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Aim: The present study aimed to evaluate association of genetic variants on drug response and therapy optimization parameters in patients treated with first-line antiepileptic drugs (AEDs). Genetic variants from ion channels, their functionally related genes, and synaptic vesicle cycle (SVC) genes with a potential role in epilepsy pathophysiology were thus prioritized., Methods: A total of 12 genes from ion channels and related gene set and seven genes from SVC comprising 155 SNPs were genotyped and evaluated with drug response, dose levels, and drug levels in 408 patients with epilepsy., Results: Both GABRA1 and SCN1A variants showed haplotypic and diplotypic associations in response to phenytoin (PHT). Diplotype analysis of GABRA1 variants revealed association of rs12658835|rs7735530 (AG/AG) (P-valuecorrected  = 0.034, OR = 3.75, 95% CI = 1.36-11.05) and rs12658835|rs7735530|rs7732641|rs2279020 (AGCA/AGCA) (P-valuecorrected  = 0.035, OR = 2.48, 95% CI = 0.96-6.41) with recurrent seizures. SCN1A haplotype rs6432860|rs3812718 (AC: P-valuecorrected  = 0.022, OR = 2.72, 95% CI = 1.39-5.35) and diplotype (AC/AC: P-valuecorrected  = 0.034, OR = 6.42, 95% CI = 1.10-65.76) were further observed to be associated with recurrent seizures. With respect to therapy optimization parameters, we observed significantly lower dose-adjusted drug levels at maximum dose of PHT in patients carrying AC/AC diplotype (P-value = 0.021)., Conclusion: The results further substantiate the role of GABRA1 in PHT mode of action and contribution of SCN1A in response and therapy optimization with PHT monotherapy., (© 2016 John Wiley & Sons Ltd.)

Literature indicates key role of glutamatergic pathway genes in antipsychotic response among schizophrenia patients. However, molecular basis of their underlying role in antipsychotic response remained unexplained. Thus, to unravel their molecular underpinnings, we sought to investigate interactions amongst GRM3, SLC1A1, SLC1A2, SLC1A3, SLC1A4 gene polymorphisms with drug response in south Indian schizophrenia patients. We genotyped 48 SNPs from these genes in 423 schizophrenia patients stratified into low and high severity of illness groups. The SNPs and haplotypic combinations of associated SNPs were examined for their association with antipsychotic response. Multifactor-dimensionality-reduction was further used to explore gene-gene interaction among these SNPs and 53 SNPs from previously studied genes (BDNF, RGS4, SLC6A3, PI4KA, and PIP4K2A). Single SNP and haplotype analyses revealed no significant association with drug response irrespective of severity of illness. Gene-gene interaction analyses yielded promising leads, including an observed synergistic effect between PI4KA_rs165854 and GRM3_rs1468412 polymorphisms and incomplete antipsychotic response in schizophrenia patients with low severity of illness (OR = 12.4; 95%CI = 3.69-41.69). Further, this interaction was also observed in atypical monotherapy (n = 355) and risperidone (n = 260) treatment subgroups (OR = 11.21; 95%CI = 3.30-38.12 and OR = 13.5; 95%CI = 3.03-121.61 respectively). PI4KA is known to be involved in the biosynthesis of phosphatidylinositol-4, 5-bisphosphate which regulates exocytotic fusion of synaptic vesicles (glutamate, dopamine) with the plasma membrane and regulates duration of signal transduction of GPCRs. Whereas GRM3 regulates glutamate and dopamine transmission. Present findings indicate that PI4KA and GRM3 polymorphisms have potential to jointly modulate antipsychotic response. These results warrant additional replication studies to shed further light on these interactions., (© 2014 Wiley Periodicals, Inc.)

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.

Aims: It is hypothesized that functionally relevant polymorphisms in genes encoding metabolizing enzymes of sex steroids may influence drug response by directly predisposing women with epilepsy to seizure exacerbation. An alteration in estradiol:progesterone ratio is believed to play a role in seizure occurrence in women. CYP1A1 is a key enzyme involved in the metabolism of estradiol, with variants of the CYP1A1 gene having been reported to play a role in the alteration of sex hormone metabolism in women. The objective of the present study was to test for the association of genetic variants in CYP1A1 with seizure recurrence in patients diagnosed with epilepsy., Materials & Methods: In the study, the association of five variants in CYP1A1 with seizure control in 228 patients with epilepsy on first-line antiepileptic drug therapy for a minimum period of 12 months was investigated., Results: A significant association of an intronic SNP, IVS1 +606C>A (rs2606345), with respect to seizure recurrence (genotypic: p = 3.3 × 10(-4); allelic: p = 7.2 × 10(-4); OR: 2.86; 95% CI: 1.5-5.3) in women with epilepsy from North India was observed., Conclusion: Since CYP1A1 is not involved in the metabolism of any of the first-line antiepileptic drugs, these results imply that variants from genes encoding sex hormone metabolizing enzymes might act as markers for predicting response to antiepileptic drug therapy in women with epilepsy.

Aim: We investigated the catechol-O-methyltrasferase (COMT) gene, which is a strong functional and positional candidate gene for schizophrenia and therapeutic response to antipsychotic medication., Materials & Methods: Single-locus as well as detailed haplotype-based association analysis of the COMT gene with schizophrenia and antipsychotic treatment response was carried out using seven COMT polymorphisms in 398 schizophrenia patients and 241 healthy individuals from a homogeneous south Indian population. Further responsiveness to risperidone treatment was assessed in 117 schizophrenia patients using Clinical Global Impressions (CGI). A total of 69 patients with a CGI score of 2 or less met the criteria of good responders and 48 were patients who continued to have a score of 3 and above and were classified as poor responders to risperidone treatment., Results: The association of SNP rs4680 with schizophrenia did not remain significant after adjusting for multiple testing. Haplotype analysis showed highly significant association of seven COMT marker haplotypes with schizophrenia (CLUMP T4 p-value = 0.0001). Our results also demonstrated initial significant allelic associations of two SNPs with drug response (rs4633: chi(2) = 4.36, p-value = 0.036, OR: 1.80, 95% CI: 1.03-3.15; and rs4680: chi(2) = 4.02, p-value = 0.044, OR: 1.76, 95% CI: 1.01-3.06) before multiple correction. We employed two-marker sliding window analysis for haplotype association and observed a significant association of markers located between intron 1 and intron 2 (rs737865, rs6269: CLUMP T4 p-value = 0.021); and in exon 4 (rs4818, rs4680: CLUMP T4 p-value = 0.028) with drug response., Conclusion: The present study thus indicates that the interacting effects within the COMT gene polymorphisms may influence the disease status and response to risperidone in schizophrenia patients. However, the study needs to be replicated in a larger sample set for confirmation, followed by functional studies.