Sibling pairs with affective disorders: resemblance of demographic and clinical features.

BACKGROUND: As part of a collaborative linkage study, the authors obtained clinical and demographic data on 160 families in which more than one sibling was affected with a bipolar illness. The aim of the study was to identify clinical characteristics that had a high degree of familiality. METHOD: Data on age at onset, gender, frequency of illness-episodes and proportion of manic to depressive episodes were examined to determine intra-pair correlations in affected sibling pairs. Dimension scales were developed measuring frequency and severity of lifetime mania, depression, psychosis and mood-incongruence of psychotic symptoms; degree of familial aggregation for scores on these dimensions was calculated. RESULTS: Sibling pairs correlated significantly for age at onset (p = 0.293, P < 0 001); dimension scores for psychosis (p = 0.332, P < 0.001); and proportion of manic to depressive episodes (p = 0.184, P = 0.002). These findings remained significant when correcting for multiple testing. Of the other test variables; mania (p = 0.171, P = 0.019); incongruence dimensions (p = 0.242, P = 0.042); .frequency of manic episodes (p = 0.152, P = 0.033); and frequency of depressive episodes (p = 0.155, P = 0.028) were associated with modest correlations but these were not significant after correction. Degree of familial aggregation was not significant for sex (kappa = 0.084) or dimension scores for depression (p = 0.078, P = 0.300). CONCLUSIONS: Significant but modest familial resemblance has been shown for some specific features of bipolar illness, particularly age at onset and degree of psychosis. Further research may establish the extent to which these findings are mediated by genetic and/or environmental factors.

The Wellcome trust UK-Irish bipolar affective disorder sibling-pair genome screen: first stage report.

We have completed the first stage of a two-stage genome wide screen designed to identify chromosomal regions that may harbour susceptibility genes for bipolar affective disorder. The first stage screening sample included 509 subjects from 151 nuclear families recruited within the United Kingdom and Republic of Ireland. This sample contained 154 narrowly defined affected sibling pairs (DSM-IV BPI) and 258 broadly defined affected sibling pairs (DSM-IV BPI, SABP, BPII, BPNOS or MDD(R)), approximately two thirds of all families contained at least one other additional typed individual. All individuals were genotyped using 398 highly polymorphic microsatellite markers from Applied Biosystems's Linkage Mapping Set Version 2. The average inter-marker distance was 9.6 cM and the mean heterozygosity was 0.78. Analysis of these data using non-parametric linkage methods (MAPMAKER/SIBS) found no evidence for loci of major effect and no regions reached genome-wide significance for either suggestive or significant linkage. We identified 19 points across the genome where the MLS exceeded a value set for follow up in our second stage screen (MLS > or = 0.74 (equivalent to a nominal pointwise significance of 5%) under the narrowest diagnostic model). These points were on chromosomes 2, 3, 4, 6, 7, 9, 10, 12, 17, 18 & X. Some of these points overlapped with previous linkage reports both within bipolar affective disorder and other psychiatric illnesses. Under the narrowest diagnostic model, the single most significant multipoint linkage was on chromosome 18 at marker D18S452 (MLS=1.54). Overall the highest MLS was 1.70 on chromosome 2 at marker D2S125, under the broadest diagnostic model.

Allelic variation of a BalI polymorphism in the DRD3 gene does not influence susceptibility to bipolar disorder: results of analysis and meta-analysis.

Bipolar disorder is a major psychiatric illness that has evidence for a significant genetic contribution toward its development. In recent years, the BalI RFLP (restriction fragment length polymorphism) in the dopamine D3 receptor gene has been examined as a possible susceptibility factor for both schizophrenia and bipolar disorder. While analysis in schizophrenia has produced examples of increased homozygosity in patients, less encouraging results have been found for bipolar disorder. Recently, however, a family-based association study has found a significant excess of allele 1 and allele 1-containing genotypes in transmitted alleles to bipolar probands over nontransmitted controls. In a large bipolar case control sample (n = 454), we have been unable to replicate the family-based association study (chi-square = 0.137, P = 0.71, 1 df) or detect an effect similar to the positive homozygosity findings in schizophrenia (chi-square = 0.463, P = 0.50, 1 df). A meta-analysis of previous association studies also revealed no difference in allele distributions between bipolar patients and controls for this polymorphism in ethnically homogeneous samples (odds ratio, OR, = 1.04; P = 0.60; 95% confidence interval, CI, = 0.89-1.20). In view of this evidence, we conclude that variation at the BalI RFLP is not an important factor influencing the susceptibility to bipolar disorder. It remains possible, however, that other sequence variations within the DRD3 gene could play a role.

Exclusion of the Darier's disease gene, ATP2A2, as a common susceptibility gene for bipolar disorder.

Bipolar affective disorder is a genetically complex psychiatric disorder with a population prevalence of approximately 1%. We have previously reported cosegregation of bipolar affective disorder and Darier's disease, a dominant skin disorder with a neuropsychiatric component. The gene for Darier's disease was mapped to chromosome 12q23-q24.1 and linkage studies by us and others have subsequently implicated this region as harbouring a susceptibility gene for bipolar affective disorder. In this study we have investigated the Darier's disease gene ATP2A2, the calcium pumping ATPase SERCA2, as a potential susceptibility gene for bipolar disorder under the hypothesis that variations in SERCA2 have pleiotropic effects in brain. Support for this hypothesis comes from clinical evidence of neuropsychiatric abnormalities in Darier's disease, genetic data produced in our study showing non-random clustering of missense mutations in ATP2A2 in neuropsychiatric Darier patients, and functional data demonstrating the role of SERCA2 in intracellular calcium regulation. In a panel of 15 unrelated bipolar patients from multiply affected families showing increased allele sharing at markers in the 12q23-q24.1 region, we performed mutational screening of the ATP2A2 coding sequence, promoter regions, and 3' untranslated region and identified six sequence variations. These were analysed in a large sample of bipolar patients (n = 324) and control subjects (n = 327). Analysis of allele and genotype distributions for all six variations, and of haplotype frequencies showed no evidence for the involvement of ATP2A2 in producing susceptibility to bipolar disorder.

Molecular genetic studies of bipolar disorder and puerperal psychosis at two polymorphisms in the estrogen receptor alpha gene (ESR 1).

A number of lines of evidence point to the possible involvement of estrogen pathways in the pathophysiology of bipolar disorder in general and puerperal psychosis in particular. There is strong evidence from clinical, follow-up, and genetic studies to support the hypothesis that most cases of puerperal psychosis are manifestations of an affective disorder diathesis with a puerperal trigger and that genes influence susceptibility to both diathesis and trigger. The nature of the trigger is unknown but in view of the abrupt onset at a time of major physiological change it is widely believed that biological, probably hormonal, mechanisms are of paramount importance, with estrogen receiving the most attention to date. We have undertaken a case control association study of bipolar disorder and puerperal psychosis at two known polymorphisms within the estrogen receptor alpha gene (ESR 1) in a sample of 219 unrelated bipolar probands and 219 controls. We could exclude these polymorphisms from an important contribution to susceptibility to bipolar disorder with a high level of confidence. We found no support for the hypothesis that they contribute specific susceptibility to the puerperal trigger, but due to the small numbers of puerperal probands (n = 26) no firm conclusions can be drawn regarding their involvement in puerperal psychosis. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:850-853, 2000.

Bipolar disorder and variation at a common polymorphism (A1832G) within exon 8 of the Wolfram gene.

A number of linkage studies provide evidence consistent with the existence of a bipolar susceptibility gene on chromosome 4p16. The gene for Wolfram syndrome, a rare recessive neurodegenerative disorder, lies in this region and has recently been cloned. Psychiatric disturbances including psychosis, mood disorder, and suicide have been reported at increased frequency in Wolfram patients and in heterozygous carriers of a Wolfram mutation. In the current investigation we have undertaken a case-control association study using a single nucleotide polymorphism (causing an amino acid change) in exon 8 of the Wolfram gene in a UK Caucasian sample of 312 Diagnostic and Statistical Manual of Mental Disorders (fourth edition; DSM IV) bipolar I probands and 301 comparison individuals. We found no evidence that variation at this polymorphism influences susceptibility to bipolar disorder. It remains possible that variation at other sites within or near the Wolfram gene plays important roles in determining susceptibility to affective illness. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:154-157, 2000.

Association analysis of the proneurotensin gene and bipolar disorder.

Neurotensin (NT) localizes within dopaminergic neurones in the mesocortical, mesolimbic and nigrostriatal systems, and it is now clear that NT can selectively modulate dopaminergic neurotransmission. It has therefore been proposed that altered NT function might contribute to the pathogenesis of neuropsychiatric disorders in which disordered dopaminergic neurotransmission is suspected. We have previously screened the gene encoding NT in a sample of schizophrenic and bipolar subjects, and identified three sequence variants. These have now been tested for association with bipolar disorder using a case-control sample of unrelated bipolar subjects and matched controls. No evidence for association was found, and our data therefore suggest that sequence variation in this gene does not make an important contribution to susceptibility to bipolar disorder.

Comparative sequencing and association studies of aromatic L-amino acid decarboxylase in schizophrenia and bipolar disorder.

Aromatic L-amino acid decarboxylase (AADC) is a relatively non specific enzyme involved in the biosynthesis of several classical neurotransmitters including dopamine and 5-hydroxytryptamine (5HT; serotonin). AADC does not catalyse the rate limiting step in either pathway, but is rate limiting in the synthesis of 2-phenylethylamine (2PE) which is a positive modulator of dopaminergic transmission and a candidate natural psychotogenic compound.1 We and others have proposed that polymorphism in AADC resulting in altered 2PE activity might contribute to the pathogenesis of psychosis. In order to test this hypothesis, we have used denaturing high performance liquid chromatography (DHPLC)3 to screen 3943 bases of the AADC gene and its promoter regions for variants that might affect protein structure or expression in 15 unrelated people with schizophrenia, and 15 unrelated people with bipolar disorder. Three polymorphisms were identified by DHPLC: a insertion/deletion polymorphism in the 5' UTR of the neuronal specific mRNA (g.-33-30delAGAG, bases 586-589 of GenBank M77828), a T>A variant in the non-neuronal exon 1 (g. -67T>A, GenBank M88070), and a G>A polymorphism within intron 8 (g. IVS8 +75G>A, GenBank M84598). Case-control analysis did not suggest that genetic polymorphism in the AADC gene is associated with liability for developing schizophrenia or bipolar disorder.

No evidence of association from transmission disequilibrium analysis of the hKCa3 gene in bipolar disorder.

OBJECTIVE: A recent case control study has suggested that modest enlargements of a highly polymorphic CAG repeat in exon 1 of the gene encoding potassium channel hKCa3 may be associated with bipolar disorder (BPD). We have examined this hypothesis by genotyping this locus in a family-based association study. METHOD: One hundred and twenty-eight parent offspring trios of British Caucasian origin were examined where the proband was diagnosed with the American Psychiatric Association's Diagnostic and Statistical Manual (DSM)-IV BPD I (n = 123) or II (n = 5). An improved assay was used, with redesigned polymerase chain reaction (PCR) primers, permitting quicker and higher resolution genotyping. The resultant genotypes were analysed using the extended transmission/ disequilibrium test (ETDT). RESULTS: The experimental data did not provide evidence for the preferential transmission of large alleles to bipolar cases (chi2 = 11.12, df = 10, p = 0.349). CONCLUSIONS: Our data provide no support for the hypothesis that variation at the hKCa3 gene contributes to susceptibility to BPD.

Family-based association studies of bipolar disorder with candidate genes involved in dopamine neurotransmission: DBH, DAT1, COMT, DRD2, DRD3 and DRD5.

The dopaminergic system has been implicated in the aetiology of mood disorders. We conducted family-based association studies for polymorphisms at three genes involved in the metabolism of dopamine: dopamine transporter (DAT1), dopamine-beta-hydroxylase (DBH) and catechol-O-methyl transferase (COMT); and three dopamine receptors: DRD2, DRD3 and DRD5. We used a sample of 122 parent-offspring trios of British Caucasian origin where the proband had bipolar disorder I (BPI), and analysed the results with the transmission/disequilibrium test (TDT) which is robust to hidden population stratification. No statistically significant differences were found between transmitted and not transmitted alleles for any of the polymorphisms studied.

CTG18.1 and ERDA-1 CAG/CTG repeat size in bipolar disorder.

Several groups have reported association between large CAG/CTG repeat sequences in the genome and bipolar disorder using the Repeat Expansion Detection (RED) method. Unfortunately, the RED method cannot identify the specific repeat(s) responsible for these findings but it has recently been proposed that around 90% of the large CAG/CTG repeats detected by RED can be explained by repeat size at either CTG18.1, which maps to 18q21.1, or ERDA-1 (also known as Dir 1), which maps to 17q21.3. These data suggest that the previous associations between bipolar disorder and large CAG/CTG repeats might be explained at least in part by a specific association between bipolar disorder and either or both of these loci. However, using a case control study design, we find no evidence for such associations. Thus we conclude that in our sample, the previous RED associations are not a result of large CAG/CTG repeats at CTG18.1 or ERDA-1.

No association between a polymorphic CAG repeat in the human potassium channel gene hKCa3 and bipolar disorder.

A recent case-control study suggested that modest enlargements of a CAG repeat in the hKCa3 potassium channel may be associated with bipolar disorder. We tried to replicate this result in a UK Caucasian sample of 203 DSM-IV bipolar I disorder patients and 206 controls group-matched for age and sex. Using the same model of analysis as the earlier study, bipolar probands did not have a higher frequency of alleles with greater than 19 repeats than controls (chi2 = 1.44, 1 df, P = 0.23). Similarly, comparison of the distributions of repeat sizes between probands and controls did not approach statistical significance (Mann-Whitney U test, P = 0.35). We conclude that our data provide no support for the hypothesis that variation at the hKCa3 gene contributes to susceptibility to bipolar disorder.

Intrafamilial association of pericentric inversion of chromosome 9, inv (9)(p11-q21), and rapid cycling bipolar disorder.

Association of a chromosome aberration and psychiatric disorder can be useful in highlighting a genomic region that can be profitably explored further using positional cloning. We report the case of a father and daughter both of whom have bipolar disorder II and a pericentric inversion of chromosome 9.

Association between functional psychosis and expanded CAG/CTG repeats is not explained by health stratification.

A number of studies have reported an association between large CAG/CTG repeats and both schizophrenia and bipolar disorder. Recently, we reported an inverse correlation between CAG/CTG repeat size and age in a health-selected population, raising the possibility that selection of control groups for physical health was a confounding factor in our previous association studies. We investigated this by health-selection of patients with schizophrenia and bipolar disorder. The maximum CAG/CTG repeat size remained significantly larger in probands with functional psychosis compared with control individuals, and in probands with a diagnosis of schizophrenia compared with control individuals. The number of probands in the healthy bipolar group was small, and although on average this group also had longer CAG/CTG repeats than control individuals, this failed to reach statistical significance. Our findings do not support the notion that the original results with psychosis as a whole, and schizophrenia specifically, are attributable to a stratification effect consequent on health selection. Nevertheless, we are unable formally to reject the hypothesis that the previously observed difference between bipolar probands and control individuals is the result of this phenomenon.

Association studies of bipolar disorder at the human serotonin transporter gene (hSERT; 5HTT).

The human serotonin transporter gene (hSERT) is a strong candidate for involvement in the pathogenesis of mood disorder and, using a UK Caucasian case-control sample, Collier et al found a significant association between bipolar disorder and the 12 allele of the VNTR polymorphism in intron 2 of this gene. In a European collaborative sample, Collier et al found a significant association between affective disorder and a functional deletion polymorphism in the promoter of hSERT. We have undertaken association studies using these polymorphisms in a British Caucasian sample comprising 171 DSM-IV bipolar probands, 80 DSM-IV major depression probands and 121 unrelated controls matched to bipolar probands for age, sex and ethnicity. We found no association between the promoter deletion and affective disorder but our findings with the VNTR polymorphism are similar to those of Collier and colleagues: we found a significant excess of the 12 repeat allele in bipolar probands (P = 0.031, one-tall) with a suggestion of a gene dosage effect (using genotypes bearing no 12 repeat allele as baseline, the increased risks conferred by genotypes bearing 12 repeat alleles were: heterozygote, OR = 1.24; homozygote, OR = 1.76). Our findings add to the evidence that variation at or near hSERT influences susceptibility to bipolar disorder in the British Caucasian population.