Search

A recent Japanese study on the angiotensin I converting enzyme gene (ACE) insertion/deletion polymorphism reported that both the D allele (P < 0.02) and the DD genotype (P < 0.002) were significantly more frequent in affective disorder cases than in controls [Arinami et al., 1996: Biol Psychiatry 40:1122-1127]. A replication study was performed by using 157 bipolar I affective disorder cases, 169 major depressive disorder cases, and 313 controls. No significant association with this polymorphism was found in either disorder or in a combined affective disorder group. These results do not support the ACE gene having a major role in the etiology of either bipolar or unipolar affective disorders. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:733-735, 2000., (Copyright 2000 Wiley-Liss, Inc.)

Genetic factors may be associated with disease subtype as well as susceptibility. We have therefore typed polymorphisms at the serotonin transporter, dopamine receptor, tryptophan hydroxylase, tyrosine hydoxylase, and monoamine oxidase A (MAOA) loci in 139 unipolar and 131 bipolar patients and investigated associations with gender, number of episodes, age of onset, history of psychotic symptoms, history of suicidal behavior, and history of substance abuse. In bipolar subjects, the promoter variable number tandem repeat (VNTR) allele 132 of MAOA was associated with history of suicide attempts, P = 0.029, particularly in females, P = 0.006. The Fnu4HI allele 1 of MAOA was also associated with history of suicide attempts in females, P = 0.0162. The serotonin transporter promoter allele 2 was associated with increasing number of manic episodes, P = 0.02, and history of psychotic symptoms, P = 0.0243. One significant association was found in the unipolar group: dopamine D2 receptor promoter allele 2 with history of psychotic symptoms, P = 0. 0165. We have tested multiple loci for a variety of different clinical variables and performed 228 tests of significance in total. It is possible that these preliminary findings are type 1 errors, because one would expect 11 of the 228 tests to reach a nominal significance level of P < 0.05 by chance alone if all the tests were independent. The associations with the MAOA and serotonin transporter loci are consistent with previous data suggesting associations with susceptibility to bipolar affective disorder. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:36-42, 2000, (Copyright 2000 Wiley-Liss, Inc.)

A recent report has shown that Wolfram syndrome carriers (heterozygotes) are 26-fold more likely to require psychiatric hospitalization compared with non-carriers, and that Wolfram syndrome heterozygotes may constitute approximately 25% of individuals hospitalized with depression and suicide attempts. We analyzed a His611Arg polymorphism of the wolframin gene by the polymerase chain reaction (PCR) and HhaI restriction digestion, in 158 bipolar I and 163 unipolar major affective disorder cases, and 316 controls. Statistical analyses of allele or genotype frequencies do not support a major role for wolframin in affective disorder. HhaI restriction digestion and sequencing of PCR products from four affective disorder cases showed a heterozygous Ala559Thr change. The Ala559Thr variant was not detectable in 382 controls tested. Thus, the rare wolframin 559Thr allele deserves consideration as a risk allele for affective disorder.

Monoamine oxidases catalyse the oxidative degradation of biogenic amines including neurotransmitters such as noradrenaline, dopamine, and 5-hydroxytryptamine (5-HT). Three groups have reported positive associations of the monoamine oxidase A (MAOA) gene with bipolar affective disorder although other studies have been negative. In an extension of a previous study [Rubinsztein et al., 1996: Human Molec Genet 5:779-782] we report association studies of MAOA polymorphic markers and affective disorders. The polymorphisms comprised a CA-repeat microsatellite in intron 2 and a Fnu4HI G/T silent polymorphism at position 941 of the cDNA sequence. No significant differences were found when the control allele frequencies were compared with those in bipolar, unipolar, or combined bipolar + unipolar groups. Meta-analyses were then performed to include the data of all published studies using the MAOA microsatellite and Fnu4HI polymorphisms. Separate meta-analyses were performed for Caucasian and Japanese studies, as allele frequencies of the microsatellite in these populations were markedly different. Associations of bipolar affective disorder in pooled male and female groups were found with the MAOA microsatellite in both the Caucasian (P < 0.02) and the Japanese (P < 0.02) meta-analyses. In view of these positive associations, and as previous results have shown that coding variants do not account for the normal population variation in MAOA activity, over 1,300 bp of the promoter were sequenced in 22 bipolar cases and 1 control. A novel polymorphic promoter variable number of tandem repeats (VNTR) located approximately 1,200 bp upstream from the translation start site was demonstrated. However, there was no association of this promoter VNTR with affective disorder. These results suggest that there may be functional variants in other regions of the MAOA gene or neighbouring genes that affect bipolar affective disorder risk., (Copyright 1999 Wiley-Liss, Inc.)

Previous reports of preferential transmission of bipolar affective disorder (BP) from the maternal versus the paternal lines in families suggested that this disorder may be caused by mitochondrial DNA mutations. We have sequenced the mitochondrial genome in 25 BP patients with family histories of psychiatric disorder that suggest matrilineal inheritance. No polymorphism identified more than once in this sequencing showed any significant association with BP in association studies using 94 cases and 94 controls. To determine whether our BP sample showed evidence of selection against the maternal lineage, we determined genetic distances between all possible pairwise comparisons within the BP and control groups, based on multilocus mitochondrial polymorphism haplotypes. These analyses revealed fewer closely related haplotypes in the BP group than in the matched control group, suggesting selection against maternal lineages in this disease. Such selection is compatible with recurrent mitochondrial mutations, which are associated with slightly decreased fitness. Although such mismatch distribution comparisons have been used previously for analyses of population histories, this is, as far as we are aware, the first report of this method being used to study disease.

Tyrosine hydroxylase (TH) is the rate-limiting enzyme in the synthesis of dopamine and noradrenaline. While positive associations between TH and bipolar affective disorder have been found in several studies, many studies have failed to reproduce these results. In order to clarify this situation, association studies of bipolar and unipolar affective disorder groups and metaanalyses of published data on the TH tetranucleotide repeat polymorphism were done. The association studies used the TH tetranucleotide repeat polymorphism in intron 1 and a PstI polymorphism at the 3' end of the gene. The study comprised 124 unrelated bipolar patients, 126 unipolar patients, and 242 controls. There was no significant association of either bipolar or unipolar affective disorder with the TH tetranucleotide repeat polymorphism. However, a weak association (chi2 = 3.946, 1 df, P = 0.047; odds ratio, allele 2 vs. allele 1 = 0.71 (95% CI, 0.51-0.996)) was observed in the unipolar sample with the TH-PstI polymorphism. Three metaanalyses of published data on the TH tetranucleotide repeat polymorphism in major affective disorder were performed: bipolar I + II vs. control using 583 cases and 745 controls; unipolar vs. control using 204 cases and 359 controls; and bipolar + unipolar vs. control using 846 cases and 823 controls. In each analysis there was no association of the TH tetranucleotide repeat polymorphism and affective disorder. These results do not support the tyrosine hydroxylase gene having a major role in the etiology of bipolar affective disorder. However, our data suggest that this locus should be examined in larger samples of unipolar affective disorder.

The dopaminergic system, along with the serotonergic and noradrenergic systems, has been implicated in the etiology of mood disorders. An association study of a functional variant in the promoter region of the dopamine D2 receptor (DRD2) with bipolar affective disorder I or unipolar major affective disorders was performed. Variable expression of the DRD2 gene in vitro has been shown with this promoter polymorphism. One hundred and thirty-one unrelated bipolar patients, 128 unrelated unipolar patients, and 262 controls were used in the study. There were no significant differences in DRD2 allele or genotype frequencies between the affective disorder and control groups. These results do not support a major role for the DRD2 gene in the etiology of either bipolar or unipolar affective disorders.

Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of 5-hydroxytryptamine (5-HT). An association study in bipolar affective disorder I or unipolar major affective disorder was performed by using a Bfa I restriction site polymorphism within intron 7 of the tryptophan hydroxylase gene. A total of 118 bipolar, 125 unipolar, and 437 control subjects were used in the study (1:3.7 bipolar:control, 1:3.5 unipolar:control). There were no significant differences in TPH allele or genotype frequencies between the affective disorder and control groups. In addition, bipolar and/or unipolar subjects with or without a history of suicide attempts were compared for the TPH polymorphism. No significant differences were found between suicidal and non-suicidal groups in major affective disorder, in contrast to a previous study suggesting an association of this polymorphism with a history of suicide attempts among alcoholic violent offenders.

The serotonin transporter is a compelling candidate gene to examine in bipolar and unipolar affective disorder, since drugs that specifically inhibit the serotonin transporter can successfully treat depression. Previous association studies of a VNTR polymorphism in intron 2 and a functional insertion/deletion polymorphism in the promoter of this gene have produced conflicting results. The present study examined allele and genotype frequencies for both of these polymorphisms and resulting haplotypes in 87 English Caucasian bipolar patients, 125 English Caucasian unipolar affective disorder patients, and 174 controls. No significant associations were detected when these unipolar or bipolar cases were compared either separately or as a pooled "affective disorder" group to the controls. A meta-analysis of over 1,400 individuals of European Caucasian origin was then performed, comprising 772 controls, 375 bipolar and 299 unipolar patients for the VNTR polymorphism, and 739 controls, 392 bipolar and 275 unipolar patients for the promoter polymorphism. A significant association of promoter allele 2 was shown with bipolar (estimated odds ratio 1.21; 95% confidence interval 1.00-1.45), unipolar (OR 1.23; 95% CI 1.01-1.42), and combined bipolar + unipolar groups (OR 1.22; 95% CI 1.04-1.42). There was no demonstrable allelic association of the VNTR polymorphism with affective disorder: for the combined bipolar + unipolar group the odds ratios for VNTR alleles 9 and 10, compared with the common allele 12 were 1.05 (95% CI 0.56-1.95) and 0.90 (95% CI 0.77-1.05). These results suggest that the promoter allele 2, which has previously been shown to result in lower levels of serotonin transporter transcription, may be associated with affective disorder risk.

A new class of disease (including Huntington disease, Kennedy disease, and spinocerebellar ataxias types 1 and 3) results from abnormal expansions of CAG trinucleotides in the coding regions of genes. In all of these diseases the CAG repeats are thought to be translated into polyglutamine tracts. There is accumulating evidence arguing for CAG trinucleotide expansions as one of the causative disease mutations in schizophrenia and bipolar affective disorder. We and others believe that the TATA-binding protein (TBP) is an important candidate to investigate in these diseases as it contains a highly polymorphic stretch of glutamine codons, which are close to the threshold length where the polyglutamine tracts start to be associated with disease. Thus, we examined the lengths of this polyglutamine repeat in normal unrelated East Anglians, South African Blacks, sub-Saharan Africans mainly from Nigeria, and Asian Indians. We also examined 43 bipolar affective disorder patients and 65 schizophrenic patients. The range of polyglutamine tractlengths that we found in humans was from 26-42 codons. No patients with bipolar affective disorder and schizophrenia had abnormal expansions at this locus.

The monoamine oxidase A locus (MAOA) at Xp11 was considered a good candidate to investigate in bipolar affective disorder since this enzyme plays an important role in the degradation of various neurotransmitters and a mutation in this gene has been associated with borderline mental retardation and a behavioural phenotype that has some resemblance to the manic syndrome. Previous association studies comparing allele frequencies of a microsatellite and RFLP at the monoamine oxidase A locus in bipolar affective disorder cases and controls in the UK have yielded conflicting results: Lim and colleagues reported a positive association, while no evidence for allelic association was obtained by Cradock and co-workers. A significant allelic association was observed between Japanese bipolar cases and controls at the MAOA microsatellite but different alleles seemed to be overrepresented in the bipolar cases in this population compared to the UK. In order to resolve these differences, we have examined this locus in our series of unrelated bipolar cases and age- and sex-matched controls and found significantly different MAOA microsatellite allele frequencies. In addition, we have pooled the data from the two previous UK studies with ours to create a total data set including 67 males and 113 females with bipolar affective disorder and a similar number of matched controls. No evidence for heterogeneity was observed for the control MAOA microsatellite or RFLP allele frequencies in these three studies. However, we found a significant difference between the pooled normal and bipolar allele frequencies both for the microsatellite and the RFLP at MAOA.

A group of diseases are due to abnormal expansions of trinucleotide repeats. These diseases all affect the nervous system. In addition, they manifest the phenomenon of anticipation, in which the disease tends to present at an earlier age or with greater severity in successive generations. Many additional genes with trinucleotide repeats are believed to be expressed in the human brain. As anticipation has been reported in schizophrenia and bipolar affective disorder, we have examined allele distributions of 13 trinucleotide repeat-containing genes, many novel and all expressed in the brain, in genomic DNA from schizophrenic (n = 20-97) and bipolar affective disorder patients (23-30) and controls (n = 43-146). No evidence was obtained to implicate expanded alleles in these 13 genes as causal factors in these diseases.