Genetics of unipolar major depressive disorder.

Major depressive disorder (MDD) is a heterogeneous, highly prevalent, and moderately heritable disorder. A complex and diverse genetic-environmental interplay converges to set apart a significant minority that is susceptible to MDD, from among those who experience shorter lived and less recurrent intensive and incapacitating forms of sadness. The major technological advances of deciphering the human genome reference sequence and its common gene variations are beginning to allow cost effective genetic studies of unprecedented scale, applying increasingly denser genome wide mapping to increasingly larger case control samples. This effort is now at the initial stages of unraveling the genetic architecture of several complex phenotypes. Despite a tardy beginning, MDD genetic research is maturing from modest scale candidate gene association studies to include family-based linkage studies, and will soon allow genome wide case control association studies. Replicated risk conferring gene variants discovered so far exert a modest effect size that appears to contribute to overt phenotype expression in the context of a highly intricate concert of interrelated epigenetic and epistatic modifiers. The unraveling of additional previously unimplicated MDD risk conferring genes, that will throw light on molecular mechanisms mediating such susceptibilities, is necessary for progressing beyond current generation monoamine modulating antidepressant drugs. The review outlines basic concepts and current progress briefly overviews major replicated gene findings that to date mostly stem from hypotheses driven candidates, and ends with a discussion of current directives, including sample size and phenotype considerations and advancement of systematic studies of the functional significance of implicated gene variants, beyond their current exploratory stage.

Why do young women smoke? IV. Role of genetic variation in the dopamine transporter and lifetime traumatic experience.

Cigarette smoking is a complex behavior to which environmental, psychological, and genetic factors contribute. Applying a multifactorial model, we examined the role of genetic variation in the dopamine transporter (DAT1) in smoking initiation (SI) and nicotine dependence. The participants were female college students who had never smoked (n = 148) or had smoked daily for at least a year (n = 242). All participants provided extensive background information and completed a series of psychological instruments. Five SNPs were genotyped in the 3' and 5' regions of DAT1. Data were analyzed by logistic regression. The best fitting model for SI (P = 1.9 x 10(-17), Nagelkerke R2 = 0.33) revealed novelty seeking (OR = 1.14, P = 0.000004) and lifetime traumatic experience (OR = 2.3, P = 0.001) as risk factors and a DAT1_E15 + 274-DAT1_VNTR G-9 haplotype as protective (OR = 0.57, P = 0.03). In the model for nicotine dependence (P = 1.4 x 10(-8), Nagelkerke R2 = 0.27) novelty seeking was a risk factor (OR = 1.07, P = 0.03); the DAT1_E15+274-DAT1_VNTR G-9 haplotype (OR = 0.37, P = 0.001) and the interaction between trauma and a DAT1_E15 + 274-DAT1_VNTR C-9 haplotype (OR = 0.15, P = 0.01) were protective. Lifetime experience of trauma was associated with high nicotine dependence among non-carriers of the C-9 haplotype but not among carriers of this haplotype. These findings indicate that in the context of a multifactorial model, haplotypes in the 3' region of DAT1 influence the propensity of young women to initiate smoking as well as the severity of nicotine dependence once the habit is established. A haplotype in the 3' untranslated region of DAT1 modifies the effect of lifetime traumatic experience on the severity of nicotine dependence.

AHI1, a pivotal neurodevelopmental gene, and C6orf217 are associated with susceptibility to schizophrenia.

Schizophrenia, a severe neuropsychiatric disorder, is believed to involve multiple genetic factors. A significant body of evidence supports a pivotal role for abnormalities of brain development in the disorder. Linkage signals for schizophrenia map to human chromosome 6q. To obtain a finer localization, we genotyped 180 single nucleotide polymorphisms (SNPs) in a young, inbred Arab-Israeli family sample with a limited number of founders. The SNPs were mostly within a approximately 7 Mb region around the strong linkage peak at 136.2 Mb that we had previously mapped. The most significant genetic association with schizophrenia for single SNPs and haplotypes was within a 500 kb genomic region of high linkage disequilibrium (LD) at 135.85 Mb. In a different, outbred, nuclear family sample that was not appropriate for linkage analysis, under-transmitted haplotypes incorporating the same SNPs (but not the individual SNPs) were significantly associated with schizophrenia. The implicated genomic region harbors the Abelson Helper Integration Site 1 (AHI1) gene, which showed the strongest association signal, and an adjacent, primate-specific gene, C6orf217. Mutations in human AHI1 underlie the autosomal recessive Joubert Syndrome with brain malformation and mental retardation. Previous comparative genomic analysis has suggested accelerated evolution of AHI1 in the human lineage. C6orf217 has multiple splice isoforms and is expressed in brain but does not seem to encode a functional protein. The two genes appear in opposite orientations and their regulatory upstream regions overlap, which might affect their expression. Both, AHI1 and C6orf217 appear to be highly relevant candidate genes for schizophrenia.

Pharmacogenetics of antipsychotic therapy: pivotal research issues and the prospects for clinical implementation.

The core hypothesis underlying pharmacogenetics is that genetic factors play a significant role in the well-recognized differences between individuals in response to medication and susceptibility to adverse effects. If these genetic factors can be identified and understood, they may serve as predictors to guide clinicians in tailoring medication to the individual patient. Recent developments in the field of antipsychotic drug treatment suggest that pharmacogenetics could play an important role, permitting the use of first-generation antipsychotics (FGAs) for patients in whom the use of second-generation antipsychotics (SGAs) is limited by efficacy considerations or adverse effects. In this paper, key issues that need to be taken into consideration in designing and interpreting pharmacogenetic studies of antipsychotic drugs are discussed against the background of data emanating from studies on the genetics of tardive dyskinesia (TD), an important adverse effect of FGAs. The issues considered include the advantages and potential pitfalls of case-control association studies of pharmacogenetic traits, the role of demographic factors such as age and gender, additive effects of genes, and gene-gene and gene-environment interaction. The prospects for implementation of pharmacogenetic testing in the clinic are considered in the context of a preliminary model that has been tested for prediction of susceptibility to TD.

Combined analysis of 635 patients confirms an age-related association of the serotonin 2A receptor gene with tardive dyskinesia and specificity for the non-orofacial subtype.

Tardive dyskinesia (TD) is an important limiting factor in the use of typical antipsychotic drugs. Genetic variability in the serotonin 2A (5-HT(2A)) receptor may influence risk for TD but the results of prior studies are not confirmatory. The objective of this study was to determine association of T102C and His452Tyr polymorphisms in the 5-HT(2A) receptor gene (HTR(2A)) with TD in a large, multicentre patient sample. The design employed case-control analysis controlling for possible confounders using pooled, original data from published and available unpublished samples and employing logistic regression, analysis of variance and meta-analysis. The study sample consisted of 635 patients with schizophrenia or schizoaffective disorder (256 with TD and 379 without TD) drawn from five research centres, divided into six groups based on population origin. The main outcome measure was association of a categorical diagnosis of TD based on the Research Diagnostic Criteria for TD with HTR(2A) T102C and His452Tyr genotypes and haplotypes. The findings indicate significant association of TD with HTR(2A) T102C genotype (p=0.002) over and above the effect of population group, also when controlling for age and gender (p=0.0008), but not with His452Tyr genotype. The T102C genotype was significantly associated with TD in older (>median age 47 yr, p=0.002) but not younger patients and in patients with non-orofacial (limb-truncal) (p=0.001) but not orofacial TD. By meta-analysis the Mantel-Haenszel (M-H) pooled odds ratio (OR) across all the available data was 1.64. A T102C-His452Tyr haplotype was significantly associated with TD (p=0.0008). These findings confirm that genetic variability in HTR(2A) contributes a small but significant degree of risk for the expression of TD, particularly in older patients and specifically for the non-orofacial (limb-truncal) type. Together with other genetic variants associated with TD the findings could be used to assess risk in patients who are candidates for treatment with typical antipsychotic medications.

Fine mapping of a schizophrenia susceptibility locus at chromosome 6q23: increased evidence for linkage and reduced linkage interval.

We previously reported an autosomal scan for schizophrenia susceptibility loci in a systematically recruited sample of Arab Israeli families. The scan detected significant evidence for linkage at chromosome 6q23 with a nonparametric LOD score (NPL) of 4.60 (P=0.000004) and a multipoint parametric LOD score of 4.16. In order to refine this finding we typed 42 additional microsatellite markers on chromosome 6q between D6S1570 (99.01 cM from the pter) and D6S281 (190.14 from the pter) in the same sample (average intermarker distance approximately 1.7 cM). In the 23 cM region between D6S1715 and D6S311, markers were more closely spaced ( approximately 1.1 cM). Multipoint nonparametric and parametric and single point linkage analyses were performed. The peak NPL rose to 4.98 (P=0.00000058) at D6S1626 (136.97 cM), immediately adjacent to D6S292 (NPL 4.98, P=0.00000068), the marker that gave the highest NPL in the original genome scan, under the broad diagnostic category. The putative susceptibility region (NPL-1) was reduced from 12.0 to 4.96 cM. The peak multipoint parametric LOD score was 4.63 at D6S1626 under a dominant genetic model, core diagnostic category and the LOD-1 interval was 2.10 cM. The maximum single point LOD score (3.55, theta=0.01) was also at D6S1626 (dominant model, core diagnostic category). Increased evidence for linkage in the same sample as in the original genome scan and consistent localization of the linkage peak add further support for the presence of a schizophrenia susceptibility locus at chromosome 6q23. Moreover, the markedly reduced linkage interval greatly improves prospects for identifying a schizophrenia susceptibility gene within the implicated region.

Attention deficit and hyperactivity disorder: review of genetic association studies.

Attention Deficit and Hyperactivity Disorder (ADHD) is a common idiopathic childhood neurodevelopmental disorder, exacting a significant clinical and public health toll. It impairs schooling and social adaptation, resulting in high rates of depression, conduct disorder, school dropouts, and substance abuse, and necessitating exposure of many children to prolonged courses of stimulant psychotropic medication. Although the biological basis of ADHD is unknown, it has been shown to possess considerable heritability. Candidate gene association studies proved to be a productive strategy leading to replicated association findings of genetic loci contributing to susceptibility to ADHD. Based on the mechanism of action of stimulant drugs effective in the alleviation of ADHD symptoms, current association studies have focused mainly on dopaminergic genes. Promising exploratory findings have also been reported for genes affecting other neurotransmitter systems. The current article reviews the rationale, methodology, and main findings in the field, and outlines future directions. Locating the actual genes mediating ADHD susceptibility will have far reaching implications for understanding the pathophysiology of ADHD as well as for understanding mechanisms of therapeutic drug action and genetic determinants of response.

Genetics of posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is a prevalent anxiety disorder marked by behavioral, physiologic, and hormonal alterations. PTSD is disabling and commonly follows a chronic course. The etiology of PTSD is unknown, although exposure to a traumatic event constitutes a necessary, but not sufficient, factor. A twin study of Vietnam veterans has shown significant genetic contribution to PTSD. The fact that PTSD's underlying genotypic vulnerability is only expressed following trauma exposure limits the usefulness of family-based linkage approaches. In contrast to the other major psychiatric disorders, large studies for the search of underlying genes have not been described in PTSD to date. Complementary approaches for locating involved genes include association-based studies employing case-control or parental genotypes for transmission dysequilibrium analysis and quantitative trait loci studies in animal models. Identification of susceptibility genes will increase our understanding of traumatic stress disorders and help to elucidate their molecular basis. The current review provides an up-to-date outline of progress in the field of PTSD.

Pharmacogenetics of tardive dyskinesia: combined analysis of 780 patients supports association with dopamine D3 receptor gene Ser9Gly polymorphism.

Variability among individuals in their therapeutic response to psychotropic drugs and in susceptibility to adverse effects is considerable. Pharmacogenetics addresses the contribution of genetic factors to this variability. An important focus of interest in pharmacogenetics has been on candidate genes that play a role in susceptibility to the antipsychotic drug-induced adverse effect, tardive dyskinesia (TD). Four published studies have reported an association between a serine (ser) to glycine (gly) polymorphism in exon 1 of the dopamine D3 receptor gene (DRD3) and TD; three failed to replicate this finding and one found an insignificant trend. We examined the association in a pooled sample of 780 patients (317 with TD and 463 without TD) drawn from 6 research centers, who were divided into 8 groups based on their population origin. The analysis employed stepwise logistic regression so as to allow confounding effects of group, age, and gender to be taken into account. TD was significantly associated with DRD3 gly allele carrier status (x(2)=4.46, df 1, p =.04) and with DRD3 genotype (x(2)=6.62, df 2, p =.04) over and above the effect of group. Similar positive effects were observed when controlling for age and gender (x(2)=5.02, df 1, p =.02 for gly allele carrier status; x(2) = 7.51, df 2, p =.002 for genotype). Examining abnormal involuntary movement scores as a continuous variable, we found that patients homozygous for the gly allele had significantly higher scores than ser-gly heterozygotes (p =.006) or ser-ser homozygotes (p <.0001). We also performed a meta-analysis that included, besides the groups in the combined analysis, three other published studies on DRD3 and TD. The Mantel-Haenszel pooled odds ratio for DRD3 gly allele carrier status increasing susceptibility to TD was 1.33 (95% CI 1.04-1.70, p =.02); the cumulative pooled estimate showed an odds ratio of 1.52 (95% CI 1.08-1.68, p <.0001). These findings support a small but significant contribution of the DRD3 ser9gly polymorphism to TD susceptibility that is demonstrable over and above population effects and the effect of age and gender on the phenotype.

Angiotensin converting enzyme gene insertion/deletion polymorphism: case-control association studies in schizophrenia, major affective disorder, and tardive dyskinesia and a family-based association study in schizophrenia.

Angiotensin converting enzyme (ACE) is a candidate gene for psychiatric disorders. We examined the frequency of a functional insertion/deletion (I/D) polymorphism in the 16th intron of the ACE gene (located on chromosome 17q23) in groups of patients with schizophrenia (n = 104 and 113), major depression (n = 55), and bipolar disorder (n = 87) compared to healthy control subjects (n = 87). There was no evidence for allelic or genotypic association of the polymorphism with any of the disorders or with tardive dyskinesia (TD) in patients with schizophrenia. In a sample of nuclear families (n = 61) made up of one or more patients with schizophrenia recruited with their parents, there was no evidence for biased transmission of ACE I/D alleles. Particularly in the case of schizophrenia, these findings do not support an association of the ACE I/D polymorphism with the phenotypes examined.

Investigation of linkage and association/linkage disequilibrium of HLA A-, DQA1-, DQB1-, and DRB1-alleles in 69 sib-pair- and 89 trio-families with schizophrenia.

The hypothesis that HLA antigens confer susceptibility to schizophrenic disorders has been tested by studying linkage and association in a family sample with 69 sib-pair families. Suggestive evidence for linkage was obtained by nonparametric multipoint LOD score analysis with a maximum around DQB CAR (P = 0.0004), a microsatellite marker that is in linkage disequilibrium with the HLA antigen DQB1. Spurious evidence for negative association as calculated by the transmission disequilibrium test was found for HLA- DRB1*11 (chi-square = 11.72, corrected P value = 0.03) and for the haplotype DQB1*301-DQA1*501-DRB1*11 (chi-square = 11.3, corrected P value = 0.043). No evidence of association with these alleles was obtained in a sample of 89 trios with schizophrenic offspring and parents. Our results are not in favor of a direct involvement of the HLA system in development of schizophrenia, but are compatible with the possible existence of a susceptibility gene in the MHC region at chromosome 6p 21.31.

Positive association of dopamine D2 receptor polymorphism with bipolar affective disorder in a European Multicenter Association Study of affective disorders.

Convincing evidence for a genetic component in the etiology of affective disorders (AD), including bipolar affective disorder (BPAD) and unipolar affective disorder (UPAD), is supported by traditional and molecular genetic studies. Most arguments lead to the complex inheritance hypothesis, suggesting that the mode of inheritance is probably not Mendelian but most likely oligogenic (or polygenic) and that the contribution of genes could be moderate or weak. The purpose of the present European multicenter study (13 centers) was to test the potential role in BPAD and UPAD of two candidate dopaminergic markers, DRD2 and DRD3, using a case-control association design. The following samples were analyzed for DRD2: 358 BPAD/358 control (C) and 133 UPAD/ 133 C subjects, and for DRD3: 325 BPAD/ 325 C and 136 UPAD/136 C subjects. Patients and controls were individually matched for sex, age ( plus minus five years) and geographical origin. Evidence for significant association between BPAD and DRD2 emerged, with an over-representation of genotype 5-5 (P=0.004) and allele 5 (P=0.002) in BPAD cases compared to controls. No association was found for DRD2 in UPAD, and for DRD3 neither in BPAD or UPAD. Our results suggest that the DRD2 microsatellite may be in linkage disequilibrium with a nearby genetic variant involved in the susceptibility to BPAD. Our large European sample allowed for replicating of some previous reported positive findings obtained in other study populations.

Interactive effect of cytochrome P450 17alpha-hydroxylase and dopamine D3 receptor gene polymorphisms on abnormal involuntary movements in chronic schizophrenia.

BACKGROUND: Tardive dyskinesia is a chronic adverse effect of anti psychotic drugs, where association with a polymorphic site in the dopamine D3 receptor gene has been previously reported. Cytochrome P 450 17alpha-hydroxylase activity has been implicated with modulation of central dopamine release as well as neuroprotection. We investigated the association of a T -->C variation in the cytochrome P 450 17alpha-hydroxylase gene with tardive dyskinesia in patients with chronic schizophrenia. METHODS: Cytochrome P 450 17 allele and genotype frequencies were compared between matched schizophrenia patients with (n = 55) or without tardive dyskinesia (n = 58). Interactive effects of cytochrome P 450 17alpha-hydroxylase with the dopamine D3 Ser9Gly polymorphism on abnormal involuntary movements were examined. RESULTS: There was no difference in cytochrome P 450 17alpha-hydroxylase genotype distribution between patients with and without tardive dyskinesia; however, patients carrying the cytochrome P 450 17alpha-hydroxylase A2-A2 genotype and the dopamine D3gly allele had the highest orofacial (p <.04), distal (p <.05), and incapacitation (p <.04) scores on the Abnormal Involuntary Movements Scale. CONCLUSIONS: Schizophrenia patients who carry the dopamine D3gly allele and the cytochrome P 450 17alpha-hydroxylase A2-A2 genotype may be more likely to develop abnormal orofoacial and distal involuntary movements and to be incapacitated by these movements when chronically exposed to classical antipsychotic drugs.

An association between clozapine-induced agranulocytosis in schizophrenics and HLA-DQB1*0201.

A group of 18 Israeli, clozapine-treated, schizophrenia patients underwent molecular and serological HLA typing in order to determine whether the major histocompatibility complex is associated with the development of clozapine-induced agranulocytosis. While under treatment with clozapine, 2 of the 18 patients developed agranulocytosis (total white blood cell count <3000/mm(3) and absolute polymorphonuclear count <500/mm(3)) and 3 developed granulocytopenia (total white blood cell count <3500/mm(3) and absolute polymorphonuclear count <1000/mm(3)). HLA-DQB1*0201 was present in all five patients who developed agranulocytosis or granulocytopenia (5/5; 100%), but in only 54% (7/13) of the patients who did not develop those complications. These findings indicate that DQB1*0201 or a gene located nearby could be involved in clozapine-induced agranulocytosis.