Biomedical subjects
Publications and source records attributed to N Craddock.
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.
OBJECTIVE: The clinical and pathologic features of hereditary dysphasic disinhibition dementia (HDDD) are described to determine whether it is a variant of known dementias. BACKGROUND: Several dementing disorders have clinical and pathologic similarities with AD, Pick's disease, and the "nonspecific" dementias. A detailed description of clinical and pathologic presentation will aid classification, but ultimately the discovery of causative gene(s) will define these disorders. METHODS: The authors performed a clinical assessment: gross and microscopic pathologic evaluation of brain tissue, genetic linkage studies, and sequence analyses. RESULTS: HDDD is an autosomal-dominant frontotemporal dementia with many similarities to Pick's disease. Salient clinical features are global dementia with disproportionate dysphasia and "frontotemporal" symptoms. A linkage between HDDD and 17q21-22 was shown, with a maximum lod score of 3.68 at zero recombination. CONCLUSIONS: Several dementias have been linked to the same region and have been termed frontotemporal dementia with parkinsonism linked to chromosome 17. These disorders may represent phenotypic variants arising from mutations within a common gene.
The hypothesis that expanded trinucleotide repeats (TNRs) contribute to the pathogenesis of bipolar disorder has received strong support from recent studies showing that, on average, bipolar patients carry larger repeat sequences of the TNR motif CAG/CTG than do controls. It has been postulated that intergenerational expansion of a TNR may be responsible for the tendency for age of onset to become earlier in younger generations (anticipation) observed in some bipolar pedigrees, and that length polymorphism may account for variability in clinical phenotype. We have used the method of repeat expansion detection to examine these predictions in a sample of 133 Caucasian DSM-III-R bipolar I probands from the British Isles. We found no evidence to support the notion that CAG/CTG TNR genes are major determinants of phenotypic severity or age at onset in the population examined, and conclude that for most cases of bipolar disorder TNR genes may operate as susceptibility genes rather than as single genes of major effect.
The hypothesis that expanded trinucleotide repeats contribute to the pathogenesis of schizophrenia and bipolar disorder has been recently supported by three independent studies which have shown that patients with either disorder 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 schizophrenia and bipolar disorder, we determined the repeat size at CAG/CTG loci mapping to candidate regions for psychosis. In this study we report our findings from eight loci which map to chromosome 4. We conclude that these loci are unlikely candidates for CAG/CTG repeat expansion in schizophrenia and bipolar disorder.
Explore the source record for details and available documents.
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.
Explore the source record for details and available documents.
OBJECTIVE: The purpose of this study was to identify the specific expanded CAG/CTG trinucleotide repeat associated with bipolar disorder. METHOD: The study employed an efficient multistage approach for using a genomic CAG/CTG screening set. RESULTS: The authors found no evidence of expanded repeats at 43 polymorphic autosomal loci and seven X chromosomal loci. Secondary screening was pursued at the only locus that contained a large allele (37 repeats) in the primary screening. No association was found between allele size and diagnostic status. CONCLUSIONS: It is highly unlikely that expansions in repeat size at any of the 50 candidate trinucleotide repeat loci examined are responsible for the association between expanded CAG/ CTG repeats and bipolar disorder. However, although the authors prioritized the repeats that were a priori most likely to be involved, the study does not reject the more general hypothesis that expanded CAG/CTG repeats are implicated in the pathogenesis of bipolar disorder.
Detection of linkage with a systematic genome scan in nuclear families including an affected sibling pair is an important initial step on the path to cloning susceptibility genes for complex genetic disorders, and it is desirable to optimize the efficiency of such studies. The aim is to maximize power while simultaneously minimizing the total number of genotypings and probability of type I error. One approach to increase efficiency, which has been investigated by other workers, is grid tightening: a sample is initially typed using a coarse grid of markers, and promising results are followed up by use of a finer grid. Another approach, not previously considered in detail in the context of an affected-sib-pair genome scan for linkage, is sample splitting: a portion of the sample is typed in the screening stage, and promising results are followed up in the whole sample. In the current study, we have used computer simulation to investigate the relative efficiency of two-stage strategies involving combinations of both grid tightening and sample splitting and found that the optimal strategy incorporates both approaches. In general, typing half the sample of affected pairs with a coarse grid of markers in the screening stage is an efficient strategy under a variety of conditions. If Hardy-Weinberg equilibrium holds, it is most efficient not to type parents in the screening stage. If Hardy-Weinberg equilibrium does not hold (e.g., because of stratification) failure to type parents in the first stage increases the amount of genotyping required, although the overall probability of type I error is not greatly increased, provided the parents are used in the final analysis.
Straub et al. (1994: Nature Genet. 8. 291-296) have suggested that a susceptibility gene for bipolar affective disorder is located at chromosome 21q22.3, on the basis of linkage analysis in one large family. This result has been supported by Gurling et al. (1995: Nature Genet. 10, 8-9) who also found some evidence for linkage to this region under locus heterogeneity. In order to investigate the validity of these results and to estimate how broadly applicable they are, we performed a linkage study between bipolar affective disorder and two DNA markers (D21S171 and PFKL) from 21q22.3 using 60 bipolar pedigrees from three European centres and Brazil. The most positive result obtained was a maximised admixture lod score of 1.2 for the marker PFKI, under the assumption of locus heterogeneity, dominant transmission and a diagnostic classification which included recurrent unipolar depression. However, since lod scores obtained for both markers were substantially negative overall, we conclude that there is no common major gene for bipolar affective disorder at 21q22.3. It remains possible that a gene of major effect in this region operates in a minority of families.
The ApoE-epsilon 4 allele is a predisposing factor for late onset Alzheimer's disease (AD), however it is neither necessary nor sufficient to cause the disease. A candidate for explaining part of the remaining genetic component is alpha 1-antichymotrypsin (AACT). In a case-control study we genotyped a polymorphism within the AACT gene to test for association with the disease. No allele of this gene showed an increased incidence among the population with AD compared with controls, even when taking ApoE genotype into account. This contrasts with the results of a recently published report. The mean age of onset was apparently lowered by the presence of the AACT AA genotype among ApoE-epsilon 4 bearers. If AACT genotype has an effect on risk for AD it may be predominantly amongst individuals with early onset AD.
We used computer simulation method to address the question of power in an initial collaborative sample of 51 bipolar affective disorder pedigrees. Simulations were performed for all possible combinations using (1) two levels of diagnostic stringency, (2) three transmission models, (3) locus heterogeneity, and (4) different assumed phenocopy rates. Some of the factors affect the power to detect linkage are (1) the specification of the correct genetic model, (2) the degree of locus heterogeneity, and (3) the frequency of phenocopies. The first two assertions were supported by our simulation results, but varying the rates of phenocopy did not substantially alter the power of the sample until a critical point. However, it is important to point out that these results are dependent on the genetic models under study and on the use of the "correct" model (i.e., the one used to simulate the data). If we assume a dominant mode of inheritance and locus homogeneity, the power to detect linkage is 97.5% at a theta of .01. However, the power declines dramatically, to 60.5% and 14.7%, if only 75 and 50% of the families are linked, respectively. Locus heterogeneity has a similar effect on the power of the sample to exclude linkage. The relative lack of power in our data, in the presence of significant locus heterogeneity, and for an intermediate mode of inheritance, underscores the need for multicenter collaboration.
Recent studies have suggested that expanded CAG/CTG repeats contribute to the genetic aetiology of schizophrenia and bipolar disorder. However, the nature of this contribution is uncertain and difficult to predict from other known trinucleotide repeat diseases that display much simpler patterns of inheritance. We have sought to replicate and extend earlier findings using Repeat Expansion Detection in an enlarged sample of 152 patients with schizophrenia, 143 patients with bipolar disorder, and 160 controls. We have also examined DNA from the parents of 62 probands with schizophrenia or bipolar disorder. Our results confirm our earlier, preliminary findings of an association between expanded trinucleotide repeats and both schizophrenia and bipolar disorder. However, our data do not support the hypothesis that trinucleotide repeat expansion can alone explain the complex patterns of inheritance of the functional psychoses neither can this mechanism fully explain apparent anticipation.
Major advances in molecular genetics over the last 15 years have made it possible to identify the genes responsible for human diseases using purely genetic approaches that do not require knowledge about disease pathophysiology. Many successes have been achieved for single gene disorders and methods are being adapted and refined for complex diseases. The main strategies include linkage and association studies to map the position of disease genes followed by investigation of potential candidate genes within these genomic regions. Successes have already been achieved in complex disorders such as diabetes and Alzheimer's disease, and it is almost certain that genes predisposing to the major psychiatric disorders will be identified over the next few years. This will lead to major advances in treatment, prevention and classification of mental illness and is likely to have a dramatic impact on clinical practice.
We have previously described a pedigree in which affective disorder and Darier's disease cosegregate and, in an independent sample of 45 bipolar pedigrees, reported evidence in support of linkage between a putative susceptibility locus for bipolar disorder and markers in the Darier's disease region of chromosome 12q23-q24.1. The maximum evidence for linkage was given by a polymorphism at the gene encoding secretory phospholipase A2 (PLA2A), a candidate gene for affective disorder. Dawson et al. (Psychiatric Genetics, 5, 177-180) recently reported allelic association with the same polymorphism at PLA2A in a sample of 54 bipolar probands and 56 controls. We have been unable to replicate the association in 127 Caucasian British DSMIII-R bipolar probands and 223 Caucasian British controls. However, on the basis of several lines of evidence discussed in the paper, we believe that this genomic region in general, and the PLA2A gene in particular, are worthy of further study as candidates in the search for susceptibility genes for the functional psychoses.
The majority of common psychiatric disorders pose problems for geneticists because of their complex and non-Mendelian modes of inheritance. Early attempts to map genes for mental illness have so far largely overlooked this and sought genes of major effect in multiplex families using the lod score method of linkage analysis. However it seems that major genes are likely to be at best rare causes of common mental disorders, and the majority of cases probably reflect the interaction of several and perhaps many genes of comparatively small effect. There are two complementary sets of strategies that allow such genes to be identified. The first is to perform linkage analysis based on allele sharing in pairs of affected relatives. The second is to carry out association studies on samples of unrelated individuals. These methods and their applicability to psychiatric disorders are described. Psychiatric genetics has traditionally focussed on categorical phenotypes, but if valid continuous measures can be developed, powerful quantitative trait loci (QTL) approaches may also become feasible. Another important area is likely to be the study of relevant models in animals such as rodents in which genetic studies have many advantages. Finally we should not overlook the possibility that there are molecular explanations for irregular patterns of transmission such as mitochondrial inheritance, genomic imprinting and dynamic mutations.