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In a case control study, we examined the association of DRD2 Taq1A and Taq1B polymorphisms and risk of PD, and evaluated the strength of linkage disequilibrium of the polymorphisms. The Taq1A and Taq1B polymorphisms were in strong linkage disequilibrium. There was, however, no significant association of the two polymorphisms with PD.
To examine the possible association between three recently identified structural polymorphisms of the dopamine D2 receptor (DRD2) gene and alcoholism, we compared allele frequencies of these polymorphisms in 280 Japanese alcoholics and 289 normal controls. The results revealed that only one of three variants identified in white individuals existed in the alcoholic and control Japanese. The frequency of the Cys311 variant allele was significantly higher in alcoholics (.063) than in controls (.029). All of the subjects with the variant allele were heterozygous Ser311/Cys311. Patients with Cys311 allele had less severe symptoms of alcoholism than did those with homozygous Ser311, especially symptoms related to loss of control over drinking. The coprevalence of other psychiatric disorders including schizophrenia did not differ between the two patient groups. These results suggest that the D2/Cys311 variant is associated with some type of alcoholism in Japanese.
Molecular heterosis occurs when subjects heterozygous for a specific genetic polymorphism show a significantly greater effect (positive heterosis) or lesser effect (negative heterosis) for a quantitative or dichotomous trait than subjects homozygous for either allele. At a molecular level heterosis appears counterintuitive to the expectation that if the 1 allele of a two-allele polymorphism is associated with a decrease in gene expression, those carrying the 11 genotype should show the greatest effect, 12 heterozygotes should be intermediate, and 22 homozygotes should show the least effect. We review the accumulating evidence that molecular heterosis is common in humans and may occur in up to 50% of all gene associations. A number of examples are reviewed, including those for the following genes: ADRA2C, C3 complement, DRD1, DRD2, DRD3, DRD4, ESR1, HP, HBB, HLA-DR DQ, HTR2A, properdin B, SLC6A4, PNMT, and secretor. Several examples are given in which the heterosis is gender-specific. Three explanations for molecular heterosis are proposed. The first is based on an inverted U-shaped response curve in which either to little or too much gene expression is deleterious, with optimal gene expression occurring in 12 heterozygotes. The second proposes an independent third factor causing a hidden stratification of the sample such that for in one set of subjects 11 homozygosity is associated with the highest phenotype score, while in the other set, 22 homozygosity is associated with the highest phenotype score. The third explanation suggests greater fitness in 12 heterozygotes because they show a broader range of gene expression than 11 or 22 homozygotes. Allele-based linkage techniques usually miss heterotic associations. Because up to 50% of association studies show a heterosis effect, this can significantly diminish the power of family-based linkage and association studies.
There is substantial information supporting the role of genetic factors in the susceptibility for alcohol dependence. However, the identification of specific genes that contribute to this predisposition has proven elusive, although several theoretically relevant candidates, e.g. DRD2 or 5-HT(1B), have been considered. The difficulty in identifying specific genes may be related to the clinical heterogeneity of the disorder resulting in a poorly defined phenotype for genetic analysis. An alternative approach to the use of a diagnostic phenotype for identifying alcoholism susceptibility genes may lie in the examination of the neurobiological correlates of the disorder, the so-called endophenotypes. One possible endophenotype of alcohol dependence may be related to the P300 waveform of the event-related brain potential (ERP). Using data obtained from the Collaborative Study on the Genetics of Alcoholism (COGA), a multi-site family-based study, the utility of P300 amplitude as an endophentype was examined. Differences in P300 amplitude were found between alcoholics and nonalcoholics, between unaffected relatives of alcoholics and relatives of controls, as well as between unaffected offspring of alcoholic fathers and offspring of controls. A genetic analysis indicated that attributes of the P(3) ERP waveform are heritable, and a quantitative trait locus analysis found linkage to several chromosomal regions. These data provide significant support for P300 as an endophenotype for alcohol dependence.
Converging data suggest that the identification of the molecular variants that influence antipsychotic drug response may soon be feasible. For the most part, these studies have focused on the new atypical antipsychotic agents, particularly clozapine. Although initial data in this regard has been inconclusive, recent studies have suggested that variation in the gene that codes for the dopamine D2 receptor (DRD2) may significantly influence the clinical efficacy of a number of typical and atypical antipsychotic drugs, perhaps via a variant that influences messenger RNA (mRNA) stability and translation. Studies of antipsychotic-induced weight gain have been more consistent than studies of antipsychotic drug efficacy, perhaps because weight dysregulation represents a more powerful phenotype for genetic studies, with a specific single nucleotide polymorphism (SNP) in the 5- hydroxytryptamine 2C (5-HT2c) receptor being associated with weight gain across diverse samples. Larger, more comprehensive studies are needed to confirm these results, but taken together, they suggest that pharmacogenetic strategies may be critical towards gaining a more precise understanding of the mechanism of action of antipsychotic drugs in the treatment of schizophrenia.
Migraine is a debilitating neurological disorder characterized by recurrent attacks of severe headache. The disorder is highly prevalent, affecting approximately 12% of Caucasian populations. It is well known that migraine has a strong genetic component, although the type and number of genes involved is not yet clear. However, the calcium channel gene, CACNA1A, on chromosome 19 contains mutations responsible for familial hemiplegic migraine, a rare and severe subtype of migraine. There is also evidence to suggest that serotonin- and dopamine-related genes may be involved in the pathogenesis of migraine. This study employed a linkage and association approach to investigate neurotransmitter-related migraine candidate genes. Polymorphisms within the dopamine beta-hydroxylase (DBH) gene, serotonin transporter gene (SERT), and dopamine receptor gene (DRD2) were tested in 177 unrelated Caucasian migraineurs and 182 control individuals. In addition, an independent sample of 82 families affected with migraine was examined. Unrelated case-control association analysis of a DBH intragenic dinucleotide polymorphism indicated altered allelic distribution between migraine and control groups (chi2 = 16.53, P=0.019). Furthermore, the transmission/disequilibrium test, which was implemented on the family data, also indicated distortion of allele transmission for the same DBH marker (chi2 = 4.44, P=0.035). Together, these results provide evidence for allelic association of the DBH gene with typical migraine susceptibility (Fisher's combined P value =0.006) and indicate that further research into the role of the DBH gene in the etiology of migraine is warranted.
Narcolepsy is a complex sleep disorder characterized by excessive daytime sleepiness and cataplexy. Mutations in genes of the hypocretin (orexin) neurotransmitter system cause narcoleptic symptoms in animal models. The absence of hypocretin in the cerebrospinal fluid of human patients is hypothesized to originate from destruction of hypocretinergic cells in the hypothalamus, the cause of which remains unknown. Due to strong HLA association autoimmune models of narcolepsy pathogenesis are still mostly favored. Genetic predisposition factors other than HLA are likely to play a role in causing the disorder. We screened three sets of gene regions ( n=254) for association with narcolepsy using a microsatellite based approach and pooled DNA: genes related to immunity, particularly apoptosis; genes related to regulation of circadian rhythmicity; genes coding for several factors of neurotransmission. In relation to apoptosis an association was found for the BAG1 gene region. Interestingly, microsatellites representing four genomic regions related to neurotransmission revealed association with narcolepsy: COMT, DRD2, GABBR1, and HTR2A. These results, although exploratory and still to be confirmed in independent samples, support a complex pathogenetic model for narcolepsy, including disturbances of neurotransmission rather than involvement of autoimmunity.
RATIONALE AND OBJECTIVES: The present study investigated possible genetic association between some polymorphisms possibly involved in antidepressant response and the occurrence of manic or hypo-manic switches during antidepressant treatment. METHODS: We retrospectively examined 169 individuals with a diagnosis of bipolar disorder (BP) type I ( n=103) and II ( n=66), who presented at least one sudden manic or hypo-manic episode (according to DSM IV criteria) during antidepressant therapy, that occurred within a period of 3 weeks from the beginning of the treatment and without any interposed period of well being ("manic switch"). They were compared with a sex, age, and ethnicity-matched group of 247 subjects, randomly selected from our pool of bipolar subjects, who never showed switches. We then randomly selected from the whole sample ("switched" and "not switched") a sub-sample of patients not under mood stabiliser treatment at the time of the index episode (65 "switched" and 117 "not switched") and compared them with a sex, age and ethnicity matched group of 133 subjects, randomly selected from our pool of major depressed patients, who did not present manic switches. The functional polymorphism in the upstream regulatory region of the serotonin transporter (SERTPR), tryptophan hydroxylase (TPH), G-protein beta 3 subunit (Gbeta3), monoamine oxidase A (MAO-A), catechol- O-methyltransferase (COMT), serotonin receptor 2A (5-HT2A), dopamine receptor D2 (DRD2) and dopamine receptor D4 (DRD4) gene variants were analysed using PCR-based techniques. RESULTS AND CONCLUSIONS: The distribution of the genetic polymorphisms was not significantly different between switched and not-switched patients ( P>0.006-Bonferroni corrected). Moreover, no significant difference was found between switched and not switched sub-samples and the sample of major depressed subjects. Further studies are required to investigate other possible related genetic variants influencing the timing of manic-depressive cycle.
Dopamine genes are candidate genes for dyslexia in the light of the well-known comorbidity between dyslexia and ADHD. Within-family association and linkage disequilibrium were tested between four genetic markers at DRD4, DRD3, DRD2, and DAT loci, and dyslexia, in a sample of 130 Italian dyslexic children, 16.9% of whom had comorbid ADHD. No evidence of either association or linkage disequilibrium was found, neither in the total sample nor in the comorbid subgroup. Negative results do not support a common genetic basis between these two disorders for these markers.
Knowledge of genetic polymorphisms in gene-environment studies may contribute to more accurate identification of avoidable risks and to developing tailor-made preventative measures. The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms (SNPs) of select genes, which may be included in future gene-environment studies on cancer in Japan. SNP typing was performed on middle-aged Japanese men randomly selected from the general population in five areas of Japan. We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes: CYP1A1, CYP1B1, CYP2C9, CYP2C19, CYP2E1, CYP17A1, CYP19A1, AHR, ESR1, ESR2, ERRRG, PGR, EPHX1, EPHX2, HSD17B2, HSD17B3, GSTM2, GSTM3, GSTT2, GSTP1, NAT1, NAT2, COMT, ADH1A, ADH1B, ADH1C, ALDH2, NOS2A, NOS3, IL1A, IL1B, OGG1, NUDT1 [MTH1], DRD2, DRD3, DRD4, SLC6A4, NR3C1 [GCCR], MTHFR, and NQO1. In the present study, the Japanese allele frequencies were verified by using nationwide population samples.
The purpose of the present study was to understand the tissue specificity of DNA methylation and the relationship between methylation and expression of genes with essential roles in neurodevelopment and brain function. We chose dopamine receptor genes (DRD1 and DRD2), NCAM, and COMT as examples of genes with CpG islands around the promoter region, and serotonin receptor genes (HTR2A and HTR3A), HCRT, and DRD3 as genes without CpG islands. Methylation states were investigated in fetal brain, fetal liver, placenta, and in adult peripheral leukocytes from three individuals by Southern blot and bisulfite-modified DNA sequencing. A repetitive sequence, human endogenous retrovirus (HERV)-K was also examined. All genes examined were almost completely unmethylated in brains. The genes with CpG islands were unmethylated regardless of their expression state. In contrast, genes without CpG islands showed various methylation patterns, which did not necessarily reflect the transcriptional activity of the genes. Most HERV-K loci were methylated, but some loci showed relatively low methylation in the placenta and liver. Interestingly, we found inter-individual differences in methylation levels in HTR2A and HCRT in the placenta and in some loci of HERV-K in the placenta and liver. The sample with the lowest methylation levels in the two unique genes showed higher methylation of HERV-K loci than the other samples. These results provide detailed information about the methylation states of the genes analyzed and evidence for inter-individual variations in methylation in both unique and repetitive sequences.
The depletion of dopamine levels in the brain due to degeneration of dopaminergic neurons of substantia nigra pars compacta is a hallmark of Parkinson's disease (PD). The cumulative contribution of genetic variations in genes from the dopaminergic pathway has been widely implicated to confer susceptibility to idiopathic PD. We present in this paper an extensive association analysis of a total of 20 markers including single nucleotide polymorphism/short tandem repeat/variable number tandem repeat/duplication markers from five candidate genes (namely, dopamine receptors DRD1, DRD2, DRD3, and DRD4, and dopamine transporter) with PD among two independent sample sets. The allelic, genotypic, and haplotypic association of these markers with PD was tested in South Indian (SI) samples (147 cases, 130 controls) and replicated in a larger North Indian (NI) sample set (340 cases, 344 controls). Of the several markers analyzed, 120 bp duplication marker of DRD4 gene showed promising results with PD in both of the sample sets. A significant allelic association in SI [odds ratio, OR (95% confidence interval, CI)=0.67 (0.47-0.97) for 120 bp dup; 1.48 (1.03-2.13) for 120 bp WT] and genotypic association in SI [OR (95% CI)= 0.56 (0.35-0.91) for 120 bp dup/dup; 1.62 (0.99-2.64) for 120 bp dup/120 bp WT] and in NI [OR (95% CI)= 1.41 (1.03-1.93) for 120 bp dup/120 bp WT] was observed. This is the first report on the association of dopaminergic gene polymorphisms with PD from the Indian sub-continent.
The person-to-person variability of drug response is a major problem in clinical practice and in drug development. It can lead to therapeutic failure or adverse drug reactions (ADRs) in individuals or subpopulation of patients. In addition to the high occurence of ADRs and the associated morbidity and mortality, substantial costs are incurred. Potential risk factors for drug inefficacy or toxicity include drug-drug interactions, the patient's age, renal and liver functions or other disease factors, and lifestyle variables such as smoking and alcohol consumption. In addition, it has become clear in recent years that genetic factors may also significantly modify drug responses or increase the risk for ADRs. Genetic variations in genes (polymorphisms) for drug-metabolizing enzymes, drug receptors, and drug transporters have been associated with individual variability in the efficacy and toxicity of drugs. It is now widely accepted that migraine is a polygenic and multifactorial disorders, thus considered to be a genetic complex disease. Genetic studies on migraine suggested a role of CACNA1A and DRD2 genes as susceptibility genes in this disorder.
The article reviews literature on methods for meta-analysis of genetic linkage and association studies, and summarizes and comments on specific meta-analysis findings for psychiatric disorders. The Genome Scan Meta-Analysis and Multiple Scan Probability methods assess the evidence for linkage across studies. Multiple Scan Probability analysis suggested linkage of two chromosomal regions (13q and 22q) to schizophrenia and bipolar disorder, whereas Genome Scan Meta-Analysis on a larger sample identified at least 10 schizophrenia linkage regions, but none for bipolar disorder. Meta-analyses of pooled ORs support association of schizophrenia to the Ser311Cys polymorphism in DRD2 and the T102C polymorphism in HTR2A, and of attention deficit hyperactivity disorder to the 48-bp repeat in DRD4. The 5-HTTLPR polymorphism in the serotonin transporter gene (SLC6A4) may contribute to the risk of bipolar disorder, suicidal behavior, and neuroticism, but association to the lifetime risk of major depression has not been shown. Meta-analyses support linkage of schizophrenia to regions where replicable associations to candidate genes have been identified through positional cloning methods. There are additional supported regions where susceptibility genes are likely to be identified. Linkage meta-analysis has had less clear success for bipolar disorder based on a smaller dataset. Meta-analysis can guide the prioritization of regions for study, but proof of association requires biological confirmation of hypotheses about gene actions. Elucidation of causal mechanisms will require more comprehensive study of sequence variation in candidate genes, better statistical and meta-analytic methods to take all variation into account, and biological strategies for testing etiologic hypotheses.
The D2 dopamine receptor gene (DRD2) displays Taq I restriction fragment length polymorphisms (RFLPs) at two different loci, termed A and B. One of the three different Taq I A 'alleles' described at this site, the A1 allele (size = 6.6 kb), has been found to be associated with alcoholism and with drug abuse in the majority of studies reported to date. A complete map of the Taq I A RFLP site has been constructed, through hybridization with different fragments of the 3' flanking region and polymerase chain reaction (PCR). When screening 432 unrelated individuals to establish possible A1 allelic association with drug abuse or dependence, we have encountered a novel Taq I A RFLP, which we have named 'A4' (size = 8.6 kb). This sequence variant displays a frequency of approximately 1% in our sample and shows a Mendelizing genetic pattern in an Italian nuclear family. Primers suitable for detecting A4 using PCR have been designed. The A4, but not the A3 'allele', displays substantial overlap with the A1. In particular, A2 and A3 share the presence of a Taq I restriction site, whose absence in A1 and A4 is apparently associated with substance abuse vulnerability. Therefore, in association studies it is proper to contrast individuals displaying A1 and A4 RFLP patterns, with individuals displaying A2 and A3 RFLPs.
There have been relatively few studies of genetic factors in drug abuse. Childhood Attention Deficit Hyperactivity Disorder (ADHD) has been implicated as a risk factor, and pedigree studies of Tourette Syndrome (TS), a hereditary impulse disorder closely related to ADHD, show an increased prevalence of substance abuse in relatives. These observations suggest the genes for TS and ADHD may play an important role in the development of drug abuse. To examine this hypothesis 217 TS probands and 328 of their relatives, 58 ADHD probands and 35 of their relatives, and 50 controls were prospectively studied using a structured questionnaire based on the Diagnostic Interview Schedule. All subjects were Caucasians 16 to 49 years of age. The responses concerning the use of 8 different drugs and 8 different symptoms of drug abuse were compared. The results showed a highly significant increase in positive responses with increased loading for the TS and ADHD genes for 6 of the 8 drugs and all of the drug abuse symptoms. The percentage of positive responses in TS probands was markedly influenced by the presence of comorbid ADHD, as well as discipline, obsessive-compulsive, or alcohol problems. These results suggest that the genes responsible for TS and ADHD play an important role in drug abuse/dependence. The dopamine D2 receptor gene (DRD2) appears to be one of these genes since variants at this locus are significantly increased in frequency in TS, ADHD, conduct disorder and drug abuse.
Molecular cloning studies have now identified five structurally homologous genes encoding the biosynthesis of the human dopamine receptors, DRD1, DRD2, DRD3, DRD4, and DRD5. Two of these dopamine receptors (DRD1 and DRD5) are encoded by intronless genes. To ascertain whether there are other intronless genes that share identity with the gene (DRD5) encoding the DRD5 receptor, we used a cloning method based on the polymerase chain reaction (PCR). Human genomic DNA was amplified by PCR with oligodeoxyribonucleotides (oligos) based on the DRD5 nucleotide (nt) sequence. Amplification of nt sequences between these oligos allowed the isolation of two independent intronless genes that share identity with DRD5. The full-length clones have also been isolated by screening human genomic libraries. The deduced amino acid sequences for these genes, PG-1 and PG-2, share 91% and 92% identity to DRD5, respectively. However, each of the genes contains differences in the coding regions that would render these genes incapable of encoding functional receptors. Thus, the human genome contains at least two DRD5 pseudogenes, consistent with in situ human chromosomal hybridization analysis which reveals the presence of two pseudogenes.
Dopaminergic pathophysiology is important in several psychiatric illnesses. The recently cloned D4 dopamine receptor gene (DRD4) shows considerable homology to the D2 and D3 dopamine receptors (DRD2 and DRD3); pharmacologically, its affinity for the atypical antipsychotic clozapine is much higher than that of these other dopamine receptors. Probe pB28 for this locus recognizes an informative HincII polymorphism. We typed this polymorphism on several large reference families (a total of about 271 individuals) to place DRD4 in the genetic linkage map. Pairwise linkage analysis (using ILINK) provided evidence for close linkage to the distal 11p loci tyrosine hydroxylase (TH) and the Harvey ras oncogene (HRAS). We used our version of LINKMAP adapted to run under distributed parallel processing (Linda-LINKMAP) for an analysis moving DRD4 across a fixed map with HRAS set 3.8 cM distal to TH. This localized DRD4 close to HRAS, with no crossovers observed between those loci and a maximum lod score of 19.9 (2 cM distal to HRAS). The one LOD unit support interval extends from about 1 cM proximal to HRAS to 8 cM distal to HRAS. Crossovers identified in one kindred place DRD4 distal to TH, providing further evidence for its location close to HRAS, making DRD4 one of the most telomeric of 11p markers. (This also places DRD4 in band 11p15.5.)