Although the prominent role of genetics in psychiatric diseases has been established in various family, twin and adoption studies over the last decades, the identification of concrete contributing genes has been demanding. The reasons for this are manifold, including inconsistencies in psychiatric classification systems, complexity and heterogeneity of psychiatric disorders, epistatic effects and intervening environmental factors. In recent years interest has focused increasingly on the concept of endophenotypes. Genetic analyses have concentrated on discrete phenotypes supposedly linked to a particular psychiatric disorder by common neurobiological pathways, instead of studying the complex disease itself. Several endophenotypes have been established for psychiatric diseases including electrophysiological abnormalities and alterations in structural and functional brain imaging. Although results seem to be getting more consistent and reliable, several concerns have also emerged with the experience gained on the topic. This review will give an overview of the prospects and limitations related to endophenotypes in psychiatric diseases. We will also summarize essential prerequisites for successful endophenotypes in the future as well as applications for psychiatric diseases which have been envisioned.
[Show abstract][Hide abstract] ABSTRACT: A database of 86 Permian brachiopod families, 411 genera and 1931 species of the Asian-western Pacific region was analysed using a range of statistical measures to unravel the changing patterns of diversity, origination and extinction rates through six Permian intervals. Prior to the quantitative analysis, the evolutionary pattern of the Permian marine provincialism of the region was reviewed to provide a framework for investigating possible palaeogeographical patterns of the Permian brachiopod extinctions and the likelihood of biogeographical control on the extinctions. It was revealed that the Permian brachiopod diversity variation and extinction patterns are broadly compatible among the Gondwanan, Palaeo-equatorial and Boreal Realms as well as with the overall diversity and extinction pattern of the Asian-western Pacific region. Two major extinctions are recognised regardless of taxonomic ranks (species, genera, or families): one occurring during the Kazanian-Midian (end-Guadalupian) and the other at the Changhsingian. The end-Guadalupian extinction is most pronounced in the Gondwanan and Boreal Realms and less well expressed in the Palaeo-equatorial Realm. On a regional scale, the end-Guadalupian extinction appears to have lasted through the whole Kazanian-Midian interval. The Changhsingian extinction is recorded only in the Palaeo-equatorial and Gondwanan Realms. This event appears to be much more severe than the end-Guadalupian extinction and also lasted a much shorter duration than the latter event. The two major extinction episodes were coupled with low originations. Comparatively high originations occurred in the Sterlitamakian-Aktastinian (middle Early Permian) and Wuchiapingian (early Late Permian). It was also revealed that there appears to be a positive correlation between provinciality and species and generic diversity, but not direct, consistent correlation between Permian palaeolatitude and brachiopod species diversity in the Asian-western Pacific region. Discussion on the causes of Permian extinctions was not intended. However, we found that there is a good correlation in timing between the end-Guadalupian extinction and at least a regional (Asian-western Pacific wise) regression. The relationship between eustatic motion and the Changhsingian extinction is far less clear. Although an end-Changhsingian transgression appears evident in view of our field observations of several sections in South China, the exact timing of this event in relation to the timing of the Changhsingian extinction requires further study.
Developments in Palaeontology and Stratigraphy 01/2000; 18. DOI:10.1016/S0920-5446(00)80019-9
[Show abstract][Hide abstract] ABSTRACT: AbstractIn this thesis we have studied genetic elements potentially contributing to the pathophysiology of psychiatric disorders, focusing on different sources of human genome variability, including SNPs and CNVs, which can affect not only coding genes but also RNA regulatory elements, such as miRNAs. First, we have interrogated different candidate genes for psychiatric disorders overlapping with known CNVs, finding 14 different genes variable in copy number in psychiatric disorders but not in control individuals. Then, narrowing the analysis on mood disorders, we explored GSK3β gene considering both SNPs and a partially overlapping CNV. The GSK3β promoter and intron 1 region was found significantly associated with an earlier onset of the major depressive disorder. Finally, we have found evidence possibly pointing to a precise post-transcriptional regulation of circadian rhythms by miRNAs in mood disorder patients. Concretely, a variant in the precursor form of miR-182 could play an important role in fine-tuning its target sites involved in the control of sleep/wake cycles. Overall, we have provided evidence of different types of genome variation on neuronal genes or miRNA regulatory regions that can potentially contribute to the development of psychiatric disorders.ResumEn aquesta tesi hem estudiat elements genètics que podrien contribuir potencialment en la fisiopatologia dels trastorns psiquiàtrics, centrant-nos en diferents fonts de variabilitat genòmica humana, incloent els SNPs i els CNVs, els quals poden afectar no només a gens codificants sinó també a elements reguladors, com els miRNAs. Primer, vam interrogar diferents gens candidats per trastorns psiquiàtrics solapats amb CNVs coneguts, trobant que 14 gens eren variables en el número de còpia en pacients però no en individus controls. Després, restringint lanàlisi a trastorns afectius, vam explorar el gen GSK3β considerant SNPs així com també un CNV que se solapa parcialment amb el gen. Vam trobar la regió del promotor i de lintró 1 del gen GSK3β associada de manera significativa amb una inferior edat dinici del trastorn de depressió major. Finalment, hem trobat evidències que possiblement indiquen una precisa regulació post-transcriptional dels ritmes circadians per miRNAs en pacients amb trastorns afectius. Concretament, una variant en la forma precursora del miR-182 podria jugar un paper important en la fina regulació dels seus gens diana implicats en el control dels cicles de son i vigília. En general, hem aportat evidències de què diferents tipus de variació genòmica en gens neuronals o regions reguladores com els miRNAs podrien contribuir potencialment en el desenvolupament de trastorns psiquiàtrics.
[Show abstract][Hide abstract] ABSTRACT: Associations between the well-known functional single nucleotide polymorphism Val (158)Met in the gene encoding catechol- O-methyltransferase (COMT) and cognitive do-mains affected in schizophrenia are inconsistent regarding directionality and specific impact and call for a more fundamental cognitive endophenotype. Recent studies suggest that the COMT genotype contributes to cognitive flexibility, a fundamental cognitive ability that potentially influences an individual's performance in a variety of other neurocognitive tasks.
We investigated the association between COMT Val (158)Met genotype and cognitive flexibility as assessed by signal discrimination in the Continuous Performance Test - Identical Pairs version in a cohort of 111 German schizophrenic patients.
COMT genotype was significantly associated with signal discrimination index d' in schizophrenia. The Val/Val genotype was associated with the highest and the Met/Met genotype with the lowest scores; heterozygous individuals displayed an intermediate performance.
Our data suggest that allelic variation at the COMT Val (158)Met locus may influence signal discrimination capacity in schizophrenia and confirm that Val loading, probably due to decreased prefrontal dopamine availability, is associated with greater cognitive flexibility, which in turn may influence other cognitive measures that have been associated with COMT to date.
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