DRD2 Gene Polymorphisms in Schizophrenia Patients

Zieske Maritska

, Miranti Dwi Hartanti

, Benediktus Wicaksono Widodo

, Fitri

, Bintang

Arroyantri Prananjaya

, Irsan Saleh

4 f

and Nita Parisa

Department of Biology Medicine, Faculty of Medicine, Universitas Sriwijaya, Palembang, Indonesia

Department of Psychiatry, Faculty of Medicine, Universitas Sriwijaya, Palembang, Indonesia

Department of Pharmacology, Faculty of Medicine, Universitas Sriwijaya, Palembang, Indonesia

Department of Biomedicine, Faculty of Medicine, Universitas Sriwijaya, Palembang, Indonesia

Keywords: DRD2, Dopamine Receptor, Schizophrenia, Polymorphisms

Abstract: Schizophrenia is one of the most common mental health issues worldwide, affecting millions of people.

Schizophrenia is a multifactorial condition with many risk factors, including genetics. Recent studies on the

genetic factors underlying schizophrenia have focused on the genes such as the DRD2 gene that regulate

dopamine function. The dopaminergic system plays a pivotal role as a modulator of affective and cognitive

functions. Dopamine is a catecholamine that acts on the central nervous system and is inhibitory or excitatory,

depending on the dopamine receptors activated. DRD2 is the main presynaptic receptor of the dopaminergic

system. Polymorphisms of the DRD2 gene are known as risk factors for the occurrence of schizophrenia.

Some of the known DRD2 gene polymorphisms that play a pivotal role in the incidence of schizophrenia are

the Taq1A, -141C Ins/Del, and C957T polymorphisms. We summarize the effects of these polymorphisms

on the risk of schizophrenia in different populations.

1 INTRODUCTION

Schizophrenia is a major global health problem. In

2017, 1.1 million people worldwide were affected by

schizophrenia. About 70% of the cases occur in

individuals within the age group of 25-55 years

(James et al., 2018). Globally, the prevalence of

schizophrenia is estimated at 0.28% of the population

(Charlson et al., 2018). The prevalence of

schizophrenia in Indonesia has reached 1.7 incidents

per 1,000 individuals according to Penelitian and

Pengembangan (2013).

Polymorphisms of the dopamine receptor DRD2

gene have been identified as a risk factor for

schizophrenia. Single nucleotide polymorphisms

(SNPs) at this receptor can also play a role in the

https://orcid.org/0000-0002-4904-0703

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https://orcid.org/0000-0003-1459-7015

effectiveness of antipsychotics and influence their

side effects (Ye et al., 2019). These SNPs are

determining factors for clinical symptoms as well

(Vijayan et al., 2007).

Dopamine (DA) is a catecholamine that acts on

the central nervous system, and is inhibitory or

excitatory, depending on the activated dopamine

receptors (Pradnyawati, 2017). DRD2 is the main

presynaptic receptor of the dopaminergic system. The

DRD2 gene in humans resides on chromosome

11q22-23 and is 270 kb in size. Several DRD2

polymorphisms related to schizophrenia have been

identified (He et al., 2013). The Taq1A

polymorphism causes a decrease in the ability to

inhibit behavior and impairs the activation of the

brain's frontal lobe. The -141C Ins/Del polymorphism

and the C957T mutation are also considered as risk

Maritska, Z., Hartanti, M., Widodo, B., Fitri, ., Prananjaya, B., Saleh, I. and Parisa, N.

DRD2 Gene Polymorphisms in Schizophrenia Patients.

DOI: 10.5220/0010489101390142

In Proceedings of the 1st Jenderal Soedirman International Medical Conference in conjunction with the 5th Annual Scientiﬁc Meeting (Temilnas) Consortium of Biomedical Science Indonesia

(JIMC 2020), pages 139-142

ISBN: 978-989-758-499-2

139

factors for schizophrenia (Wang et al., 2016; Lawford

et al., 2005).

2 DOPAMINE RECEPTOR D2

Dopamine (3-hydroxytryptamine) is a catecholamine

neurotransmitter that functions as a precursor for the

synthesis of the neurotransmitter norepinephrine. DA

is synthesized from tyrosine in a dual-step process,

wherein tyrosine hydroxylase acts as a rate-limiting

enzyme (Speed, 2010).

The dopamine receptor is a transmembrane

(TM)-7 member of the G protein-coupled receptor

(GPCR) family, and consists of five subtypes (DRD1-

DRD5) divided into two major groups, namely the

D1-like receptors and D2-like receptors. Analysis of

the dopamine receptor structure reveals similarities

and differences between the D1-like receptor and D2-

like receptor groups. The D1-like receptors have a -

COOH terminal end that is seven times longer than

that of the D2-like receptors and a third intracellular

loop that is larger than that observed in the D2-like

receptors. DRD1 and DRD5 exhibit 80% similarity in

their TM domains, while DRD2 and DRD3 exhibit

75% similarity, and DRD2 and DRD4 exhibit 53%

similarity in this domain. DRD1 and DRD5 have two

glycosylation sites (N-glycosylation), while DRD2

has four, DRD3 has three, and DRD4 has one such

site (Missale et al., 1998).

DRD2 exhibits negative feedback such that it

causes the release of neurotransmitters when

activated. α -2 receptors are also present on platelets,

and function as mediators in platelet aggregation by

influencing the concentration of the enzyme platelet

adenylosuccinase. In the CNS, post-synaptic

stimulation of α-2 using drugs such as clonidine or

dexmedetomidine increases conduction and

membrane hyperpolarization, which reduces the need

for anesthetics. The TM signal system consists of the

following three parts: (a) the recognition side, (b) the

effector or catalytic side, and (c) the protein

transducing or coupling side. The role of dopamine as

a neuromodulator that promotes psychosis is shown

by the administration of psychostimulant agents that

result in dopamine release. These psychostimulants

can cause psychosis, which can be overcome by

administration of dopamine-blocking agents.

Neuroimaging studies confirm that schizophrenic

patients possess increased dopamine synthesis

(Stoelting, 2005).

As the main presynaptic autoreceptor of the

dopaminergic system, DRD2 is expressed throughout

the DA region of the brain. DRD3, another member

of the same receptor family, inhibits the production of

is cyclic adenosine mono phosphate (cAMP). The

diversity of dopamine receptors expressed at the

given synapses can help determine the response of the

neurons when DA is absent. Furthermore, the

response depends not only on the identity of the

receptors present at the synapse, but also on the

number of receptors (Speed, 2010).

3 THE DRD2 GENE

The human gene DRD2 resides on the 11q22-23

chromosome. It is divided into eight exons, spanning

at least 270 kilobases. Some studies have shown that

D2 antagonists interfere with attributions of value to

rewards and cause decrease in productivity, according

to self-reported responses. Several polymorphisms

have been identified in this gene in the last few

decades, including Taq1A, rs6277, and -141C

Ins/Del. One such polymorphism in this gene is

Taq1A at the locus rs1800497 where cytosine (A2-

allele) is replaced with thymine (A1-allele). Several

studies have explored the association of this

polymorphism with Major Depressive Disorder

(MDD); however, the results are elusive. Other

polymorphisms of the DRD2 gene that have been

studied include -141C Ins/Del (rs1799732) and

C957T (rs6277). Neither SNP displays a connection

to MDD. However, carriers of the SNP C957T variant

with T/T showed more depressive symptoms in the

MDD patients than carriers of other SNPs. Some

potential causes for this disparity could be limited

sample size, ethnic variation, associations with other

mood disorders, and biases in reporting. The

association of the three DRD2 gene polymorphisms

with major depressive disorder in the Chinese

population is inadequately understood (He et al.,

2013).

DRD2 performs specific functions within the

limbic and caudal regions of the brain. Thus, it is a

common target for antipsychotic drugs (Gejman et al.,

2010). The pathophysiology of schizophrenia is also

associated with alterations in dopamine production

and receptor activation (Murray et al., 2008).

Therefore, the DRD2 gene is widely considered as a

causative factor in schizophrenia (Bulayeva et al.,

2007).

The specificity of numerous antipsychotic drugs

such as dopamine receptor antagonists is related to

their capacity to suppress DRD2 activity. Many

antipsychotic drugs, including aripiprazole and

risperidone, strongly block post-synaptic DRD2

activity in the central nervous system, particularly in

JIMC 2020 - 1’s t Jenderal Soedirman International Medical Conference (JIMC) in conjunction with the Annual Scientiﬁc Meeting

(Temilnas) Consortium of Biomedical Science Indonesia (KIBI )

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the mesolimbic and striatal-frontal systems (Sadock,

2008; Katzung, 2018).

4 DRD2 GENE POLYMORPHISM

The two single nucleotide polymorphisms (SNPs) of

the DRD2 gene, Taq1A and -141C Ins/Del

polymorphisms, may be linked to schizophrenia

susceptibility. Several studies have explored the link

between Taq1A polymorphisms and the risk of

developing schizophrenia. However, the outcomes of

these reports are conflicting. Some studies have

shown that the Taq1A polymorphism increases the

risk of developing schizophrenia. Similarly, the -

141C Ins/Del (rs1799732) polymorphism was

deemed to be related to the risk of schizophrenia as

well. However, these findings are inconsistent.

Several similar case-control studies were

conducted to determine the potential role of the

DRD2 gene polymorphisms in the incidence of

schizophrenia. For example, Arinami et al. (1997)

identified a positive correlation for -141C Ins/Del

with susceptibility for schizophrenia. The results of

studies reported by Betcheva et al. (2009) in the

Bulgarian community are consistent with the positive

correlations observed in different Caucasian

populations between the C957T (rs6277)

polymorphism and schizophrenia.

Two variants of G allele, which coincides with

the C allele in both the database and the literature for

the single nucleotide polymorphism, was defined as a

risk allele. After an initial study by Lawford et al.

(2005), which recorded a relationship between rs6277

and schizophrenia in an Australian (Caucasian)

population, three other studies documented markedly

higher frequencies of C alleles and C/C genes in

schizophrenic patients of European origin (natural

populations of Finland, Spain, and Russia). However,

case-control studies using Indian subjects did not

confirm a positive correlation with schizophrenia.

(Kukreti et al., 2006).

Moreover, the findings of two meta-analyses

using data from five studies or a Caucasian

population revealed a relationship between the C

allele and the C/C genotype with a combined odd

ratio of 1.42 (95% confidence interval (CI): 1.26-

1.61) and 1.45 (95% CI: 1.21–1.73), and the OR

estimates for the genotype were 1%. Since all positive

associations are found in European ancestral

populations, the effects of ancestry must be

understood and the genetic effects of this variant

should be tested across populations with different

ancestral descent (Betcheva et al., 2009).

5 CONCLUSIONS

Various studies suggest that Taq1A, -141C Ins/Del,

and C957T polymorphisms in the DRD2 gene play a

major role in the incidence of schizophrenia. They

can affect the pathophysiology and the degree of

severity of clinical symptoms experienced by

patients. Therefore, further studies on the

polymorphisms of the DRD2 gene at Taq1A, -141C

Ins/Del, and C957T are necessary.

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