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      Incorporation of molecular data and redefinition of phenotype: new approaches to genetic epidemiology of bipolar manic depressive illness and schizophrenia Translated title: Incorporación de información molecular y redefinición del fenotipo: nuevas aproximaciones a la epidemiología genética de la enfermedad bipolar maníaco-depresiva y de la esquizofrenia Translated title: Prise en compte des données moléculaires et redéfinition du phénotype: avancées dans le domaine de l'épidémiologie génétique de la maladie bipolaire maniacodépressive et de la schizophrénie

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          Abstract

          Considerable advances have been made in identifying specific genetic components of bipolar manic depressive illness (BP) and schizophrenia (SZ), despite their complex inheritance. Meta-analysis of all published whole-genome linkage scans reveals overall support for illness genes in several chromosomal regions. In two of these regions, on the lonq arm of chromosome 13 and on the long arm of chromosome 22, the combined studies of BP and SZ are consistent with a common susceptibility locus for the two disorders. This lends some plausibility to the hypothesis of some shared genetic predispositions for BP and SZ. Other linkages are supported by multiple studies of specific chromosomal regions, most notably two regions on chromosome 6 in SZ. The velocardiofacial syndrome is associated with deletions very close to the linkage region on chromosome 22, and with psychiatric manifestations of both BP and SZ. Endophenotypes of SZ, previously demonstrated to be heritable, have been found to have chromosomal linkage in at least one study. These include eye-tracking abnormalities linked to the short arm of chromosome 6, and abnormality of the P50 cortical evoked potential linked to chromosome 15. Variants in specific genes have been associated with susceptibility to illness, and other genes have been associated with susceptibility to side effects of pharmacological treatment. These genetic findings may eventually be part of an integrated genetic, environmental, and interactive-factor epidemiology of the major mental illnesses.

          Translated abstract

          Se han realizado avances significativos en la identificación de componentes genéticos específicos de la enfermedad bipolar maníacodepresiva (BP) y de la esquizofrenia (EQZ) a pesar de su compleja herencia. El meta-análisis de todos los mapeos de enlaces del genoma completo publicados revela una fuerte base para genes enfermos en regiones de algunos cromosomas. En dos de estas regiones, en el brazo largo del cromosoma 13 y en el brazo largo el cromosoma 22, los estudios combinados de BP y EQZ son consistantes con un locus de susceptibilidad común para los dos trastornos. Esto proporciona alguna credibilidad a la hipótesis de cierta predisposición genética compartida para BP y EQZ. Otros enlaces están sustentados por múltiples estudios de regiones cromosómicas específicas, más notablemente dos regiones en el cromosoma 6 en la EQZ. El síndrome velocardiofacial está asociado con supresiones muy cercanas a la región de enlace en el cromosoma 22 y con manifestaciones psiquiátricas tanto de BP como de EQZ. Endofenotipos de EQZ, que previamente demostraron ser heredados, al menos en un estudio se ha encontrado que tienen ligazón cromosómica. Estos incluyen anormalidades del seguimiento ocular, el cual está ligado al brazo corto del cromosoma 6 y anormalidades del potencial evocado cortical P50 ligado al cromosoma 15. Se han asociado variantes en genes específicos con la susceptibilidad para la enfermedad, y otros genes se han vinculado con susceptibilidad a los efectos colaterales del tratamiento farmacológico. Estos hallazgos genéticos pueden ser parte, eventualmente, de una integración genética, ambiental y de un factor epidemiológico interactive en las principales enfermedades mentales.

          Translated abstract

          Des avancées très importantes ont été réalisées dans l'identification des composants génétiques spécifiques porteurs de la psychose maniacodépressive (PMD) et de la schizophrénie (SZ) malgré l'hérédité complexe de ces deux maladies. Une métaanalyse de la carte des liaisons génétiques publiées sur l'ensemble du génome révèle un consensus général sur l'atteinte des gènes dans plusieurs régions chromosomiques. Dans deux de ces régions, sur le bras long du chromosome 13 et celui du chromosome 22, les résultats des études combinées sur la PMD et la SZ sont concordants et incriminent un gène commun de susceptibilité pour les deux maladies. L'hypothèse de prédispositions génétiques communes à la PMD et à la SZ se trouve donc confortée. D'autres régions chromosomiques spécifiques, surtout deux régions sur le chromosome 6 dans la SZ, ont fait l'objet de multiples études qui ont mis en évidence d'autres liaisons. Le syndrome vélo-cardio-facial est associé à des délétions très proches du groupe de liaison sur le chromosome 22 et à des manifestations psychiatriques identiques à celles de la PMD et à la SZ. Une étude au moins a mis en évidence des liaisons chromosomiques avec les endophénotypes de la SZ, connus comme étant héréditaires. Ces liaisons concernent les anomalies de la poursuite oculaire liées au bras court du chromosome 6 et une anomalie du potentiel évoqué cortical P50 liée au chromosome 15. Des variantes de gènes spécifiques ont été associées à une prédisposition à la maladie et d'autres gènes à une susceptibilité aux effets secondaires du traitement. Ces données génétiques pourraient un jour trouver leur place dans le cadre d'une définition épidémiologique des principales maladies psychiatriques intégrant les aspects génétiques et environnementaux ainsi que les facteurs interactifs.

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          Most cited references 112

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          Parametric and nonparametric linkage analysis: a unified multipoint approach.

          In complex disease studies, it is crucial to perform multipoint linkage analysis with many markers and to use robust nonparametric methods that take account of all pedigree information. Currently available methods fall short in both regards. In this paper, we describe how to extract complete multipoint inheritance information from general pedigrees of moderate size. This information is captured in the multipoint inheritance distribution, which provides a framework for a unified approach to both parametric and nonparametric methods of linkage analysis. Specifically, the approach includes the following: (1) Rapid exact computation of multipoint LOD scores involving dozens of highly polymorphic markers, even in the presence of loops and missing data. (2) Non-parametric linkage (NPL) analysis, a powerful new approach to pedigree analysis. We show that NPL is robust to uncertainty about mode of inheritance, is much more powerful than commonly used nonparametric methods, and loses little power relative to parametric linkage analysis. NPL thus appears to be the method of choice for pedigree studies of complex traits. (3) Information-content mapping, which measures the fraction of the total inheritance information extracted by the available marker data and points out the regions in which typing additional markers is most useful. (4) Maximum-likelihood reconstruction of many-marker haplotypes, even in pedigrees with missing data. We have implemented NPL analysis, LOD-score computation, information-content mapping, and haplotype reconstruction in a new computer package, GENEHUNTER. The package allows efficient multipoint analysis of pedigree data to be performed rapidly in a single user-friendly environment.
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            Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus.

            Type 2 or non-insulin-dependent diabetes mellitus (NIDDM) is the most common form of diabetes worldwide, affecting approximately 4% of the world's adult population. It is multifactorial in origin with both genetic and environmental factors contributing to its development. A genome-wide screen for type 2 diabetes genes carried out in Mexican Americans localized a susceptibility gene, designated NIDDM1, to chromosome 2. Here we describe the positional cloning of a gene located in the NIDDM1 region that shows association with type 2 diabetes in Mexican Americans and a Northern European population from the Botnia region of Finland. This putative diabetes-susceptibility gene encodes a ubiquitously expressed member of the calpain-like cysteine protease family, calpain-10 (CAPN10). This finding suggests a novel pathway that may contribute to the development of type 2 diabetes.
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              Allele-sharing models: LOD scores and accurate linkage tests.

              Starting with a test statistic for linkage analysis based on allele sharing, we propose an associated one-parameter model. Under general missing-data patterns, this model allows exact calculation of likelihood ratios and LOD scores and has been implemented by a simple modification of existing software. Most important, accurate linkage tests can be performed. Using an example, we show that some previously suggested approaches to handling less than perfectly informative data can be unacceptably conservative. Situations in which this model may not perform well are discussed, and an alternative model that requires additional computations is suggested.
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                Author and article information

                Contributors
                Department of Psychiatry, University of Chicago, Chicago, III, USA
                Department of Psychiatry, University of Chicago, Chicago, III, USA
                Journal
                Dialogues Clin Neurosci
                Dialogues Clin Neurosci
                Dialogues in Clinical Neuroscience
                Les Laboratoires Servier (France )
                1294-8322
                1958-5969
                March 2001
                March 2001
                : 3
                : 1
                : 63-71
                Affiliations
                Department of Psychiatry, University of Chicago, Chicago, III, USA
                Department of Psychiatry, University of Chicago, Chicago, III, USA
                Author notes
                Article
                3181639
                22034205
                Copyright: © 2001 LLS

                This is an open-access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by-nc-nd/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Categories
                Clinical Research

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