Pharmacogenomics of neuropsychiatric disorders: analysis of genetic variability in 162 identified neuroreceptors using 1000 Genomes Project data

Abstract

Background: Neuroreceptors are considered to be primary drug targets and their abrupt signaling is a notable cause of interindividual drug response variability and treatment failure for complex neuropsychiatric diseases. In view of recent evidence, it is believed that common genetic risk factors mainly highly polymorphic neuroreceptors are being shared among neuropsychiatric disorders. Materials & methods: We identified 162 neuroreceptors from the 639 known receptors in Homo sapiens and investigated 231,683 SNPs using 1000 Genomes Project data and evaluated their biological effect using in silico tools including RegulomeDB, SIFT, PolyPhen-2 and CAROL. Furthermore, data from the 1000 Genomes Project was utilized to retrieve minor allele frequency and calculate pairwise logartithm of the odds score among these SNPs for African, American, Asian and European populations separately as well as when combined together using Haploview v4.2. LRTag was used to identify tagSNPs in populations. Results: A total of 52,381 (22.60%) SNPs were predicted as functionally important genetic variations. We identified sets of 603, 495, 450, 453 and 646 informative tagSNPs for African, American, Asian, European and combined populations, respectively. We propose construction of a 'neuroreceptor variants array' with these informative SNPs for future pharmacogenomic studies of neuropsychiatric disorders. Conclusion: Such an approach might improve genotype–phenotype correlation across different populations and lead to identification of reliable genetic markers and novel drug targets. Integration of these SNPs in literature would further provide evidence relevant to underlying mechanisms of genetics based nosology, pathophysiology and development of new drugs for the treatment of neuropsychiatric disorders. Original submitted 8 March 2013; Revision submitted 22 July 2014