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Strategies for the Study of Neuropsychiatric Disorders Directed by Genes

by Kathy Jones on  December 20, 2011 at 8:55 PM Genetics & Stem Cells News   - G J E 4
Conventional genetic approach has not helped in the identification of genes that contribute to a susceptibility to complex neuropsychiatric disorders such as schizophrenia, major depression and bipolar disorders.
 Strategies for the Study of Neuropsychiatric Disorders Directed by Genes
Strategies for the Study of Neuropsychiatric Disorders Directed by Genes
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There are several problems associating with this conventional approach including carriers of genes cannot be identified in the absence of manifest symptoms and the heterogeneity of neuropsychiatric disorders. A new direction that appears encouraging is the identification of neurobiological or neurobehavioural characteristics associated with these complex neuropsychiatric disorders, or endophenotypes, that may be more closely linked to gene expression. Endophenotype is a biomarker associating with genetic components as well as the clinical symptoms of neuropsychiatric disorders. It plays an important role to bridge the gap between microscopic level and macroscopic level of neuropsychiatric disorders. The identification of endophenotype, along with the advanced genetic analysis such genomewise association studies, is very crucial to the identification of genes that predispose someone to neuropsychiatric disorders. Therefore, the study of endophenotype is of particular useful for us to understand the underlying mechanism of the illness process of neuropsychiatric disorders, aiding the clinicians to make accurate diagnosis and for early detection purposes.

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With the supported from the National Basic Research Programme of China (973 Progamme) (2007CB512302), The Key Laboratory of Mental Health of the Institute of Psychology, Chinese Academy of Sciences has organized a strategic symposium for endophenotypes, titled ""Endophenotype strategy for psychotic disorders and summit meeting of Key Laboratory of Mental Health, Institute of Psychology, CAS". International renowned scholars of this field presented their updated findings on endophenotypes. Professor Irving Gottesman, the founder of the endophenotype for neuropsychiatric disorders, was also giving a video lecture to all the participants. Their work was published in the special issue of Chinese Science Bulletin, 2011, Vol. 56(32).

Cognitive deficits have been widely recognized as core features of schizophrenia, and as major contributors to the clinical outcome of the disorder. They are also studied widely as 'endophenotypes', reflecting a growing consensus that schizophrenia is a broader, more multidimensional illness than the diagnostic criteria required for its formal diagnosis. Stone and Hsi adopted this evolving view of cognition underlying its utilization in recent initiatives for intervention and assessment in schizophrenia, and illustrated it with the use of the MATRICS Cognitive Consensus Battery, a standardized battery of neuropsychological tests developed to assess the effectiveness of cognitive enhancing treatments in schizophrenia. They then further provided evidence to show the utilization of neuropsychological deficits in the identification, validation and remediation of a liability syndrome for schizophrenia ('schizotaxia'). Taken together, the inclusion of cognition in broader consortium and other collaborative efforts to assess interrelationships across multiple dimensions of function will provide important catalysts for progress in each individual dimension. Utilization of cognition underscores its functional importance in the clinical outcome of schizophrenia. Moreover, it helps to illuminate indicators of liability for schizophrenia that might be amenable to remediation.

On the other hand, Prof. Pak Sham and colleagues have addressed the statistical issues and approaches in endophenotype research. In this paper, they argued that in reality, a putative endophenotype is unlikely to be a perfect representation of the genetic component of disease liability. The magnitude of the correlation between a putative endophenotype and the genetic component of disease liability can be estimated by fitting multivariate genetic models to twin data. A number of statistical methods have been developed for incorporating endophenotypes in genetic linkage and association analyses with the aim of improving statistical power. The most recent of such methods can handle multiple endophenotypes simultaneously for the greatest increase in power. In addition to increasing statistical power, endophenotype research plays an important role in helping to understand the mechanisms which connect the associated genetic variants with disease occurrence. The causal pathways are likely to be very complicated and involve endophenotypes at multiple levels: from RNA expression profiles and patterns of protein expression, through neuronal and synaptic properties, to neurophysiological and neurocognitive function. Novel statistical approaches may be required for the analysis of the complex relationships between endophenotypes at different levels and how they converge to cause the occurrence of disease.

In the paper of Consortium for the Human Information and Neurocognitive Endophenotype (CHINE) in mainland China: An example from neurological soft signs for neuropsychiatric disorders, Chan made a strategic paper on endophenotypes and argued the need for establishing a central consortium for neuropsychiatric disorders in mainland China, namely the CHINE. The CHINE is intentionally established to pave the roadmap for neuropsychiatric disorders research. It not only identifies the biosignatures for neuropsychiatric disorders but also serves as the central databank for examining the etiologies of major complex neuropsychiatric disorders as well as serving as the main basis for corresponding treatment development. The CHINE emphasizes on two main features, i.e., the supposedly universal basic cognitive functioning such as attention, and the supposedly culturally specific social cognitive functioning such as emotion perception and expression. In this consortium, data collected highlights the genetic level (susceptibility genes associating with major neuropsychiatric disorders, neuroanatomical level (structural and functional imaging data), and behavioural level (neurocognitive function performances, social cognitive functioning, neurological and clinical manifestations). Target groups include both the clinically diagnosed patients suffering from neuropsychiatric disorders (mainly schizophrenia and bipolar disorders at the current moment, but will be extended to other clinical groups later), non-psychotic first-degree relatives of the patients, and healthy controls. Chan specifically illustrated an example of a promising endophenotype for schizophrenia, namely neurological soft signs, in detailing the steps for building the consortium. It is also noteworthy that the potential translational usage of neurological soft signs as a quick, quantifiable, sensitive and user-friendly bedside early detection and screening tool for clinical practice.



Source: Eurekalert
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