The causes of mental disorders are often unclear, making prevention difficult and delaying development of better treatment alternatives. The latest genetic studies (genome-wide association studies, GWAS) have successfully detected genetic variants associated with schizophrenia [1], but only a small fraction of heritability can be explained using the GWAS approach. Other types of analyses (gene-set/pathway-based methods) are promising in providing a biologically oriented bridge between genetic variants and disease [2,3]. However, most of them place constraints on the size of the gene-set (set of genes that share some common feature), which may exclude information about specific molecules that have an important function in the brain, such as ion channels.
Ion channels are proteins on the cell membrane that are involved in diverse physiological processes, including release of signaling substances in the brain [4]. Ion channels are large molecules (macromolecules), and most of them contain several subunits. Perturbations on any of their subunits may contribute to disease. It is interesting to investigate how ion channels are associated with mental disorders. These subunits are physically binding together, but their encoding genes are localized far away or even on different chromosomes. It will help to find more risk factors when we consider differently located channel genes as a set.
In my project, a molecule-based genetic association study was designed. By considering the composition of ion channel subunits, biologically meaningful gene-sets are defined and investigated. During the early stage of the study, the results suggest that abnormalities of specific ion channels (calcium channels) may play an important role in the pathophysiology of schizophrenia. More genetic variants with weak or moderate effects could be identified when combining such molecule information with gene data. In the later stage, more ion channel types and other psychiatric disorders will be investigated. We hope molecule-based genetic association studies offer more power for discovery and natural connections to biological mechanisms of mental disorders. The interesting ion channels could represent appropriate drug targets for therapeutics.
References
1. Ripke S, Neale BM, Corvin A, Walters JTR, Farh KH, Holmans PA, et al. Biological insights from 108 schizophrenia-associated genetic loci. Nature 2014; 511(7510): 421-427.
2. Ramanan VK, Shen L, Moore JH, Saykin AJ. Pathway analysis of genomic data: concepts, methods, and prospects for future development. TRENDS in Genetics 2012; 28(7): 323-332.
3. Wang K, Li M, Hakonarson H. Analysing biological pathways in genome-wide association studies. Nature Reviews Genetics. 2010; 11(12): 843-854.
4. Simms BA, Zamponi GW. Neuronal voltage-gated calcium channels: structure, function, and dysfunction. Neuron 2014; 82(1): 24-45.