS have successfully detected genetic variants associated with schizophrenia [Ripke et al., 2014]. However, only a small fraction of heritability can be explained. Gene-set/pathway based methods can overcome limitations arising from single SNP-based analysis, but most of them place constraints on size which may exclude highly specific and functional sets [Ramanan et al., 2012], like macromolecules. Ion channels, belonging to macromolecules, are created by polymerization of several subunits whose encoding genes are located far away or even on different chromosomes. We combined such molecules information with GWAS genotype data to investigate how functional channels associated with psychiatric disorders. Methods We defined a biologically meaningful gene-set based on channel structure and performed association study applying the SNP-set (Sequence) Kernel Association Test [Wu et al., 2010] to the Psychiatric Genomics Consortium (PGC) genotype data from bipolar disorder and schizophrenia. Results In the first stage of study (Voltage-gated calcium (Cav) channels vs schizophrenia), we identified 8 out 9 subtypes of Cav channels significantly associated with schizophrenia, including the L-type channels (Cav1.1, Cav1.2, Cav1.3), P-/Q-type Cav2.1, N-type Cav2.2, R-type Cav2.3, T-type Cav3.1 and Cav3.3. Only genes from Cav1.2 and Cav3.3 have been implicated by the largest GWAS (N = 82,315). In the second stage of study, more ion channels (K+ channels, Na+ channels, …) have been analyzed and data from bipolar disorder was investigated. The results will be presented. Discussion The results suggest that abnormalities of Cav channels may play an important role in the pathophysiology of schizophrenia. Analyzing subunit-encoding genes of a macromolecule in aggregate is a more powerful approach to identify the genetic architecture of polygenic diseases. Molecule-based genetic association study offers the potential of power for discovery and natural connections to biological mechanisms of psychiatric disorders. Significant channels may represent appropriate drug targets for therapeutics.