Research Highlights: Highlights from the latest articles in pharmacogenomics
of antipsychotics
Eugene Lin1,2, Hsien-Yuan Lane1,3
1Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan 2Vita Genomics, Inc., 7 Fl., No. 6, Sec. 1, Jung-Shing Road, Wugu Shiang, Taipei, Taiwan 3Departments of Psychiatry, China Medical University Hospital, Taichung, Taiwan
Corresponding author: Hsien-Yuan Lane E-mail addresses: [email protected] Phone: +886-921067260
Financial & competing interests disclosure
This work was funded by Vita Genomics, Inc., the National Science Council, Taiwan (NSC-101-2314-B-039-030-MY3 and NSC-101-2325-B-039-009), Department of Health Clinical Trial and Research Center of Excellence in Taiwan (DOH102-TD-B-111-004), and China Medical University Hospital, Taiwan (CMU 101-AWARD-13, DMR-100-117 and DMR-100-119).
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Genetic association of the
NDUFS1 gene with antipsychotic-induced weight
gain in schizophrenia
Evaluation of: Gonçalves VF, Zai CC, Tiwari AK et al. A hypothesis driven
association study of 28 nuclear-encoded mitochondrial genes with antipsychotic-induced weight gain in schizophrenia. Neuropsychopharmacology 2013 Nov 7. [Epub ahead of print] (2013).
Schizophrenia represents one of the most devastating mental ailments and affects about one percent of the population in all cultures. It is a complex polygenic and multi-factorial mental disorder, and the mainstay of treatment for schizophrenia is antipsychotic medication [1-4]. However, a wide inter-individual variability exists in the response to antipsychotic treatments [1-4]. More and more genetic markers associated with antipsychotic drug response in schizophrenia are being discovered [5-8]. Accumulating evidence in pharmacogenomics studies reveals that some single nucleotide polymorphisms (SNPs) could be employed as genetic variants to predict clinical drug response for antipsychotic drugs in patients with schizophrenia using the genome-wide association study
(GWAS) and the candidate-gene approach [5-8]. Pharmacogenomics studies may provide an approach to fulfill the promise of personalized medicine by tailoring treatment based on individual variations of SNPs and genetic markers [5-8].
To explore the potential of the nuclear-encoded mitochondrial genes that affect drug response for antipsychotics, Gonçalves and colleagues monitored whether schizophrenia patients’ genotypes in 28 genes were associated with antipsychotic-induced weight gain [9]. A total of 283 schizophrenia patients, who received atypical medications for up to 14 weeks, were genotyped [9]. Gonçalves and colleagues found that the rs6435326 SNP in the NADH dehydrogenase Fe-S protein 1 75kDa (NDUFS1) gene was associated with antipsychotic-induced weight gain in patients with schizophrenia [9]. They also observed a significant gene-gene interaction between the NDUFS1 rs6435326 SNP and the rs3762883 SNP in the COX18 cytochrome C oxidase assembly factor (COX18) gene [9]. Furthermore, there were significant effects detected in analyses of the replication study of the rs6435326, rs1053517, and rs1801318 SNPs in the NDUFS1 gene [9].
This study uncovers a novel mechanism of the nuclear-encoded mitochondrial genes such as the NDUFS1 gene on antipsychotic-induced weight gain. This study is limited to a single genetic model of weight gain in schizophrenia. It remains to be seen if whether other
antipsychotic side effects such as metabolic syndrome share the same mechanism. It will be interesting to learn whether other genetic or pharmacological models of side effects in schizophrenia are subjected to the similar genes. Future studies will help to better understand the mechanisms of the nuclear-encoded mitochondrial genes on other antipsychotic-induced side effects.
References
1. Picchioni MM, Murray RM. Schizophrenia. BMJ 335(7610), 91-5 (2007).
2. Buckley PF, Miller BJ, Lehrer DS, Castle DJ. Psychiatric comorbidities and schizophrenia. Schizophr. Bull. 35(2), 383-402 (2009).
3. Lin E, Tsai SJ. Gene-gene interactions in a context of individual variability in antipsychotic drug pharmacogenomics. Current Pharmacogenomics and Personalized
Medicine 9(4), 323-331 (2011).
4. van Os J, Kapur S. Schizophrenia. Lancet 374(9690), 635-45 (2009).
5. Lane HY, Lee CC, Liu YC, Chang WH. Pharmacogenetic studies of response to risperidone and other newer atypical antipsychotics. Pharmacogenomics 6(2), 139-149 (2005).
schizophrenia. Psychiatry Clin. Neurosci. 65(1), 3-19 (2011).
7. Lin E, Tsai SJ. Novel diagnostics R&D for public health and personalized medicine in Taiwan: current state, challenges and opportunities. Current Pharmacogenomics and
Personalized Medicine 10(3), 239-246 (2012).
8. Lin E. Novel drug therapies and diagnostics for personalized medicine and nanomedicine in genome science, nanoscience, and molecular engineering. Pharmaceutical
Regulatory Affairs: Open Access 1:e116 (2012).
9. Gonçalves VF, Zai CC, Tiwari AK et al. A hypothesis driven association study of 28 nuclear-encoded mitochondrial genes with antipsychotic-induced weight gain in schizophrenia. Neuropsychopharmacology 2013 Nov 7. [Epub ahead of print] (2013)
Genetic association of the MTHFR gene with antipsychotic-induced weight
gain in schizophrenia
Evaluation of: Srisawat U, Reynolds GP, Zhang ZJ et al. Methylenetetrahydrofolate
reductase (MTHFR) 677C/T polymorphism is associated with antipsychotic-induced weight gain in first-episode schizophrenia. Int J Neuropsychopharmacol 2013 Nov 13 [Epub ahead of print] (2013).
It has been reported that the methylenetetrahydrofolate reductase (MTHFR) gene is associated with antipsychotic drug-induced weight gain in patients with schizophrenia [1]. Two of the most investigated polymorphisms in the MTHFR gene are the functional C677T (rs1801133) and A1298C (rs1801131) SNPs.
To address possible effects of the MTHFR gene in antipsychotics drug response, Srisawat and colleagues examined whether two functional C677T and A1298C SNPs in the
MTHFR gene were associated with antipsychotic-induced weight gain [2]. Two cohorts of
first-episode, initially drug-naive Chinese (n = 182) and Spanish (n = 72) schizophrenia patients, who received antipsychotics for 10 weeks and 3 months respectively, were genotyped [2]. Srisawat and colleagues found that the 677C/T SNP in the MTHFR gene
was associated with antipsychotic-induced weight gain in patients with schizophrenia in both Chinese and Spanish samples [2]. They also identified an additive effect between the
MTHFR 677C/T SNP and the -759C/T SNP in the 5-hydroxytryptamine receptor 2C
(HTR2C) gene [2]. However, there was no evidence of association between the MTHFR 1298A/C SNP and antipsychotic-induced weight gain in the sample population [2].
It is intriguing that two functional SNPs (677C/T and 1298A/C) in the MTHFR gene predict antipsychotic-induced weight gain in patients with schizophrenia. This will require further study. Limitation of the small size of the sample does not allow drawing definite conclusions. In future work, large prospective clinical trials are necessary to answer whether these two functional SNPs are associated with antipsychotic-induced weight gain. It would also be interesting to investigate other SNPs within the MTHFR gene.
References
1. Kuzman MR, Müller DJ. Association of the MTHFR gene with antipsychotic-induced metabolic abnormalities in patients with schizophrenia. Pharmacogenomics 13(8), 843-6 (2012).
2. Srisawat U, Reynolds GP, Zhang ZJ et al. Methylenetetrahydrofolate reductase (MTHFR) 677C/T polymorphism is associated with antipsychotic-induced weight gain
in first-episode schizophrenia. Int J Neuropsychopharmacol 2013 Nov 13 [Epub ahead of print] (2013).
Genetic association of the SLC6A3 and COMT genes with
antipsychotic-induced extrapyramidal adverse effects in schizophrenia
Evaluation of: Zivković M, Mihaljević-Peles A, Bozina N et al. The association study
of polymorphisms in DAT, DRD2, and COMT genes and acute extrapyramidal adverse effects in male schizophrenic patients treated with haloperidol. J Clin Psychopharmacol 33(5):593-9 (2013).
Extrapyramidal symptoms are movement adverse effects of antipsychotic medication. It has been reported that extrapyramidal symptoms of antipsychotic drugs are linked with the dopamine receptor D2 (DRD2), catechol-o-methyl transferase (COMT), and dopamine transporter (SLC6A3) genes in patients with schizophrenia [1-4].
To explore the potential of the dopaminergic system genes that affect drug response for antipsychotics, Zivković and colleagues investigated whether schizophrenia patients’ genotypes at the DRD2 Taq1A (rs1800497), COMT Val158Met (rs4680), and SLC6A3 variable number tandem repeat (VNTR) variants were associated with extrapyramidal symptoms [5]. A total of 240 male schizophrenia patients, who received haloperidol over a period of 2 weeks, were genotyped [5]. Zivković and colleagues found that the SLC6A3
VNTR and COMT Val158Met variants were associated with antipsychotic-induced extrapyramidal symptoms in patients with schizophrenia [5]. However, there was no statistically significant association between the DRD2 Taq1A polymorphism and extrapyramidal symptoms [5].
This study reveals a novel mechanism of the SLC6A3 VNTR and COMT Val158Met variants on antipsychotic-induced extrapyramidal symptoms for schizophrenia patients treated with haloperidol. This study is limited to a single genetic model of extrapyramidal symptoms in schizophrenia. It remains to be seen if whether other antipsychotic side effects such as metabolic syndrome share the same mechanism. It will be interesting to learn whether other genetic or pharmacological models of side effects in schizophrenia are subjected to the similar genes. Future studies will help to better understand the mechanisms of the SLC6A3 VNTR and COMT Val158Met variants on other antipsychotic-induced side effects.
References
1. Lane HY, Lee CC, Liu YC, Chang WH. Pharmacogenetic studies of response to risperidone and other newer atypical antipsychotics. Pharmacogenomics 6(2), 139-149 (2005).
2. Cacabelos R, Hashimoto R, Takeda M. Pharmacogenomics of antipsychotics efficacy for schizophrenia. Psychiatry Clin. Neurosci. 65(1), 3-19 (2011).
3. Lin E, Tsai SJ. Novel diagnostics R&D for public health and personalized medicine in Taiwan: current state, challenges and opportunities. Current Pharmacogenomics and
Personalized Medicine 10(3), 239-246 (2012).
4. Lin E. Novel drug therapies and diagnostics for personalized medicine and nanomedicine in genome science, nanoscience, and molecular engineering. Pharmaceutical
Regulatory Affairs: Open Access 1:e116 (2012).
5. Zivković M, Mihaljević-Peles A, Bozina N et al. The association study of polymorphisms in DAT, DRD2, and COMT genes and acute extrapyramidal adverse effects in male schizophrenic patients treated with haloperidol. J Clin
