from dopaminergic genes to psychiatric disorders

Individual vulnerability to develop neurological and psychiatric disorders is associated with both genetic and environmental factors. Association studies in patients have explored the contribu-tion of gene variants in the dopaminergic system in these disorders. This system is involved in motor control, endocrinological function, the reward system and cognition. The diverse physi-ological functions of dopamine are mediated by five different dopamine receptors, encoded by the genes DRD1, DRD2, DRD3, DRD4 and DRD5. These genes have various types of poly-morphisms that can produce changes in the genetic product or expression levels. In recent years, the development of new technologies for genetic analysis, and a wider comprehension of the genetic sequences of these genes have increased our understanding of the implications of the dopaminergic system in both health and pathological states. It has also allowed the iden-tification of genetic variants that may represent risk or protection factors for a variety of psychi-

atric disorders.

Keywords: Dopamine; Dopamine genes; Psychiatric disorders; DRD1; DRD2; DRD3; DRD4; DRD5; Genes; Genetic analysis; Environment; Reward; Cognition; ADHD; Attention deficit hyperactivity disorder; Schizophrenia; Bipolar disorder; Drug abuse

GENES AND FREQUENT PSYCHIATRIC DISORDERS

The genetic cause of many disorders with Mendelian-type inheritance can be clearly deter-mined by studying families containing several affected individuals, because dominant or recessive relationships between alleles of a single gene estab-lishes the clinical phenotype. Still, the challenge is the understanding of the genetic basis of frequent psychiatric disorders present in the general popula-tion, such as schizophrenia, bipolar disorder and drug use and abuse, that exhibit a complex pattern of inheritance, where the disease is the result of the contribution of multiple genes' variants, that on there own would usually produce a minor effect; and their interaction with the environment. This interaction establishes a continuous gradient of clinical phenotypes and pharmacological treatment responses in the affected population. The sequenc-ing of the human genome and the development of massive genotyping techniques are providing the necessary tools for the development of case-control association studies of candidate genes containing the genetic variants or polymorphisms. Genetic polymorphisms are variations in the primary structure of DNA nucleotide sequence that can lead to a modification in the expression levels of the gene or in a functional variation of the encoded

F.P. Graham Publishing Co.

From Dopaminergic Genes to Psychiatric Disorders

JANET HOENICKAa,*,†, MARÍA ARAGÜÉSa,†, GUILLERMO PONCEa, ROBERTO RODRÍGUEZ-JIMÉNEZa,

MIGUEL A. JIMÉNEZ-ARRIEROa and TOMÁS PALOMOa

aUnidad de Conductas Adictivas, Servicio de Psiquiatría, Hospital Universitario 12 de Octubre, Av. de Córdoba s/n, Madrid 28041, Spain; bDepartamento de Bioquímica, Facultad de Medicina, Universidad Complutense de Madrid, Av. Complutense s/n, Madrid 28040, Spain; cHospital Gregorio Marañón, Servicios de Salud Mental, Retiro, Madrid 28007, Spain. [email protected]

†These authors contributed equally to this work.

(Submitted 19 October 2005; Revised 24 April 2006; In final form 24 April 2006) Epub ahead of print: December 27, 2006

*Corresponding author. Tel.: +34-913908022; FAX: +34-913908538; E-mail: [email protected] 1029 8428 print/ ISSN 1476-3524 online. © 2007 FP Graham Publishing Co., www.NeurotoxicityResearch.com

Neurotoxicity Research, 2007, VOL. 11(1). pp. 61-71

J. HOENICKA et al.62 DOPAMINE GENES AND PSYCHIATRIC DISORDERS

protein. For instance, in the brain these variations can be directly related to changes in the neuron proteome (group of proteins present in these cells), which can lead to changes in structure, function and/or response of specific neural circuits during development or in the adult. The small individual differences in the genetic sequence represent the biological basis that confers either susceptibility or protection to a specific disease. The genetic mark-ers most frequently used at the moment are single nucleotide polymorphisms (SNPs) that are defined in a specific position in the genome where two or more nucleotide bases are present in the popula-tion with a frequency greater than 1%. The appeal of SNPs lies in that they are very abundant in the genome, they have a low mutational rate, they can cause visible effects in genotype expression, and that their genotyping can be automated. However, SNP analysis is still limited due to the fact that it's still unknown which ones and how many must be studied to determine if a relationship exists between a given disorder and gene variations. For these rea-sons, genotyping of several polymorphisms within a single candidate gene has been incorporated to the human molecular genetic analysis of a particular gene, consequently allowing haplotype identifica-tion and study. A haplotype is made up of the alleles of a gene's polymorphisms which tend to be inherited in block. This means that the alleles of a haplotype are not segregated by recombination events and therefore are transmitted as a whole; as such, it is possible to detect combinations of variations that might be implicated in the phenotype. In the human genome, haplotypes tend to cover a distance of approxi-mately 60,000 base pairs (bp) and contain up to 60 SNPs that are transmitted in block from parents to offspring. Recently, more or less variable haplotype regions along the human genome of a particular population have been identified. The HapMap International Project is currently studying these genetic varia-tions; their purpose is to build a haplotype map, or "HapMap" of the human genome, and determine if there are haplotype variations within different pop-ulations. The study of haplotypes can be used as a tool for the identification of genes and their variants implicated in different pathologies. The principle of genetic mapping by means of haplotypes assumes that a mutation present in a specific disease always

appears in the population within an existing haplo-type, called an "ancestral haplotype". This ances-tral haplotype can undergo recombination events across several generations, which can alter the combinations of the polymorphism's alleles of a gene. Nevertheless, the mutation/polymorphism and nearby SNPs will always tend to be transmitted together; therefore, if this haplotype is identified in a group of patients, the genotyping of some of these SNPs may help us recognize the related variation. Since haplotyping detects the variants or alleles of a particular gene, its main advantage in genetic association studies is that it increases the detection power of genetic analyses. This review summarizes the latest and most rel-evant findings in the study of the structure and vari-ants of the genes that encode dopamine receptors whose polymorphisms, as abovementioned, could be related to the expression of a variety of mental disorders. Without doubt this data, insofar it can be replicated and validated, will greatly influence psy-chiatric practice, which will have at hand various biological and molecular markers that might help specify clinical diagnoses or aid in the selection the best pharmacological treatment for a patient. The ultimate objective is to allow the identification of the genes involved in each psychiatric disorder, and the relevant variations in each person's health in terms of vulnerability or protection.

GENES ENCODING DOPAMINE RECEPTORS

The dopaminergic system is involved in motor control, endocrine function, the reward system and cognition. Dopamine's (DA) effects are mediated by its interaction with one of five different DA recep-tor subtypes. These receptors have been grouped in two families - D1-like and D2-like - according to their structure and pharmacological characteris-tics; D1-like family includes receptors D1 and D5, and D2-like family includes receptors D2, D3 and D4. The specific role of each type of receptor in vivo is not completely understood due to the lack of ligands with absolute receptor specificity. Even though both DA receptor families belong to the superfamily of G-protein coupled receptors, they differ in their pharmacological effect: whereas the D1-like receptor family (D1 and D5) is coupled to a G protein that stimulates adenylyl cyclase and

J. HOENICKA et al. DOPAMINE GENES AND PSYCHIATRIC DISORDERS 63

activates a cAMP-dependent protein kinase, the D2-like receptor family is coupled to inhibitory G proteins. Knockout (null) mice models have been generated for each one of the five DA receptors; besides detecting alterations in DA-related func-tions, these mice are viable models that preserve their reproductive function. The pharmacogenomic of DA receptors stud-ies the genetic polymorphisms that encode these receptors, and that could be potentially involved in disease vulnerability or in the individual response to pharmacological treatments. Numerous phar-macogenomic studies of the genes that encode DA receptors, have explored the existence of possible associations between polymorphisms present in these genes and the development of neurological and psychiatric disorders. Figure 1 shows the struc-ture of the genes that encode the five DA receptors: DRD1, DRD2, DRD3, DRD4 and DRD5. The following section summarizes the studies published during the last years pertaining to varia-tions in these genes, and also recent association studies from patients with psychiatric disorders.

Dopamine D1 Receptor Gene (DRD1) OMIM126449The DA D1 receptor is the most abundant DA recep-tor in the central nervous system. D1 regulates neu-ronal growth and differentiation, mediates several behavioural responses, and modulates D2 receptor activity. The DRD1 gene that encodes D1 extends from 174,800,643 bp to 174,803,769 bp in chromo-some 5q35.1, and contains two exons (Grandy et al., 1989). The promoter region, located between nucleotides -1.1061 and -1.040, contains multiple transcription initiation sequences. The alternative splicing of this gene results in the expression of two different transcripts. The genetic analysis of the DRD1 sequence has allowed the identifica-tion of various polymorphisms located within the gene; the possible functional consequences of these polymorphisms are still under study. Table I contains general information about several SNPs belonging to the DRD1 gene located in untrans-lated, intronic and codifying regions. The study of the involvement of DRD1 variants in a number of psychiatric disorders has revealed an associa-tion between DRD1 and some addictive disorders,

FIGURE 1 Schematic representation of sense strand for the five DA receptor gene structures. Both intronic and exonic polymorphisms mentioned in the text are given and located in relation to the ATG start codon. Introns are shown as grey boxes and exons as diagonally shaded boxes.


principally pathological gambling and alcoholism (Comings et al., 1997). The recent genotyping of SNPs -1251A/G, -800T/C, -48A/G and 1043T/C (see FIG. 1) in 156 families affected with Attention Deficit/Hyperactivity Disorder (ADHD), allowed the identification of three haplotypes in this specific sample, from which haplotype 3 was transmitted with a significantly higher frequency (measured by Transmission/Disequilibrium Test) from heterozy-gous parents to the affected offspring (Misener et

al., 2004). This finding has been recently replicated by Bobb et al. (2005). In bipolar disorder (BD) the individual and hap-lotypic analysis of SNPs -800T/C, -48A/G and 1043T/C of DRD1 gene from sporadic patients and Canadian families, suggests that the variants of this gene might contribute to disease vulnerability (Ni et al., 2002). An association between BD and the SNP -48A/G has also been found in European patients (Severino et al., 2005). In schizophrenia (EZ), it


has been suggested that a changes in D1 receptor

function could be involved in the development of negative symptoms and the cognitive deficit that these patients display. Even though case/control studies associating DRD1 gene with EZ have not been reported in published literature, cerebral tissue obtained from 15 control, schizophrenic, bipolar, and major depression patients has been studied to compare levels of calcyon, a D1 DA receptor-inter-acting protein. In the study, the EZ group displayed nearly twice the normal levels of calcyon in the dorsolateral prefrontal cortex than the other three groups (Koh et al., 2003). Calcyon regulates DRD1 affinity, meaning that the differences observed in calcyon levels in EZ patients may well be related to the low levels of D1 activity observed in these patients (Koh et al., 2003). Pharmacogenetic and neuroimaging studies in schizophrenic patients treated with clozapine, have demonstrated that a significant association exits between DRD1 geno-types, brain metabolism, and clinical response to clozapine (Potkin et al., 2003).

Dopamine D2 Receptor Gene (DRD2) OMIM126450The DRD2 gene that encodes DA receptor D2, located in chromosome 11q22-23, extends from 112,785,527 bp to 112,851,103 bp, and contains 8 exons (Grandy et al., 1989). Two isoforms are derived from the DRD2 gene: isoform L (post-synaptic) and isoform S (presynaptic). The DRD2 gene has been extensively studied in neurological and psychiatric disorders. Null mice for this gene have a delay in movement onset and lack motor response to psychostimulants. The detailed study

of the DRD2 promoter has allowed the identifica-

tion of Cys elements for some transcription factors, amongst them a RARE (retinoic acid response elements) motif that has been related to EZ vulner-ability (Goodman, 1998). The analysis of DRD2 sequence has demonstrated the existence of various polymorphisms. Some of these are SNPs that alter TaqI (TaqIA, TaqIB, TaqIC and TaqID) restriction enzyme targets. TaqIA SNP (dbSNP rs1800497; g.32806C>T, GenBank AF050737.1), located at 9.5 kilobases in the 3´ untranslated region of the DRD2 gene has been thoroughly studied in alco-holism and other substance abuse disorders. Blum (1990) described the first allelic association of the DA D2 receptor gene in alcoholism; in their study, brain samples from patients with severe alcoholism presented an overexpression of the TaqIA1 allele. Nevertheless, subsequent studies of this poly-morphism in alcoholism and in endophenotypes such as D2 receptor density and cerebral glucose metabolism in central nervous system structures closely linked with prefrontal-cortico-subcortical circuits, have reported contradictory results. The most recent meta-analysis of genetic association studies, which includes 1,837 patients and 1,492 Caucasian controls, reviews the most important investigations involving this SNP, and confirms the genotypic difference that exists between alcoholic and control subjects for this polymorphism. The analysis of the total sample shows that there are statistical differences in TaqIA1/TaqIA1, TaqIA1 /TaqIA2, TaqIA2/TaqIA2 distribution between both groups (p=7.93 x 10-8), allele TaqIA1 being signifi-cantly more frequent (p=2.14 x 10-7), and prevalent (p=1.54 x 10-8) in alcoholic subjects than in con-

FIGURE 2 The genomic organization and selected polymorphisms of DRD2 and ANKK1 genes. DRD2 and ANKK1 gene exons are shown as diagonally shaded boxes and meshed boxes, respectively.


trols (Noble, 2003). A study of clinical and molecular variables in 103 Spanish alcoholic patients carried out in our laboratory, showed that 39% of the subjects were carriers of TaqIA1 allele; 60% of the patients of this subgroup also had an antisocial personality disorder, and 72% a family history of alcoholism (Ponce et al., 2003). These findings suggest the possible existence of common genetic variations influencing susceptibility to both alcoholism and antisocial personality disorder. DRD2 gene has also been related to other addictive disorders, such as cocaine, nicotine and opiate abuse, as well as with obesity (Noble, 2003). Altogether, these findings have lead to consideration of the DRD2 gene as the "reward system gene". Additionally, the study of the 3´-untraslated region of DRD2 has revealed the existence of an adjacent gene that encodes a protein belonging to a signal transduction pathway family of proteins. The gene encodes a protein named ANNK1 that contains a single serine/treonine kinase motif and eleven ankyrin repeat domains (Neville et al., 2004) (FIG. 2). In ANNK1 11th ankyrin repeat domain, TaqIA would produce a substitution of glutamic acid for lysine at position 713, probably leading to a change in function (Dubertret et al., 1998). If this were the case, the biochemical and molecular characteriza-tion of this new protein could be another plausible explanation for the positive findings associated to TaqIA1 allele, not only in addictive disorders, but also in other psychiatric pathologies. Hence, TaqIA may well be a functional polymorphism of a protein different than D2 DA receptor. Table I shows some examples of DRD2 SNPs located in the promoter, intronic or codifying regions. The nucleotide changes that produce a substitution of one amino acid for another in a receptor are well known, but only until recently have some silent SNPs of this gene been studied. Of the C132T, G132T, G423A, T765C, C939T and G1101A SNPs in DRD2, the C957T SNP localized in Pro319 codon, alters messenger RNA conformation and stability, leading to a decrease of DRD2 gene expression (Duan et al., 2003). In this study, C957T polymorphism was in linkage dis-equilibrium in subjects carrying the -141CIns/Del functional polymorphism and TaqIA. These results, indicating that TaqIA is transmitted together with

other functional variations of DRD2, validate the study of this polymorphism in traits that might be associated with this gene. DRD2 gene has also been widely studied in EZ, since the D2 receptor is one of the main pharmaco-logical targets of antipsychotic drugs. Nevertheless, results have been inconsistent and even contradic-tory (Basile et al., 2002). The meta-analysis of 24 independent studies concerning the Cys311Ser polymorphism in patients with EZ, has demonstrat-ed a highly significant association with the Cys311 allele, suggesting that variations in DRD2 may well influence vulnerability to EZ (Glatt et al., 2003). A recent study by Lawford et al. (2005) comprising 153 EZ patients carrying the C957T polymorphism, established that EZ is associated with the homozy-gous C957 genotype. These findings are in agree-ment with preliminary results from our group of a study involving 111 Spanish patients diagnosed with schizophrenia.

Dopamine D3 Receptor Gene (DRD3) OMIM126451 The D3 receptor gene extends from position 115,330,247 to position 115,380,446 bp in chromo-some 3q13.3. DRD3 contains 6 exons and express-es five alternative mRNAs (Schwartz et al., 1993). D3-null exhibits a faster habituation to novel stimuli than wild type mice (McNamara et al., 2002). Of DRD3 polymorphisms, Ser9Gly, located in the receptor's amino-terminal extracellular domain, has been one of the most studied. In scientific literature, Ser9 variant is referred to as allele 1, and Gly9 as allele 2. The functional analysis of Ser9Gly has established that DA receptor binding affinity is significantly higher in Gly9 homozygotes (Lundstrom and Turpin, 1996). The study of the Ser9Gly polymorphism in patients diagnosed with EZ has been carried out in various populations, but the role of this gene's variations in EZ vulnerability is still not clear. Although it has been reported that Ser9Gly is in linkage disequilibrium with other DRD3 gene SNPs, the relationship between the identified haplotypes and schizophrenia is still a matter of debate. A study of three DRD3 SNPs (Ser9Gly, -205G/A, -7685G/C) obtained from a sample of schizophren-ic and schizoaffective patients determined the exis-tence of an overrepresentation of allele -7685C in


an isolated Navarrian population of Basque origin, (Staddon et al., 2005). Haplotype analysis shows the three markers to be in strong linkage disequi-librium (p<0.0001) and strongly associated with this disease (p<1x 10-5). It has also been observed that having a homozygous Ser9 genotype is associ-ated with a worse therapeutic response and more severe executive dysfunctions in patients with EZ (Szekeres et al., 2004). It has been postulated that the DA D3 recep-tor is involved in the development of antipsy-chotic induced tardive dyskinesia in schizophrenic patients; nevertheless, Ser9Gly association studies are inconsistent, since some authors affirm that Ser9 homozygosis (Basile et al., 1999; 2002) and others that Ser9 heterozygosis (Liao et al., 2001), is a risk factor for the development of this move-ment disorder. Also, DRD3 gene polymorphisms have been implicated in impulsivity: In a sample of violent delinquents higher scores in the Eysenck's EIQ and German short version of the Wender Utah Rating Scale (WURS-k) have been observed in Ser9Gly heterozygous individuals, while homozy-gotes had significantly lower rating scores (Retz et al., 2003). On the other hand, a transmission disequilibrium test study of Ser9Gly in 39 ADHD trios did not show a statistically significant asso-ciation (χ2=0.360; df=1; p=0.54) (Muglia et al., 2002). Also, no association has been observed between DRD3 and some addictive disorders, such as alcoholism (Gorwood et al., 2001; Lee and Ryu, 2002) or heroin addiction (Li et al., 2002), whereas it has been observed in cocaine (Comings et al., 1999) and opiate (Duaux et al., 1998), addiction. In schizophrenic patients with lifetime substance abuse comorbidity, Ser9Gly analysis demonstrated that homozygosity for this polymorphism is more frequent in schizo-phrenics with substance abuse than in those that have EZ alone (Krebs et al., 1998).

Dopamine D4 Receptor Gene (DRD4) OMIM126452D4 receptor gene extends from position 627,305 to position 630,703 bp in chromosome 11p15.5 (Gelernter et al., 1992). The gene promoter is immediately adjacent to the initiation codon; a reg-ulatory region can be observed between positions -591 and -123. Exon 3 of DRD4, that encodes a cytoplasmic region of the receptor, contains a poly-

morphism characterized by a varying number of 48-bp repeats in the gene (VNTR: variable number of tandem repeats) (Lichter et al., 1993). Nineteen different 48-bp repeats in 25 different haplotypes, that would encode D4 receptors containing 18 dif-ferent amino acid sequences, have been identified. Although alleles with 2, 4 and 7 repetitions are the most frequent ones, considerable variations exist depending on the population. There is no linear genotypic/phenotypic relation-ship between the VNTR and the functional or phar-macological activity of the receptor. In fact, it has been demonstrated that D4 has a different binding capacity to certain ligands depending on the num-ber of repeats present in the receptor: D4 containing 10 repetitions, has a two-to threefold increase in its binding capacity to adenylyl cyclase than D4 with 2 repetitions; and D4 with 7 repeats binds to this enzyme two-to three times more than D4 with 2 or 4 repeats. Besides the VNTR, several SNPs, a 120 bp functional duplication in the 5´ regulatory region (D'Souza et al., 2004), and multiple small inser-tions and deletions (Sidenberg et al., 1994) have been identified in DRD4. Variants of this gene have been studied in psy-chiatric disorders and certain behavioural traits such as novelty seeking (NS) (Ekelund et al., 1999; Tomitaka et al., 1999), yet the studies' findings are contradictory. A significant number of studies have described a positive association between DRD4 and ADHD, a clinical syndrome related to impulsivity and NS behaviour. The study of DRD4 promoter region SNPs (120 bp insertion/deletion, genetic variants -616, -521, -376) and exon 3 VNTR has revealed a significant association between DRD4 7-repeat allele transmission and ADHD children with comorbid conduct disorders and a family history of ADHD, but no significant relationship with inattentive or hyperactive-impulsive subtypes (Kirley et al., 2004). Also, ADHD children carrying the DRD4 7-repeat allele, require higher doses of methylphenidate to achieve symptomatic and clini-cal improvement (Hamarman et al., 2004).

Dopamine D5 Receptor Gene (DRD5) OMIM126453 The DA D5 receptor gene extends from position 9,459,872 to position 9,461,902 bp in chromo-some 4p15.1-3 (Sherrington et al., 1993). Of all the genes encoding DA receptors, D5 has been the least


studied. Table I, depicts several polymorphisms of this gene. Some polymorphisms, such as Leu88Phe (Feng et al., 1998) have been linked to neuro-leptic-receptor binding capacity, and Asn351Asp with DA-receptor binding. DRD5 knockout mice have decreased motor activity spontaneity and an increased motor response to psychostimulants (Centonze et al., 2003). Also a (CA)n dinucleotide repeat polymorphism closely linked to the DRD5 gene has been associ-ated with ADHD (Daly et al., 1999; Payton et al., 2001; Kustanovich et al., 2004). The analysis of this micro-satellite in 164 trios has confirmed the preferential transmission from parents to affected children of the 148-bp allele (Manor et al., 2004). Data obtained from the study of this polymorphism is also consistent with an association between markers close to the DRD5 gene and schizophre-nia, but not with bipolar disorder or unipolar major depression (Muir et al., 2001).

FINAL CONSIDERATIONS

The recent advances in the technology applied to genomic analysis are creating new pathways for the exploration, study and understanding of the genetic factors involved in behaviour and mental disorders. Although last decade's optimistic previsions have not been completely achieved, human molecular genetic analyses in psychiatric disorders will surely revolutionize clinical practice in several aspects, including:

1. Clinical redefinition of phenotypes2. Understanding of pathologic mechanisms underlying diverse disorders3. Development of new drugs based on the study of specific genes, in order to increase the number of available pharmacological com pounds tailored for each patient 4. Study of each patient's genetic profile to aid in the selection of the pharmacological treatment with the greatest efficacy and the least adverse reactions

The replication of genetic findings and the deter-mination of each gene's participation in the devel-opment of a variety of pathological phenotypes can be accomplished by unifying the criteria employed for the study of genetic samples, and defining

informative endophenotypes. These studies will be further facilitated by the large arrays of markers and their linkage disequilibrium relationships and allele frequencies that are available through the HapMap Project. This project allows the selection of infor-mative panels of marker loci, as well as known and potential functional loci, for almost any gene. In addition, the study of gene-environment interac-tions will allow the identification of the genetic variations and correlations underlying individual susceptibility towards specific environmental risk factors. In any case, what seemed unthinkable not so long ago, regarding the analysis of behaviour-related traits, will slowly but steadily be incorpo-rated into everyday psychiatric practice.

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