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Biomedical subjects

N Craddock

Publications and source records attributed to N Craddock.

At least 73 records · Page 4Linked to original sources
PubMed1999

Eleven trinucleotide repeat loci that map to chromosome 12 excluded from involvement in the pathogenesis of bipolar disorder.

The hypothesis that one or more genes containing expanded trinucleotide repeats contribute to the pathogenesis of bipolar disorder has received support from three independent studies demonstrating that bipolar patients tend to have larger CAG/CTG repeat expansion detection products than controls. In an attempt to identify the specific expanded CAG/CTG locus or loci which are associated with bipolar disorder, we determined repeat size at CAG/CTG loci mapping to candidate regions for bipolar disorder. Recent linkage studies suggest the existence of a bipolar susceptibility gene on chromosome 12q23-q24.1 in the region of the Darier's disease (DAR) gene. In this study we report our findings from 11 loci which map to chromosome 12, including CAG repeat polymorphisms within the genes SCA2 and ASH1. We conclude that all of these loci are excluded as candidates for CAG/CTG repeat expansion in bipolar disorder.

Ataxins↗
PubMed1999

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.

Adult↗
PubMed1999

Bipolar disorder and the serotonin transporter gene: a family-based association study.

BACKGROUND: The human serotonin transporter gene (5-HTT) is a strong candidate for involvement in the pathogenesis of mood disorders. Two common polymorphisms have been identified in the gene: a VNTR in intron 2 and a functional deletion/insertion in the promoter region. In previous studies we proposed that allele 12 of the VNTR might increase susceptibility for bipolar disorder. METHODS: We have genotyped 122 parent-offspring trios of British Caucasian origin where the proband had DSM-IV Bipolar I disorder (BPI). The results were analysed with the transmission/ disequilibrium test (TDT), which examines whether particular alleles are preferentially transmitted from heterozygous parents to affected offspring. RESULTS: The 12 repeat in the VNTR in intron 2 was transmitted 72 times and not transmitted 56 times (chi2 = 2.0, 1 df, P = 0.16). If we exclude 24 families in which the proband was a case in our published case-control studies (Collier et al. 1996a; Rees et al. 1997), the excess transmission of allele 12 reaches conventional levels of statistical significance: chi2 = 3.85, 1 df, P < 0.05. The deletion/insertion polymorphism in the promoter region was not associated with BPI: 66 parents transmitted the inserted (L) allele and 59 parents transmitted the deleted (S) allele (chi2 = 0.39, 1 df, P = 0.53). CONCLUSIONS: The 12 repeat of the VNTR in intron 2 of the serotonin transporter gene might be a susceptibility factor in bipolar affective disorder. The genetic effect, if true, is likely to be small, and requires confirmation in further studies using parental controls.

Adult↗
PubMed1999

Mutations in ATP2A2, encoding a Ca2+ pump, cause Darier disease.

Darier disease (DD) is an autosomal-dominant skin disorder characterized by loss of adhesion between epidermal cells (acantholysis) and abnormal keratinization. Recently we constructed a 2.4-Mb, P1-derived artificial chromosome contig spanning the DD candidate region on chromosome 12q23-24.1. After screening several genes that mapped to this region, we identified mutations in the ATP2A2 gene, which encodes the sarco/endoplasmic reticulum Ca2(+)-ATPase type 2 isoform (SERCA2) and is highly expressed in keratinocytes. Thirteen mutations were identified, including frameshift deletions, in-frame deletions or insertions, splice-site mutations and non-conservative missense mutations in functional domains. Our results demonstrate that mutations in ATP2A2 cause DD and disclose a role for this pump in a Ca(2+)-signalling pathway regulating cell-to-cell adhesion and differentiation of the epidermis.

Calcium-Transporting ATPases↗
PubMed1999

Evaluation of linkage of bipolar affective disorder to chromosome 18 in a sample of 57 German families.

Previously reported linkage of bipolar affective disorder to DNA markers on chromosome 18 was reexamined in a large sample of German bipolar families. Twenty-three short tandem repeat markers were investigated in 57 families containing 103 individuals with bipolar I disorder (BPI), 26 with bipolar II disorder (BPII), nine with schizoaffective disorder of the bipolar type (SA/BP), and 38 individuals with recurrent unipolar depression (UPR). Evidence for linkage was tested with parametric and non-parametric methods under two definitions of the affected phenotype. Analysis of all 57 families revealed no robust evidence for linkage. Following previous reports we performed separate analyses after subdividing the families with respect to the sex of the transmitting parent. Fourteen families were classified as paternal and 12 families as maternal. In 31 families the parental lineage of transmission of the disease could not be determined ('either' families). Evidence for linkage was obtained for chromosomal region 18p11.2 in the paternal families and for 18q22-23 in the 'either' families. The findings on 18p11.2 and 18q22-23 support prior evidence for susceptibility loci in these regions. The parent-of-origin effect on 18p11.2 is confirmed in our sample. The delineation of characteristics of 'either' families requires further study.

Bipolar Disorder↗
PubMed1999

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.

Adult↗
PubMed1999

ATP2A2 mutations in Darier's disease and their relationship to neuropsychiatric phenotypes.

Darier's disease (DD) is a rare, dominantly inherited disorder that affects the skin producing a variety of types of lesion. Close examination of lesional DD skin shows the presence of abnormal keratinization (epidermal differentiation) and acantholysis (loss of cohesion) of keratinocytes. A number of clinical studies have described the co-occurrence of various neurological and psychiatric symptoms with DD, including mood disorders, epilepsy, mental retardation and a slowly progressive encephalopathy. A single locus for DD has been mapped to chromosome 12q23-q24.1, and a variety of missense, nonsense, frameshift and splicing mutations in the ATP2A2 gene have been described recently in families with DD. This gene encodes the sarcoplasmic/endoplasmic reticulum calcium-pumping ATPase SERCA2, which has a central role in intra-cellular calcium signalling. In this study, we performed mutation analysis on ATP2A2 in 19 unrelated DD patients, of whom 10 had neuropsychiatric phenotypes. We identified and verified 17 novel mutations predicting conservative and non-conservative amino acid changes, potential premature translation terminations and potential altered splicing. Our findings confirm that mutations in ATP2A2 are associated with DD. In neuropsychiatric cases, there was a non-random clustering of mutations in the 3' end of the gene ( P = 0.01), and a predominance of the missense type (70% versus 38% in DD patients). This supports the hypothesis that the DD gene has pleiotropic effects in brain and that mutations in SERCA2 are implicated in the pathogenesis of neuropsychiatric disorders.

Adult↗
PubMed1999

Genetics of bipolar disorder.

Bipolar disorder (also known as manic depressive illness) is a complex genetic disorder in which the core feature is pathological disturbance in mood (affect) ranging from extreme elation, or mania, to severe depression usually accompanied by disturbances in thinking and behaviour. The lifetime prevalence of 1% is similar in males and females and family, twin, and adoption studies provide robust evidence for a major genetic contribution to risk. There are methodological impediments to precise quantification, but the approximate lifetime risk of bipolar disorder in relatives of a bipolar proband are: monozygotic co-twin 40-70%; first degree relative 5-10%; unrelated person 0.5-1.5%. Occasional families may exist in which a single gene plays the major role in determining susceptibility, but the majority of bipolar disorder involves the interaction of multiple genes (epistasis) or more complex genetic mechanisms (such as dynamic mutation or imprinting). Molecular genetic positional and candidate gene approaches are being used for the genetic dissection of bipolar disorder. No gene has yet been identified but promising findings are emerging. Regions of interest identified in linkage studies include 4p16, 12q23-q24, 16p13, 21q22, and Xq24-q26. Chromosome 18 is also of interest but the findings are confusing with up to three possible regions implicated. To date most candidate gene studies have focused on neurotransmitter systems influenced by medication used in clinical management of the disorder but no robust positive findings have yet emerged. It is, however, almost certain that over the next few years bipolar susceptibility genes will be identified. This will have a major impact on our understanding of disease pathophysiology and will provide important opportunities to investigate the interaction between genetic and environmental factors involved in pathogenesis. This is likely to lead to major improvements in treatment and patient care but will also raise important ethical issues that will need to be addressed.

Bipolar Disorder↗
PubMed1998

Linked polymorphisms upstream of exons 1 and 2 of the human cholecystokinin gene are not associated with schizophrenia or bipolar disorder.

The evidence for a significant genetic contribution to the functional psychoses (schizophrenia and bipolar disorder) is now well established. However, in both cases, the non-mendelian mode of inheritance has made the identification of susceptibility loci particularly challenging. The neuropeptide cholecystokinin (CCK) is present both in the gut and the CNS. Studies of CCK-like immunoreactivity and CCK mRNA levels in human brains have revealed high concentrations in numerous loci and shown colocalisation of CCK with, for example, dopamine and tyrosine hydroxylase. Furthermore, antagonists of CCK-B receptors, which are found most frequently in the brain, inhibit the activity of brain dopamine neurons. Such findings suggest that, with respect to neuropsychiatric disorders, CCK is a suitable candidate for analysis using methods to detect gene variations which have the potential to affect protein structure or expression. In the present study, mutation analyses were carried out on the human CCK gene. Linked polymorphisms were found in the promoter region and in intron 1 close to the 3' mRNA splice acceptor site. However, the allele frequencies of these polymorphisms in samples of individuals affected with either schizophrenia (n=117) or bipolar disorder (n=124) did not differ from those of control subjects (n=234), suggesting that these variations do not confer a predisposition to either of the functional psychoses.

Alleles↗
PubMed1998

Low activity allele of catechol-O-methyltransferase gene associated with rapid cycling bipolar disorder.

Catechol-O-methyltransferase (COMT) plays a major role in the breakdown of catecholamines. An amino acid polymorphism (val-108-met) determines high and low activity of the enzyme. A recent study in a small sample of patients with velo-cardio-facial syndrome who had bipolar affective disorder suggested that the Met (low activity) COMT allele might be associated with rapid-cycling in this population. We therefore tested the hypothesis that the Met allele might be associated with rapid cycling bipolar disorder in the wider population. We studied a sample of British Caucasian DSM-IV bipolar patients, of whom 55 met criteria for rapid cycling at some time during the illness and 110 met stringent criteria for a definite non-rapid cycling course. The COMT genotype was determined using a PCR assay. The low activity allele was more frequent in the group of rapid cyclers: 0.55 vs 0.42 (one-tailed chi 2 = 5.12, d.f. = 1, P = 0.012), and bearers of low activity alleles showed a dose-dependent increased risk of lifetime occurrence of rapid cycling: chi 2 test of linear association = 4.84, d.f. = 1, P = 0.014. Our data support the hypothesis that variation in the COMT gene modifies the course of bipolar disorder.

Alleles↗
PubMed1998

A study of chromosome 4p markers and dopamine D5 receptor gene in schizophrenia and bipolar disorder.

There are several lines of evidence which suggest that chromosome 4p may contain a major susceptibility locus for the functional psychoses. We previously reported a family (family 50) with cases of schizophrenia and schizoaffective disorder which gave maximum lod scores of 1.96 and 1.84 respectively with the markers D4S403 and a microsatellite near to DRD5 (DRD5-M). More recently Blackwood and co-workers described a family segregating bipolar and unipolar affective disorders which gives a maximum lod score of 4.1 with the marker D4S394, which lies 10 cM from D4S403. They obtained a combined maximum lod of 3.3 in their total sample of 12 bipolar families and found significant evidence of heterogeneity (chi 2 = 18.8, df = 2, P = 0.00008). Here we report the results of a linkage study of chromosome 4p markers in a sample of 24 multiply affected families with schizophrenia and related disorders. We obtained an overall maximum lod of 1.12 with D4S403 under both dominant and recessive modes of transmission, with no statistical support for heterogeneity within our sample. Examination of family by family data shows that only family 50 appears to show linkage at this locus. However, a discrepancy exists since our study examined families fulfilling criteria for a linkage study of schizophrenia while Blackwood et al examined families included in a genetic linkage study of bipolar disorder. This may be explained by the clinical features displayed by members of family 50, which show that all the affected members have some affective symptoms. It is therefore possible that a broad phenotype including unipolar depression, bipolar disorder, schizoaffective disorder and schizophrenia when accompanied by significant affective symptoms can result from mutations within a gene in this region. The dopamine D5 receptor gene lies within the region identified by the linkage studies and is therefore a major candidate for the putative disease gene. In family 50 we have looked for mutations of DRD5 by sequence analysis of the coding region and single stranded conformational polymorphism (SSCP) analysis of the promoter. SSCP analysis of the coding and promoter regions have also been carried out in unrelated cases of DSM-IIIR schizophrenia. Finally association studies of the (TC)n repeat in the promoter and schizophrenia, and DRD5-M and bipolar disorder were performed. These studies provided no further evidence supporting the possibility that mutations in DRD5 give rise to the linkage findings or are acting as susceptibility loci in schizophrenia or bipolar disorder.

Base Sequence↗
PubMed1998

Further support for an association between a polymorphic CAG repeat in the hKCa3 gene and schizophrenia.

A recent study has suggested that a polymorphism in the hKCa3 potassium channel may be associated with raised susceptibility to schizophrenia. Despite its modest statistical significance, the study is intriguing for two reasons. First, hKCa3 contains a polymorphic CAG repeat in its coding sequence, with large repeats more common in schizophrenics compared with controls. This is interesting in view of several repeat expansion detection (RED) studies that have reported an excess of large CAG repeats in psychotic probands. Second, the hKCa3 gene is a functional candidate gene because studies of antipsychotic and psychotogenic compounds suggest that glutamatergic systems modulated by SKCa channels may be important in schizophrenia pathogenesis. In the light of the above, we have tested the hypothesis of an association between schizophrenia and the hKCa3 CAG repeat polymorphism using a case control study design. Under the same model of analysis as the earlier study, schizophrenic probands had a higher frequency of alleles with greater than 19 repeats than controls (chi 2 = 2.820, P = 0.047, 1-tail). Our data therefore provide modest support for the hypothesis that polymorphism in the hKCa3 gene may contribute to susceptibility to schizophrenia.

Alleles↗
PubMed1998

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.

Bipolar Disorder↗
PubMed1998

Linkage analysis between bipolar affective disorder and markers on chromosome X.

Since 1969, several classical linkage studies suggested an X-chromosome locus for bipolar affective disorder. However, methods using highly polymorphic DNA markers have provided conflicting evidence for linkage, and an X-chromosomal locus for bipolar disorder remains controversial. More recently, Pekkarinen et al. (1995) found a maximum LOD score of 3.54 at the marker DXS994 in a large bipolar Finnish kindred. In the present study, we attempted to replicate this finding using 43 families multiply affected by bipolar affective disorder. These families were selected for the absence of male-to-male transmission of the disease, and were genotyped for two microsatellte markers, DXS1227 and DXS1062 (which is about 2 cM telomeric to DXS994). Linkage to this region was excluded either using a two-point lod score method with two plausible genetic models, or by a model-free lod score analysis which does not require specification of a particular mode of transmission. We conclude that there is no evidence of a common major gene for bipolar affective disorder at Xq25-q27 in our set of families.

Bipolar Disorder↗