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Association of Genetic Variants of Dopamine and Serotonin Receptors With Schizophrenia
Association of Genetic Variants of Dopamine and Serotonin Receptors With Schizophrenia
ORIGINAL ARTICLE
Association of Genetic Variants of Dopamine and Serotonin Receptors with
Schizophrenia
Roksana Zakharyan,a,b Hovsep Ghazaryan,c Lenka Kocourkova,d Andranik Chavushyan,c
Artur Mkrtchyan,e Veronika Zizkova,d Arsen Arakelyan,a,b and Martin Petrekd
a
Institute of Molecular Biology NAS RA, Yerevan, Armenia
b
Russian-Armenian, University, Yerevan, Armenia
c
Andranik Chavushyan, Institute of Molecular Biology NAS RA, Yerevan, Armenia
d
Department of Pathological Physiology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Olomouc, Czech Republic
e
Department of Psychiatry, National Institute of Health, MH RA, Yerevan, Armenia
Received for publication May 3, 2019; accepted December 16, 2019 (ARCMED_2019_393).
Background. Several studies indicated that antipsychotic treatment response and side ef-
fect manifestation can be different due to inter-individual variability in genetic variations.
Aim of the study. Here we perform a case-control study to explore a potential association
between schizophrenia and variants within the antipsychotic drug molecular targets
(DRD1, DRD2, DRD3, HTR2A, HTR6) and metabolizing enzymes (CYP2D6, COMT)
genes in Armenian population including also analysis of their possible relationship with
disease clinical symptoms.
Methods. A total of 18 SNPs was studied in patients with schizophrenia (n 5 78) and
healthy control subjects (n 5 77) using MassARRAY genotyping. Results: We found that
two studied genetic variants, namely DRD2 rs4436578*C and HTR2A rs6314*A are un-
derrepresented in the group of patients compared to healthy subjects. After the correction
for multiple testing, the rs4436578*C variant remained significant while the rs6314*A
reported borderline significance. No significant differences in minor allele frequencies
for other studied variants were identified. Also, a relationship between the genotypes
and age of onset as well as disease duration has been detected.
Conclusions. The DRD2 rs4436578*C genetic variant might have protective role against
schizophrenia, at least in Armenians. Ó 2019 IMSS. Published by Elsevier Inc.
Key Words: Association, Schizophrenia, Genetic variant, Antipsychotic treatment, Dopamine,
Serotonin, Metabolizing enzyme.
0188-4409/$ - see front matter. Copyright Ó 2019 IMSS. Published by Elsevier Inc.
https://doi.org/10.1016/j.arcmed.2019.12.011
14 Zakharyan et al./ Archives of Medical Research 51 (2020) 13e20
antipsychotic treatment predictive tests such as Ampli- in the study, which was approved by the Ethical Committee
chipÒ CYP450 Test, DMETÔ Plus Panel, the GeneceptÔ of the Institute of Molecular Biology of the National Acad-
Assay, the Genomas HILOmet PhyzioTypeÔ System, and emy of Sciences RA (IRB #00004079).
the GeneSightÒ Test based on the genes involved in drug
metabolism such as cytochrome P450 family enzymes,
Collection of Blood Samples and Genomic DNA
were validated and introduced (14). These tests are mainly
Extraction
designed based on the knowledge about polymorphisms
and their rates in populations present in the 1000 Genomes A total of 5 mL of the EDTA anticoagulated venous blood
and HapMap projects, and thus, the accuracy of these ge- was collected from each patient and healthy control subject.
netic tests in other, specific populations is unknown. Impor- Genomic DNA was isolated from peripheral blood leuko-
tantly, up to date there is no published data about the cytes according to the modification of salting out method
prevalence of those mutations in Armenians. with a simple introduction of chloroform step and stored
Here we perform a case-control study to explore a poten- at ‒30 C until further use at the Laboratory of Human Ge-
tial association of genetic variants within the antipsychotic nomics and Immunomics, Institute of Molecular Biology of
drug molecular targets (DRD1, DRD2, DRD3, HTR2A, the National Academy of Sciences RA. For all extracted
HTR6) and metabolizing enzymes (CYP2D6, COMT ) with DNA samples measurements of concentrations and purity
schizophrenia in Armenian population and their possible have been performed. Only highly purified samples with
relationship with disease clinical symptoms. A260/A280 ratio within the 1.8e2.0 range and concentra-
tion more or equal to 10 ng/ul were enrolled in this study.
The working concentration was adjusted if applicable to
10 ng/ul using dilution of initial samples.
Materials and Methods
Study Population SNP Selection in Candidate Genes
In this study 78 patients with schizophrenia and 76 healthy Single nucleotide polymorphisms (SNPs) within the genes
control subjects were enrolled. Clinical and demographic coding for dopamine (DRD1, DRD2, DRD3) and serotonin
data of the subjects enrolled in shown in Table 1. All pa- receptors (HTR2A, HTR6) as well as antipsychotic drug
tients were unrelated individuals of Armenian nationality metabolizing enzymes CYP2D6 and COMT have been
recruited from the National Center of Mental Health Care selected based on either SNP-drug response association re-
of the Ministry of Health of the Republic of Armenia ported in the Clinical Pharmacogenetics Implementation
(MH RA) and Department of Psychiatry of the Yerevan Consortium (PharmKB, http://www.pharmgkb.org/page/
State Medical University. The diagnosis of paranoid schizo- cpic) database or based upon previously determined associ-
phrenia was made by two independent experienced psychi- ations with treatment response in candidate-gene and/or
atrists, according to the presence of the relevant symptoms genome wide association studies (1e3,5e8,16,17). Initial
(ICD-10 code: F20.0) (15). All patients were treated with selection resulted in 42 SNPs (Supplementary Table 1).
typical and/or atypical antipsychotics. Healthy control sub- We performed initial evaluation of minor allele fre-
jects were recruited among the blood donors of the Hema- quency (MAF) for these 42 polymorphisms based on the
tology Center after prof. R. Yolyan MH RA. Exclusion GWAS dataset on 99 available Armenian subjects (18). A
criteria for all study subjects included any serious neurolog- total of 21 SNPs were not annotated in microarray chip
ical, endocrine, oncological, inflammatory, autoimmune, used in the initial publication, so we obtained MAF data
cerebrovascular, cardiovascular, metabolic or other disor- for them from 1000 Genomes European population using
der. All subjects gave their informed consents to participate LDlink application for exploring population-specific
variant and haplotype structure (19). Next, we selected
Table 1. Clinical and demographic data of subjects involved in the SNPs with MAF greater or equal 0.1. Finally, using
current study SNPclip module of the LDlink software we have pruned
the list of variants to retain the most representative ones
Parameter SCZ Controls
(R2 threshold for LD pruning 5 0.5) resulting in 12 SNPs.
Number of subjects involved 78 76 To this list, 6 SNPs were further added based on functional
Age (N s), years 48.9 11.7 38.1 10.8 effect demonstration using various functional assays (20).
Minimal age 20 23
Finally, an assay control panel containing 4 SNPs of the
Maximal age 70 65
Male/female 60/18 33/44 CYP2D6 gene, namely, rs28371725 (with common allele
Age of disease first manifestation 29.0 9.8 - CYP2D6*41), rs16947 (common allele CYP2D6*17),
(N s), years rs3892097 (common allele CYP2D6*4), and rs1065852
Duration of disease (N s), years 19.9 12.0 - (common allele CYP2D6*10) was also used. The resulting
Family history of schizophrenia 36/42 -
SNP panel and their minor allele frequencies in 1000
Dopamine and Serotonin Receptors in Schizophrenia 15
Genomes or healthy Armenians are presented in the /plink –noweb –file data/data –no-parents –no-sex
Supplementary Table 2. –allow-no-sex –adjust –logistic –covar data/data.cov
Assuming dominant model:
Assay Design, PCR Amplification and Genotyping
/plink –noweb –file data/data –no-parents –no-sex
The panel construction and genotyping were performed ac- –allow-no-sex –adjust –logistic –dominant –covar
cording to the protocol described elsewhere (21). Briefly, an data/data.cov
input list of 18 selected SNP IDs (rsSNP of each target) was
Assuming recessive model:
provided and the following steps were performed: (a) the
sequence for each rsSNP was retrieved from database and /plink –noweb –file data/data –no-parents –no-sex
formatted accordingly, (b) the proximal SNPs for each –allow-no-sex –adjust –logistic –recessive –covar
rsSNP were identified from database, (c) optimal primer data/data.cov
areas were identified that result in a unique amplicons con-
Where data.ped, data.map and data.fam contains geno-
taining a target for the extension primer. To avoid extension
types and case-control status information, and data.cov con-
primer rejection due to insufficient known bases, the prox-
tained gender and age information as covariates. Adjusted p
imal base was replaced with inosine. (d) Finally, PCR and
*/-values !0.05 were considered significant. The power of
extension primers were designed and checked for false
association under different models was calculated using
priming, hairpin/dimer formation. The primer multiplexes
‘‘genpwr’’ R package (23).
with mass separation of analytes (alleles) were created.
In order to evaluate the association between studied
For PCR amplification and single base extension (SBE) re-
SNPs and treatment prescription, drug dosages were con-
action, the primer pairs along with the extension primers
verted into haloperidol and risperidone equivalents using
were designed using Assay design suite v2.0. All primers
a standardized method for comparing exposure to various
used in this study are presented in Supplementary Table 3.
antipsychotic medications of first- and second-generation
These primers were multiplexed and genotyped using
(24). Quantitative trait association with drugs as well as
Sequenom MassARRAY platform integrating iPLEXÒ
age of onset and disease duration was performed using
SBE reaction and MassARRAYÒ technology (Agena
PLINK quantitative trait linear association (22). Linkage
Bioscience, San Diego, CA, USA). The assay consists of
disequilibrium (LD) between investigated loci were calcu-
an initial locus-specific PCR amplification followed by
lated using SNP analyzer 2.0.
SBE using mass-modified dideoxynucleotide terminators
of an oligonucleotide primer that anneals immediately up-
stream of the target polymorphic site. The distinct mass Results
of extended primer traces the alternative alleles using Mas-
Case-control Association Study
sARRAY Typer 4.0.20. For quality control (QC) step, we
determined data missing rate per individuals and missing Here we studied antipsychotic drug response-associated 22
rate per SNP. Also, for QC of SNP genotyping, positive SNPs in the drug molecular targets and metabolizing enzymes
and negative template control samples were included in genes in patients with schizophrenia and healthy subjects.
each assay plate. As a positive control a commercially Genotyping was not successful and low signal was ob-
available DNA was used, while purified water serves as a tained for four SNPs (COMT rs165599, COMT rs933271,
negative control. DRD2 rs1076560, and HTR2A rs6311) out of all studied.
The distribution of genotypes of 17 SNPs complied with
HWE both in the patients with and controls, while CYP2D6
Statistical Analysis
rs1135840 was not (Supplementary Table 4). Genotyping of
The distribution of genotypes in cases and controls for each control panel was successful in all samples.
SNP was tested for correspondence ( p O0.05) to Hardy- A logistic regression analysis was performed using three
Weinberg equilibrium (HWE) by Pearson’s c2 test. Disease different models (additive, recessive, dominant). Two out of
trait SNP association was tested using logistic regression 17 studied SNPs were associated with schizophrenia
model with age and gender included as covariates. Analysis (Table 2). Further information for 15 remaining genetic var-
assuming additive, dominant and recessive models was per- iants is shown in Supplementary Tables 5e7.
formed. For multiple testing adjustment Bonferroni, and After multiple corrections only DRD2 gene
Benjamini & Hochberg metrics were used. All calculations rs4436578*C variant remained significant while the
were performed using PLINK whole genome association rs6314*A showed borderline significance. We found that
analysis toolset version 1.09 (22). Logistic regression anal- this variant is associated with schizophrenia in Armenians
ysis accounting for additive, dominant and recessive and might have a protective effect against the disease.
models was calculated with following options: LD values for all studied SNPs are presented in the
Assuming Additive Model: Supplementary Table 8. According to the data obtained,
16 Zakharyan et al./ Archives of Medical Research 51 (2020) 13e20
Table 2. Association table for the DRD2 gene rs4436578 and HTR2A genetic variants using additive, dominant and recessive models adjusted for age and
gender
Chr.N SNP Location Minor Model NMISS OR SE 95% CI Stat p BONF FDR_BH
11 rs4436578 113436043 C additive 154 0.23 0.45 0.10e0.56 3.27 0.0001 0.02 0.02
11 rs4436578 113436043 C dominant 154 0.20 0.49 0.08e0.51 3.33 0.0009 0.02 0.02
11 rs4436578 113436043 C recessive 154 0.30 1.80 0.01e10.36 0.66 0.51 1.00 1.00
13 rs6314 46834899 A additive 154 0.28 0.49 0.11e0.73 2.59 0.01 0.17 0.09
13 rs6314 46834899 A dominant 154 0.23 0.55 0.08e0.67 2.68 0.01 0.13 0.07
13 rs6314 46834899 A recessive 154 0.27 1.60 0.01e6.29 0.81 0.42 1.00 1.00
Odds ratios (OR), standard error (SE), 95 CI%, Bonferroni and FDR-corrected p-values are presented.
strong linkage between the rs6280 and rs167771 (chr.3), positive symptom improvement and positive symptom
rs1079597 and rs1079598 (chr.11), rs2020917 and remission in schizophrenia (28). The C allele carriers had
rs5993883 (chr.22). The strongest association for the decreased risk of gastrointestinal toxicity in patients with
rs1065852 and rs3892097 (chr.22) was detected. Parkinson’s disease treated with levodopa (29) while in
Chinese patients this genotype was associated with
Association of Prescribed Treatment with the Genotypes decreased response to pramipexole (30). In Slovenian pa-
Obtained tients the DRD2 gene rs1799732 (studied here) and
DRD3 gene rs6280 variants weren’t associated neither with
The patients enrolled were treated with a variety of drugs clinical symptoms nor the occurrence of treatment-resistant
including quietapine, triphtazin, haloperidol, clozapine, schizophrenia during antipsychotic treatment (31). These
fluphenazine, levomepromazine combined with anxiolytics. differences might appear due to the fact that relatively
To make abovementioned correlations between standard low dosages of the prescribed antipsychotics, converted to
homozygotes and minor allele carriers (if applicable) for risperidone or variability between populations.
studied SNPs, all dosages prescribed by psychiatrist(s) were
converted to haloperidol equivalents using a standardized
method for comparing exposure to various antipsychotic Association with Clinical Data
medications of first- and second-generation (24). Our anal- Relationship between the clinical-demographic data of pa-
ysis showed that only when comparing the mean treatment tients and studied parameters has been performed. Correla-
dosage of haloperidol for rs6280 CC homozygotes vs. T tion analysis carried out has identified that the genotypes
allele carriers, a significant difference was obtained are linked to the disease onset and duration. In particular,
(2.49 0.64 mg/d vs. 1.04 0.36 mg/d, p 5 0.039). we found that the rs6314*A minor allele and
Further, the mean dosages prescribed were converted to ris- rs5030655*del are positively correlated with disease dura-
peridone equivalents and potential associations with geno- tion ( p 5 0.03 and 0.11, respectively). Positive correlations
types (standard homozygotes vs. minor allele carriers and between the age of schizophrenia onset and lorazepam pre-
standard allele carriers vs. minor homozygotes) using the scribed ( p 5 0.033), family history of schizophrenia
same method was explored. None of the genotypes obtained ( p 5 0.045) and the 5HTR6 rs1805054*T allele
was associated with the converted risperidone dosages ( p ( p 5 0.009) were detected.
O0.05). According to the literature data available, there
is no study on the relationship between the rs6280 geno-
types and treatment response to haloperidol in schizo-
Discussion and Conclusions
phrenia patients. However, it was shown that
schizophrenia patients with CC genotype had poorer Pharmacogenetic approaches are widely used in the devel-
response to clozapine compared with TT genotype (25). oped countries to achieve the most optimal treatment
Also, this genetic variant was associated with the DRD1 response reducing disease symptoms and minimizing mani-
rs686 polymorphism in the same study (25). In patients festation of side effects (1). Such genetic factors as variants
with autism, Correia CT, et al. for the first time reported for drug metabolizing enzymes and molecular targets, play
that the rs6280 C allele had greater symptom improvement an important role in individual response and treatment effi-
and increased response to risperidone (26) whereas another cacy (2). Therefore, studies focused on the identification of
study indicated decreased intolerability of methylphenidate pharmacogenetic markers that contribute and predict anti-
(27). Also, predictors of clinical improvement with risperi- psychotic treatment response might assist the development
done therapy among the HTR2A c.‒1438G OA, DRD3 of genetically-driven approaches for moving to a personal-
Ser9Gly, HTR2C c.995G OA, and ABCB1 1236C OT ized medicine particularly in schizophrenia research.
polymorphisms were found (26). In case of treatment with In this study we assessed the potential association of
olanzapine, CC was previously associated with greater schizophrenia with 18 SNPs within the antipsychotic drug
Dopamine and Serotonin Receptors in Schizophrenia 17
molecular targets and enzymes and found that the DRD2 response to treatment (43). Later with bigger sample size
gene rs4436578*C allele might have a protective effect and additional polymorphisms enrolled they showed no as-
against this disease and the HTR2A gene rs6314*A variant sociation of Taq1A and HTR2A ‒1438 G/A, 102T/C and
might have borderline significance. HTR2C ‒759 C/T with antipsychotic response to risperi-
Growing evidence suggest that molecular mechanisms done (44). For the same polymorphism Takase M, et al.
responsible for dopamine transmission are altered in a num- (2017) has recently found a relationship between Del car-
ber of psychiatric disorders including schizophrenia (32). riers and high-dose pharmacotherapy in schizophrenia (45).
Dopamine dysregulation together with glutamate, GABA, Previously, a rs1076560 regulatory polymorphism of the
acetylcholine, and serotonin alterations are involved in DRD2 gene has been identified as a genetic risk factor for
schizophrenia during different stages of the disease (32). Ac- schizophrenia and has been involved in schizophrenia inter-
cording to the dopamine theory of schizophrenia, hyperac- mediate phenotypes in the meta-analysis (46). Concerning
tivity of DRD2 receptor neurotransmission in subcortical the second positive finding of this study, a meta-analysis
and limbic brain regions is responsible for positive symp- has indicated the rs6311 (‒1438A/G) polymorphism of the
toms of this disease, while negative and cognitive symptoms HTR2A gene as a risk factor for schizophrenia but not major
are related to the hypoactivity of DRD1 receptor neurotrans- depressive or bipolar disorders (47). Importantly, the depen-
mission in the prefrontal cortex (33). Besides, DRD2 antag- dence of association from the ethnic origin of the study pop-
onism was considered as an essential pharmacological target ulation has been detected (47). No association of another
for antipsychotic drugs, therefore, affecting its therapeutic SNP (rs6313, T102C) of the same gene has been found in
efficacy depending on their inhibitory potency (34). The Chinese large samples with schizophrenia, bipolar disorder,
pioneer study by Carlsson and Lindqvist propose dopamine and major depressive disorder (48). While no allele or geno-
receptor blockade by chlorpromazine and haloperidol (35). type association has been detected, the combination of the
The increased subcortical release of dopamine leads to the HTR2A gene rs6311/rs6313 polymorphisms shows to predict
manifestation of disease positive symptoms such as halluci- negative symptoms performance in case of aripiprazole treat-
nations and delusions, most probably, through a disturbed ment in schizophrenia patients (49). Recently, rs6313*C
cortical pathway (36). A recently performed gene-gene inter- allele carriers were considered as having higher risk of
action analysis has identified a significant four-way interac- schizophrenia development in Greek patients with schizo-
tion of SNPs included DRD2 gene rs4436578 with verbal phrenia (50). Nisenbaum LK, et al. (2016) has found that
fluency in healthy subjects (37). the HTR2A gene rs7330461 TT genotype is consistently
It has been reported that among others the DRD2 gene associated with an increased treatment response to pomaglu-
rs4436578 SNP has an effect on antipsychotic drug- metad methionil compared to the AA genotype in Caucasian
induced weight gain in long-term treated schizophrenia pa- patients with schizophrenia (51). So far, rs1124491 and
tients and that the rs4436578 CC together with C allele con- rs9567733 SNPs of the DRD2 and HTR2A genes, respec-
taining haplotype have been considered as a risk factor for tively, have been linked to the risk of antipsychotic
weight gain (38,39). treatment-induced extrapyramidal syndrome (52). Pelka-
So far, Kaur G, et al. (2017) has studied the effect of the Wysiecka J, et al. (2013) has shown that more (31 vs.
DRD2, 5HT2A, and CYP2D6 gene polymorphisms on 17%) Val/Val homozygous of the COMT gene rs4680 SNP
response to risperidone in Indian patients with schizo- were found in the non-deficit schizophrenia (NDS) compared
phrenia (40). It has been shown that the presence of certain to the deficit schizophrenia subgroup suggesting that these
genotypes of the DRD2 and 5HT2A in patients are more genetic factors must be taken into account when analyzing
likely associated with non-response to risperidone (40). the reasons for the differentiation of schizophrenia subtypes
Also, it has been shown that the DRD2 Taq1A (53). Study of COMT-DRD4 interaction indicated that
(rs1800497 C OT) genotype has no effect on the number schizophrenia patients carrying Met allele and one or two
of cigarettes smoked per day by patients with schizophrenia DRD4 120 bp alleles had better response to clozapine (54).
but female smokers with GG genotype smoked more So far, an association of the CYP2D6*4 1846G OA genetic
compared to A allele carriers (41). Another SNP, C957T variant and CYP2D6 AA genotype with tardive dyskinesia in
(rs6277), within the same gene has been linked to the exec- chronic schizophrenia patients has been detected (55).
utive functioning and early life stress. In particular, it has To date, a number of studies were focused on the assess-
been detected that rs6277 CC homozygotes have signifi- ment of disease onset as a potential predictor of schizo-
cantly reduced performance in spatial working memory, phrenia on clinical outcome. However, contradictory data
planning, and those with early life stressful experience were obtained, suggesting both positive and negative
exhibit impaired performance in the processing test (42). impact (56e58). Menezes NM, et al. later concluded that
Alladi CG, et al. (2017) has studied schizophrenia patients age of onset have no effect on clinical outcome (59). How-
treated with risperidone during 4e8 weeks and has found ever, in original long-term studies, earlier age at onset has
that the DRD2 gene ‒141C (rs1799732) Del carriers are been associated with lower probability of symptomatic
significantly associated with increased prolactin levels in remission (57) and having more hospital admissions after
18 Zakharyan et al./ Archives of Medical Research 51 (2020) 13e20
over 10 years since onset (60). Even with these inconsistent reported in PharmKB database or based upon previously
findings, it is not uncommon that in clinical textbooks onset determined associations with treatment response in
early in life is regarded as a predictor for a poorer outcome. candidate-gene and/or genome wide association studies
Concerning the pharmacogenetic results, we have found mentioned in the manuscript. Finally, the important role
that in case of DRD3 rs6280, DRD1 rs265981, and DRD2 of other genetic variants without the same genes not studied
rs1079598 genotypes the prescribed treatment was in here must be additionally tested to extend the existing
concordance with the recommended ones according to the knowledge on contributory genetic factors of
clinical database. The application of pharmacogenetic schizophrenia.
approach widely used in the developed countries nowadays
in mostly under development in low and middle income
countries such as Armenia. Here, psychiatrists usually use Declaration of Absence of Conflicts of Interest
trial-error approach in order to find the most appropriate Authors declare no conflict of interests.
treatment maximally suppressing disease symptoms and
minimizing the manifestation of side effects. The compari-
son of the prescribed and recommended treatments Acknowledgments
described above suggested that, in fact, psychiatrists recom- This work was supported in part by RVO: 61989592 and projects
mend the most optimal treatment but using a time- reg. no. IGA PU: LF_2017_014/2019_009, targeted research proj-
consuming approach instead of genetically-driven one. ect ‘‘Genetic mapping of Armenian pathogenome (1-18/TN)’’,
Impairments in the dopamine system result from dopa- State Committee of Science, Ministry of Education and Science,
mine dysfunctions in the substantia nigra, ventral tegmental Republic of Armenia. This work was partly made possible by a
region, striatum, prefrontal cortex, and hippocampus. The research grant from the Armenian National Science and Education
‘‘original dopamine hypothesis’’ states that hyperactive Fund (PI: Andranik Chavushyan, ANSEF # molbio-5342) based in
dopamine transmission results in schizophrenic symptoms. New York, USA.
Blockage of dopamine receptors by chlorpromazine and
haloperidol is the basic concept in psychiatry, and it has
been shown that the positive symptoms of schizophrenia Supplementary Data
(hallucinations, delusions) are related to increased subcor-
Supplementary data related to this article can be found at
tical release of dopamine (61,62). The HTR2A gene
https://doi.org/10.1016/j.arcmed.2019.12.011.
rs6314*A (Tyr) allele has been previously showed lowered
antipsychotic binding affinity and decreased drug potency.
Further, it has been detected that Tyr allele was significantly
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