Understanding Of Complex Disorders Research Articles

The Panomics Approach in Neurodegenerative Disorders.

The molecular genetic technologies revolutionized the diagnostics of many disorders. Thanks to the new molecular techniques and the rapid improvement of the information technologies the number of mendelien inherited disorders has increased rapidly in the last five years. The omics era brought radical changes in the understanding of complex disorders and the underlying pathomechanisms. However, in most complex disorders the genome wide association studies could not clarify the genetic background even for disorders where a very strong heritability had been observed. In this paper the changing concept of the neurodegenerative disorders is discussed. The traditional classification of these disorders was purely based on clinical symptoms and morphological signs in the last century. Identifying the signature lesions of various neurodegenerative disorders may reveal a common pathological pathway in these disorders. New neuroimaging methods provided additional tools to assess pathological pathways in vivo already in the early stages of the diseases. Visualizing in vivo amyloid deposits and neuroinflammation improved our understanding of their role in various neurodegenerative disorders. Genetics may be the most precise way to identify the background of these disorders. However, there is only limited number of cases where true association can be proved between the disorder and the genetic mutations. Most of the neurodegenerative disorders seem to be multifactorial and cannot be traced back to one single cause. In conclusion, shifting from a classification based on symptomatology only to a modern multidisciplinary approach, based on the constantly evolving panomics findings, would improve our understanding of neurodegenerative diseases and could be the basis of novel therapeutic research.

Participation in biobanks for research by incapacitated adults: review and discussion of current guidelines

Biobanks for research and genetic research are important opportunities to create new understanding of complex disorders, such as psychiatric disorders and dementia. The management of biobanks for subjects with psychiatric disorders or dementia raises additional challenges because of the ethical issues regarding the potentially impaired decision-making capacities of the subjects. The aim of this paper is to study (i) how guidelines address the matter and (ii) how they can be implemented in real research situations with patients suffering from psychiatric disorders and dementia. We collected and analysed all the relevant guidelines and position papers from national and international organizations dealing with research on biological materials and selected documents mentioning the participation of incapacitated adults in genetic research and biobanks. Eighteen of the 30 analysed documents contain explicit references to adults who are unable to give consent. The main topics addressed by the guidelines are the following: (i) informed consent; (ii) principles of non-therapeutic research; and (iii) ethics committee review. In biomedical research, guidelines are an important instrument for facilitating research while promoting subjects' rights and well-being. Compared with legally binding documents, guidelines are more flexible and can be more easily revised according to evolving research situations and for adaptation to real persons and research settings. We suggest measures to implement the analysed guidelines taking into consideration the case for the participation of patients with neuropsychiatric disorders, who can have impairment of decision-making capacities without being obviously incompetent, in genetic research and biobanks.

Induced pluripotent stem cells: An emerging tool for the study of human inherited retinal disease

Human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) are both valuable sources of retinal cell types for in vitro and in vivo studies. However, unlike hESCs, hiPSCs can be derived from individual patients and therefore offer a unique opportunity to model human retinal disease. Using protocols developed in our laboratory, hiPSCs derived from patients with selected inherited retinal disorders (eg, gyrate atrophy (GA) and Best vitelliform macular dystrophy (BVMD)) and normal controls underwent targeted differentiation to obtain enriched cultures of affected retinal cell types. Thereafter, the retinal cell cultures were examined to determine whether disease-specific phenotypes could be recapitulated in vitro. Molecular, biochemical, and physiological analyses revealed phenotypes in hiPSC-derived cell populations that could be used to test drug efficacy and/or study the underlying disease mechanism(s). For the GA culture model, a deficit in ornithine aminotransferase activity was present in differentiated hiPSC-RPE cells that could be improved with high dose vitamin B6. In the BVMD culture model, hiPSC-RPE cells from affected patients showed greater accumulation of ingested photoreceptor outer segment material and reduced transcellular fluid flux compared to sibling control hiPSC-RPE. Subsequent investigation suggested a role for BESTROPHIN-1, the protein mutated in BVMD, in the regulation of key RPE functions. In designing a hiPSC modeling study, care should be taken to select retinal disorders that have a reasonable expectation of recapitulating key pathophysiological processes in culture. In addition, a means to enrich for cell type(s) targeted by the disease is necessary; otherwise, the task of assuring a reproducible culture environment becomes daunting. Taking these and other limitations of hiPSC modeling into consideration, inherited diseases of the retina remain appealing, particularly monogenetic, early-onset diseases that affect the RPE. As we improve our understanding of complex disorders and our ability to build more intricate culture environments, the number and types of retinal diseases amenable to hiPSC modeling will broaden. hiPSCs represent a new and potentially powerful tool that can help close the gap between our knowledge of the genetics and the biology of inherited retinal diseases. In addition, custom hiPSC retinal model systems could be used to test known therapeutics and develop drug and gene therapy screening platforms. However, limitations exist in any culture system; thus, hiPSC technology is envisioned to complement, not supplant, existing laboratory models of disease.

Detecting Rare Variants for Psychiatric Disorders Using Next Generation Sequencing: A Methods Primer

Recent advances in massively parallel sequencing (MPS) have had an extensive impact on research in medical genomics. In particular, the analysis of rare variants using MPS promises to lead to a better understanding of complex disorders. Nevertheless, for meaningful studies that address the genetic basis for neuropsychiatric disorders, at least hundreds of patient samples have to be analyzed. This undertaking is still not feasible for single research groups on a whole-genome scale and in individual samples. Thus, researchers increasingly employ strategies for reducing the amount of sequencing efforts, such as target enrichment and non-barcoded sample pooling. This review provides an overview of current technologies, discusses options for reduced experimental designs, and illustrates the successful application of the presented methodologies in a recent study of panic disorder patients. Thereby, it aims to introduce the emerging field of MPS into neuropsychiatric research and might serve as a guide for further studies.