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Dissertations / Theses on the topic 'Genetic disorders; Disease genes'
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Melin, Malin. "Identification of Candidate Genes in Four Human Disorders." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-7344.
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Warner, Thomas Treharne. "A molecular genetic study of inherited movement disorders." Thesis, University College London (University of London), 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.285185.
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Abecasis, G. R. "Methods for fine mapping complex traits in human pedigrees." Thesis, University of Oxford, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.365700.
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Melville, Scott Andrew Biotechnology & Biomolecular Sciences Faculty of Science UNSW. "Disease gene mapping in border collie dogs." Awarded by:University of New South Wales. School of Biotechnology and Biomolecular Sciences, 2006. http://handle.unsw.edu.au/1959.4/25511.
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Pedigree dog breeds are genetically isolated and inbred populations with characteristics specific to each breed. Some breeds carry genetic diseases which affect the health of the animals, but may also serve as a valuable model to identify genes involved in human disease. In the Border Collie breed in Australia, the identification of two disease genes would enable breeders to DNA test their animals and prevent future cases. Over 530 samples were collected to identify the genes responsible for these diseases through linkage mapping and candidate gene approaches. Collie Eye Anomaly (CEA) defines a group of symptoms that cause the incorrect development of different regions within the eye, and may also result in the detachment of the retina. The presence of the disease in different breeds of collies suggests that the disease originated before the differentiation of the collie breeds. The CEA gene was mapped to a region of CFA37, but the disease gene was identified by another research group. Neuronal Ceroid Lipofuscinosis (NCL) is a fatal neurodegenerative disorder that affects Border Collie dogs from approximately 16 months of age. The disease is inherited in an autosomal recessive manner and affected animals display a range of physiological and behavioural symptoms that include loss of muscular control, nervousness and sometimes aggression. Due to the debilitating nature of the disease, dogs rarely survive beyond 28 months of age. Microsatellite markers were used to exclude the Border Collie NCL gene from the region of the English Setter NCL gene (homolog of human NCL gene CLN8). Further work mapped the disease gene to CFA22, in a region containing the homolog for CLN5, one of the identified human disease genes for NCL. Subsequent sequencing of canine CLN5 revealed a nonsense mutation (c.619C>T, Q206X) that co-segregated with NCL in Border Collie pedigrees. This truncation mutation resulted in a protein product of similar size to some mutations identified in human CLN5 and therefore the Border Collie may make a good model for future NCL studies. With DNA testing now available, breeders of Border Collies can now ensure that no animal will die of NCL.
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Fisher, Simon E. "Positional cloning of the gene responsible for Dent's disease." Thesis, University of Oxford, 1995. http://ora.ox.ac.uk/objects/uuid:22f6e7a5-4f00-41c9-a1d3-1b05899f22c0.
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The hypervariable locus DXS255 in human Xp11.22 has a heterozygosity exceeding 90% and has therefore facilitated the localization of several disease genes which map to the proximal short arm of the X chromosome, including the immune deficiency Wiskott-Aldrich syndrome and the eye disorders retinitis pigmentosa, congenital stationary night blindness and Aland Island eye disease. In addition, a microdeletion involving DXS255 has been identified in patients suffering from Dent's disease, a familial X-linked renal tubular disorder which is characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis (kidney stones) and eventual renal failure. Two YAC contigs were constructed in Xp11.23-p11.22 in order to aid transcript mapping; the first centred on the DXS255 locus, the second mapping distal to the first and linking the genes GATA, TFE3 and SYP to the OATL1 cluster. Eleven novel markers were generated, one of which contains an exon from a novel calcium channel gene. Four putative CpG islands were detected in the region. Analysis of the microdeletion associated with Dent's disease using markers from the DXS255 contig demonstrated that it is confined to a 370kb interval. A YAC overlapping this deletion was hybridized to a kidney-specific cDNA library to isolate coding sequences that might be implicated in the disease aetiology. The clones thus identified detect a 9.5kb transcript which is expressed predominantly in kidney, and originate from a novel gene (CLCN5) falling within the deleted region. Sequence analysis indicates that the 746 residue protein encoded by this gene is a new member of the C1C family of voltage-gated chloride channels. The coding region of CLCN5 is organized into twelve exons, spanning 25-30kb of genomic DNA. Using the information presented in this thesis, other studies have identified deletions and point mutations which disrupt CLCN5 activity in further patients affected with X-linked hypercalciuric nephrolithiasis, confirming the role of this locus in renal tubular dysfunction.
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Oellrich, Anika. "Supporting disease candidate gene discovery based on phenotype mining." Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.648355.
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Stephenson, Nicole E. "Examination of the involvement of the Stat6-regulated genes, Gfi-1 and Gfi-1b, in the development of a lymphoproliferative disease in mice." Virtual Press, 2008. http://liblink.bsu.edu/uhtbin/catkey/1391679.
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Mouse models (that develop or can be stimulated to develop lymphomas) are used to examine cancer-related processes. Mouse models can be effective tools used to identify new, early, and pre-malignant markers of lymphomas. Signal Transducer and Activator of Transcription (STAT) 6 is a transcription factor activated through the Jak-Stat pathway. Transgenic mice expressing a constantly activated Stat6 (Stat6VT) were previously generated and characterized to have altered lymphocyte homeostasis. Some of these Stat6VT mice developed a lymphoproliferative disorder (LPD). LPD, including lymphomas, develops when lymphocytes are overproduced or act abnormally. These Stat6VT mice may serve as a model for examining lymphoma development. In order to characterize the altered lymphocytes and determine if LPD observed in the Stat6VT mice is characteristic of lymphoma, RT-PCR analysis and Western analysis were done to examine if the presence of Stat6VT alters the expression of the cell cycle genes Gfi-1 and Gfi-1b and if these genes differ in LPD Stat6VT verses control mice.Department of Biology
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Worgan, Lisa Catherine Women & Children's Health UNSW. "The role of nuclear-encoded subunit genes in mitochondrial complex 1 deficiency." Awarded by:University of New South Wales. Women and Children's Health, 2005. http://handle.unsw.edu.au/1959.4/22307.
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BACKGROUND: Mitochondrial complex I deficiency often leads to a devastating neurodegenerative disorder of childhood. In most cases, the underlying genetic defect is unknown. Recessive nuclear gene mutations, rather than mitochondrial DNA mutations, account for the majority of cases. AIM: Our aim was to identify the genetic basis of complex I deficiency in 34 patients with isolated complex I deficiency, by studying six of the 39 nuclear encoded complex I subunit genes (NDUFV1, NDUFS1, NDUFS2, NDUFS4, NDUFS7 and NDUFS8). These genes have been conserved throughout evolution and carry out essential aspects of complex I function. METHODS: RNA was extracted from patient fibroblasts and cDNA made by reverse transcription. Overlapping amplicons that together spanned the entire coding area of each gene were amplified by PCR. The genes were screened for mutations using denaturing High Performance Liquid Chromatography (dHPLC). Patient samples with abnormal dHPLC profiles underwent direct DNA sequencing. RESULTS: Novel mutations were identified in six of 34 (18%) patients with isolated complex I deficiency. Five patients had two mutations identified and one patient had a single mutation in NDUFS4 identified. All patients with mutations had a progressive encephalopathy and five out of six had Leigh syndrome or Leigh like syndrome. Mutations were found in three nuclear encoded subunit genes, NDUFV1, NDUFS2 and NDUFS4. Three novel NDUFV1 mutations were identified (R386H, K111E and P252R). The R386H mutation was found in two apparently unrelated patients. Four novel NDUFS2 mutations were identified (R221X, M292T, R333Q and IVS9+4A<G). The novel NDUFS4 mutation c.221delC was found in two patients - one in homozygous form and the other heterozygous. Specific genotype and phenotype correlations were not identified. CONCLUSIONS: Nuclear encoded complex I subunit gene mutations are an important contributor to the aetiology of isolated complex I deficiency in childhood. Screening of these genes is an essential part of the investigation of complex I deficiency.
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Ross, Colin J. D. "Immuno-isolation gene therapy for lysosomal storage disease /." *McMaster only, 2001.
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Zhou, ZiaoLei. "Molecular genetic studies of colorectal cancer /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-489-9/.
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Smotherman, Jesse M. "The Impact of Causative Genes on Neuropsychological Functioning in Familial Early-Onset Alzheimer's Disease: A Meta-Analysis." Thesis, University of North Texas, 2017. https://digital.library.unt.edu/ark:/67531/metadc984161/.
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Mutations of three genes encoding amyloid precursor protein (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) have been shown to reliably result in familial early-onset Alzheimer's disease (FAD); a rare, but catastrophic, subtype of Alzheimer's disease (AD) marked by symptom emergence before age 65 as well as accelerated cognitive deterioration. The current study represents the first known meta-analysis on the association of APP, PSEN1 or PSEN2 on neurocognitive variables. A total of 278 FAD mutation-carriers (FAD-MC) and 284 cognitively healthy non-mutation-carriers (NC) across 10 independent investigations meeting inclusion criteria were chosen for the current meta-analysis (random effects design). Findings revealed an overarching trend of poorer performance by FAD-MC individuals compared to NC individuals across the majority of cognitive domains identified. Significant differences in effect sizes suggested FAD-MC individuals exhibited worse performance on measures of attention, explicit memory, fluency, primary memory, verbal, and visuospatial functioning. Findings indicative of differential sensitivity to cognitive domain impairments across FAD-MC and NC groups inform neuropsychological descriptions of individuals in preclinical phases of FAD.
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Gui, Eng Hock. "Modelling the impact of genetic testing on insurance : early-onset Alzheimer's disease and other single-gene disorders." Thesis, Heriot-Watt University, 2003. http://hdl.handle.net/10399/432.
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Buervenich, Silvia. "Candidate genes and the dopamine system : possible implications in complex neurological and psychiatric disease /." Stockholm, 2002. http://diss.kib.ki.se/2002/91-7349-202-7.
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Prats, Balado Claudia. "Genetic risk factors in Schizophrenia and Neurodevelopmental disorders: Association and epistatic analyses of Neuritin-1 gene and white matter related genes = Factores genéticos en esquizofrenia y enfermedades del neurodesarrollo: análisis de asociación y epistáticos en el gen Neuritina-1 y en genes relacionados con la materia blanca." Doctoral thesis, Universitat de Barcelona, 2017. http://hdl.handle.net/10803/456897.
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Nowadays, it is estimated that about 450 million people suffer from a mental or behavioural disorder in the world. According to World health organization (WHO), 33% of the years lived with disability (YLD) are due to psychiatric disorders. In this regard, psychotic disorders including schizophrenia (SZ), remain one of the most mysterious and costliest mental disorders in terms of human suffering and social expenditure.
In recent years, the field of molecular genetics has been uncovering evidence of the complex polygenetic architecture of SZ and related disorders. In addition, GWAS studies have identified several genes associated with SZ, which have been shown to converge in complex and identifiable molecular pathways related to synaptic plasticity, neurotransmission and connectivity processes. Also, these studies have reported an important genetic overlap across several psychiatric disorders such as Schizophrenia (SZ), Bipolar disorder (BPD), Major Depressive Disorder (MDD) or Autism Spectrum Disorders (ASD), which adds to the consideration of common pathophysiological mechanisms among these disorders. In this sense, a growing body of evidence has established that connectivity and synaptic plasticity, modulated by neuronal activity, is an inherent feature of brain function during both development and adulthood.
The present dissertation hypothesizes that genetic variability of genes involved in either synaptic plasticity (NRN1, BDNF and DTNBP1) and/or white matter related pathways (and their interactions) will be associated with SSD. In addition, due to the clinical, cognitive, neuroimaging and genetic overlap observed across different psychiatric disorders, we also hypothesize that the studied genetic variability will be also associated with other neurodevelopmental psychiatric disorders, such as ASD and BPD. In this sense, four studies have been carried out. The first three studies, analyse genetic variability at Neuritin-1 gene (NRN1) and its relationship with the risk for developing SSD and BPD, and also with some clinical and cognitive phenotypes both in patients and in healthy subjects from the general population. Moreover, in these studies we also analyzed whether NRN1 action is modulated by other genes such as BDNF and DTNBP1. The fourth study analyses the integrative effects of a set of white matter related genes (Oligodendrocyte/myelination related genes - OMR) and its contribution to both SSD and ASD. Our results focused on the genetic variability at NRN1 gene, suggest that genetic variability of NRN1 gene has an impact on the risk for developing SSD/BPD and also on the presence of depressive symptoms in the general population. Its pleiotropic effect is also evidenced by its effect on different phenotypes: such as cognitive performance and age at onset. Moreover, our genexgene interaction results suggest that NRN1 action is modulated by the BDNF and DTNBP1 genes. On the other hand, the results of the fourth study suggest that some of the OMR genetic risk variants seem to be shared across SZ-ASD continuum. The fact that some OMR genes are marginally associated with both disorders and also, due to their involvement in the detected epistatic effects, seem to support the notion that dysregulation in myelination processes may underlie susceptibility to develop ASD or SSD. To conclude, further genetic studies are needed to elucidate the biological background underlying mental disorders, which can ultimately lead to better treatment in order to improve the quality life of the patients.Actualmente, se estima que alrededor de 450 millones de personas en el mundo sufren de un trastorno mental o de la conducta. Según la Organización Mundial de la Salud (OMS), el 33% de los años vividos con discapacidad (YLD) se asocian a trastornos psiquiátricos. En este sentido, los trastornos psicóticos, incluyendo la esquizofrenia (EQ), siguen siendo uno de los trastornos mentales más desconocidos y costosos en términos de sufrimiento humano y gasto social. En los últimos años, el campo de la genética molecular ha estado descubriendo evidencias acerca de la compleja arquitectura poligénica de la EQ y de otros trastornos relacionados. Además, los estudios GWAS han identificado varios genes asociados con EQ, los cuales se ha demostrado que convergen en vías moleculares complejas e identificables relacionados con la plasticidad sináptica, la neurotransmisión y los procesos de conectividad. Además, estos estudios han informado de un importante solapamiento genético a través de varios trastornos psiquiátricos como la esquizofrenia (EQ), el trastorno bipolar (TB), el trastorno depresivo mayor (TDM) o los trastornos del espectro autista (TEA), lo que se suma a la consideración de mecanismos fisiopatológicos comunes en estos trastornos. En este sentido, el creciente cuerpo de evidencias ha establecido que la conectividad y la plasticidad sináptica modulada por la actividad neuronal, es una característica inherente de la función cerebral durante el desarrollo y la edad adulta. La presente tesis plantea la hipótesis de que la variabilidad genética en genes implicados en la plasticidad sináptica (NRN1, BDNF y DTNBP1) y/o en las vías relacionadas con la materia blanca (y sus interacciones) se asociarán con Trastornos del Espectro de la Esquizofrenia (TEE). Además, debido al solapamiento clínico, cognitivo, de neuroimagen y genético observado a través de los diferentes trastornos psiquiátricos, también hipotetizamos que la variabilidad genética estudiada se asocia con otros trastornos psiquiátricos del neurodesarrollo, como el TEE y TEA. En este sentido, se han llevado a cabo cuatro estudios. Los tres primeros estudios analizan la variabilidad genética del gen Neuritin-1 (NRN1) y su relación con el riesgo de desarrollar TEE y TB, así como algunos fenotipos clínicos y cognitivos tanto en pacientes como en sujetos sanos de la población general. Además, en estos estudios también analizamos si la acción de NRN1 es modulada por otros genes como BDNF y DTNBP1. El cuarto estudio analiza los efectos integradores de un conjunto de genes relacionados con la materia blanca (genes relacionados con Oligodendrocitos/mielinización - OMR) y su contribución a TEE y TEA. Nuestros resultados centrados en la variabilidad genética del gen NRN1, sugieren que su variabilidad genética tendría un impacto en el riesgo de desarrollar TEE / TB y también en la presencia de síntomas depresivos en la población general. Este efecto pleiotrópico también se ve respaldado por sus efectos sobre otros fenotipos: como el rendimiento cognitivo y la edad de inicio. Además, nuestros resultados de interacción genéticas (gxg) sugieren que la acción de NRN1 es modulada por los genes BDNF y DTNBP1. Por otro lado, los resultados del cuarto estudio sugieren que algunas de las variantes de riesgo genético de los genes OMR parecen ser compartidas a través de del continuum TEE-TEA. El hecho de que algunos genes OMR estén ligeramente asociados con ambos trastornos, así como también, debido a su participación en los efectos epistáticos detectados, parece apoyar la noción de que la desregulación en los procesos de mielinización podría ser subyacente a la susceptibilidad para desarrollar TEE o TEA. Para concluir, se necesitan más estudios genéticos que ayuden a descifrar el trasfondo biológico subyacente a los trastornos mentales, lo que en última instancia puede conducir a un mejor tratamiento con el fin de mejorar la calidad de vida de los pacientes.
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Sharma, Pankaj. "Towards the identification of disease genes in monogenic disorders." Thesis, Queen Mary, University of London, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.404970.
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Hobbs, Eleanor. "Investigation of candidate risk genes for neuropsychiatric disease in vitro and in vivo using ENU mutagenesis." Thesis, University of Oxford, 2017. https://ora.ox.ac.uk/objects/uuid:6204220c-3680-4549-8399-872c6dd4b473.
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Schizophrenia is a complex mental disorder characterised by positive symptoms such as hallucinations and psychosis, negative symptoms such as avolition and anhedonia, and cognitive defects. Schizophrenia risk has a genetic component, and it is likely that this is caused by interaction between numerous genes with individually small effects. Environment also plays a role; factors associated with schizophrenia include drug use, prenatal stressors and living environment. Candidate genes linked to schizophrenia have been identified through recent GWAS of human populations with the disorder, including ANK3, TCF4 and CACNA1C. GWAS associations alone are not sufficient to identify these as definitive risk genes for the disease. In order to validate these findings, animal models (in particular the mouse) can be used to study the effect of mutations in these genes of interest. Knockouts of these genes in the mouse are lethal, so we have used the ENU mutagenesis DNA archive at MRC Harwell to screen for additional allelic variants expressing more subtle and varied behavioural phenotypes. Endophenotypes associated with schizophrenia and bipolar disorder, such as anxiety, cognitive deficits and sensorimotor gating deficits, can be characterised in these mutants and, together with molecular characterisation, this can validate these genes as risk factors. While mutations in Ank3 and Tcf4 proved to be non-functional, two mutations in Cacna1c have been associated with anxiety phenotypes and differences in EEG power spectra, as well as causing a cardiac phenotype.
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Carss, Keren Jacqueline. "Identifying and modelling genes that are associated with rare developmental disorders." Thesis, University of Cambridge, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708682.
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Zhang, Ying. "Exploring functional genetic variants in genes involved in mental disorders." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1186433668.
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Holopainen, Päivi. "Genetic susceptibility to celiac disease : HLA-unlinked candidate genes." Helsinki : University of Helsinki, 2002. http://ethesis.helsinki.fi/julkaisut/mat/bioti/vk/holopainen/.
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Marian, Ali J., Rooij Eva van, and Robert Roberts. "Genetics and Genomics of Single-Gene Cardiovascular Diseases : Common Hereditary Cardiomyopathies as Prototypes of Single-Gene Disorders." ELSEVIER SCIENCE INC, 2016. http://hdl.handle.net/10150/623130.
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This is the first of 2 review papers on genetics and genomics appearing as part of the series on “omics.” Genomics pertains to all components of an organism’s genes, whereas genetics involves analysis of a specific gene(s) in the context of heredity. The paper provides introductory comments, describes the basis of human genetic diversity, and addresses the phenotypic consequences of genetic variants. Rare variants with large effect sizes are responsible for single gene disorders, whereas complex polygenic diseases are typically due to multiple genetic variants, each exerting a modest effect size. To illustrate the clinical implications of genetic variants with large effect sizes, 3 common forms of hereditary cardiomyopathies are discussed as prototypic examples of single-gene disorders, including their genetics, clinical manifestations,
pathogenesis, and treatment. The genetic basis of complex traits is discussed in a separate paper.
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Ylönen, S. (Susanna). "Genetic risk factors for movement disorders in Finland." Doctoral thesis, Oulun yliopisto, 2019. http://urn.fi/urn:isbn:9789526223988.
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Abstract Parkinson’s disease and Huntington’s disease are progressive neurodegenerative movement disorders that typically manifest in adulthood. In this study, genetic risk factors contributing to these two movement disorders were investigated in Finnish patients. Patients with early-onset or late-onset Parkinson’s disease as well as population controls were examined. The p.L444P mutation in GBA was found to contribute to the risk of Parkinson’s disease. POLG1 compound heterozygous mutations were detected in two patients with Parkinson’s disease and rare length variants in POLG1 were associated with Parkinson’s disease. Variants in SMPD1, LRRK2 or CHCHD10, previously detected in other populations, were not detected, suggesting that they are rare or even absent in the Finnish population. Patients with Huntington’s disease were investigated for HTT gene haplotypes as well as whether these haplotypes alter the stability of the elongated CAG repeat. Haplogroup A was less common in Finns than in other European populations, whereas it was significantly more common in patients with Huntington’s disease than in the general population. Certain HTT haplotypes as well as the parental gender were found to affect the repeat instability. We found that compound heterozygous mutations in POLG1 were causative of Parkinson’s disease, rare length variants in POLG1 were associated with Parkinson’s disease and GBA p.L444P was significantly more frequent in patients than in the controls, which suggests that these mutations are associated with the development of Parkinson’s disease. The low prevalence of Huntington’s disease in Finland correlates with the low frequency of the disease-associated HTT haplogroup A. Paternal inheritance combined with haplotype A1 increased the risk of repeat expansion. Movement disorders in Finland were found to share some of the same genetic risk factors found in other European populations, but some other recognized genetic variants could not be detectedTiivistelmä Parkinsonin tauti ja Huntingtonin tauti ovat hermostoa rappeuttavia eteneviä liikehäiriösairauksia, jotka tyypillisesti ilmenevät aikuisiällä. Tässä tutkimuksessa selvitettiin näiden kahden liikehäiriösairauden geneettisiä riskitekijöitä suomalaisilla potilailla. Tutkimme potilaita, joilla oli varhain alkava Parkinsonin tauti tai myöhään alkava Parkinsonin tauti sekä väestökontrolleja. GBA-geenin p.L444P mutaation havaittiin lisäävän Parkinsonin taudin riskiä. Kaksi Parkinsonin tautia sairastavaa potilasta oli yhdistelmäheterotsygootteja haitallisten POLG1-geenin varianttien suhteen ja harvinaiset POLG1 CAG toistojaksovariantit assosioituivat Parkinsonin tautiin. Tutkittuja variantteja SMPD1-, LRRK2- ja CHCHD10-geeneissä ei löydetty tästä aineistosta lainkaan, mikä viittaa siihen, että ne puuttuvat suomalaisesta väestöstä tai ovat harvinaisia. Huntingtonin tautia sairastavilta potilailta tutkittiin HTT-geenin haploryhmiä ja niiden vaikutusta Huntingtonin tautia aiheuttavan pidentyneen toistojakson epästabiiliuteen. Haploryhmä A oli suomalaisessa väestössä harvinainen verrattuna eurooppalaiseen väestöön ja se oli huomattavasti yleisempi Huntingtonin tautipotilailla kuin väestössä. Toistojakson epästabiiliuteen vaikuttivat tietyt HTT-geenin haplotyypit samoin kuin sen vanhemman sukupuoli, jolta pidentynyt toistojakso periytyy. POLG1 yhdistelmäheterotsygoottien katsottiin aiheuttavat Parkinsonin tautia ja harvinaisten POLG1 CAG toistojaksovarianttien todettiin assosioituvan Parkinsonin tautiin Suomessa. GBA p.L444P mutaatio merkittävästi yleisempi Parkinsonin tautipotilailla kuin kontrolleilla, mikä viittaa siihen, että se on Parkinsonin taudin riskitekijä. Huntingtonin tautiin assosioituvan haploryhmä A:n matala frekvenssi selittää taudin vähäistä esiintyvyyttä Suomessa. Paternaalinen periytyminen ja haplotyyppi A1 lisäsivät HTT-geenin toistojakson pidentymisen riskiä. Liikehäiriösairauksilla todettiin Suomessa osittain samanlaisia riskitekijöitä kuin muualla Euroopassa, mutta kaikkia tutkittuja variantteja emme havainneet
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Vieira, Helena Margarida Moreira De Oliveira. "Genetic and molecular studies of genes involved in developmental eye disorders." Thesis, Imperial College London, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.405667.
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Moyer, Robert A. "Exploration of Functional Genetic Variants in Candidate Genes for Psychiatric Disorders." The Ohio State University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=osu1283184584.
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Aarts, Nicole. "Genetic dissection of disease resistance signalling pathways in Arabidopsis." Thesis, University of East Anglia, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.327511.
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Walsh, Diana Maria. "Exome sequencing and human disease : the molecular characterisation of genetic disorders." Thesis, University of Birmingham, 2016. http://etheses.bham.ac.uk//id/eprint/6664/.
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Since the completion of the human genome project in 2001, the field of genomics has advanced exponentially, largely due in part to the introduction of next generation sequencing (NGS); a technique that has revolutionised the ways in which genetic disease is investigated. NGS enables the simultaneous sequencing of multiple reads in parallel, which provides researchers with the opportunity to interrogate vast numbers of candidate genes in order to establish the genetic eitiology and key components of disease. Exome sequencing in particular offers an efficient method to investigate disease, as the exomic regions make up 1% of the whole genome, but can contain up to 85% of functional variants responsible for disease. Next generation sequencing has been employed to investigate and identify the genetic cause of Acrocallosal syndrome (a rare autosomal recessive disorder). Exome sequencing was then also applied to investigate the genetic associations with both familial and sporadic pheochromocytomas and paragangliomas (neuroendocrine tumours). This study describes the various applications, challenges and potential benefits that can be achieved by using exome sequencing as a tool to investigate rare autosomal recessive disorders in addition to more complex disorders including familial and sporadic cancer. This study aims to employ cutting edge technology to investigate human disease, in order to enhance current understandings of disease biology and pathogenesis. Through this, it is hoped that these findings may help to contribute to on-going efforts to develop novel therapeutic strategies and improve the clinical management of these disorders.
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Moore, Jill E. "Defining a Registry of Candidate Regulatory Elements to Interpret Disease Associated Genetic Variation." eScholarship@UMMS, 2017. https://escholarship.umassmed.edu/gsbs_diss/927.
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Over the last decade there has been a great effort to annotate noncoding regions of the genome, particularly those that regulate gene expression. These regulatory elements contain binding sites for transcription factors (TF), which interact with one another and transcriptional machinery to initiate, enhance, or repress gene expression. The Encyclopedia of DNA Elements (ENCODE) consortium has generated thousands of epigenomic datasets, such as DNase-seq and ChIP-seq experiments, with the goal of defining such regions. By integrating these assays, we developed the Registry of candidate Regulatory Elements (cREs), a collection of putative regulatory regions across human and mouse. In total, we identified over 1.3M human and 400k mouse cREs each annotated with cell-type specific signatures (e.g. promoter-like, enhancer-like) in over 400 human and 100 mouse biosamples. We then demonstrated the biological utility of these regions by analyzing cell type enrichments for genetic variants reported by genome wide association studies (GWAS). To search and visualize these cREs, we developed the online database SCREEN (search candidate regulatory elements by ENCODE). After defining cREs, we next sought to determine their potential gene targets. To compare target gene prediction methods, we developed a comprehensive benchmark of enhancer-gene links by curating ChIA-PET, Hi-C and eQTL datasets. We then used this benchmark to evaluate unsupervised linking approaches such as the correlation of epigenomic signal. We determined that these methods have low overall performance and do not outperform simply selecting the closest gene. We then developed a supervised Random Forest model which had notably better performance than unsupervised methods. We demonstrated that this model can be applied across cell types and can be used to predict target genes for GWAS associated variants. Finally, we used the registry of cREs to annotate variants associated with psychiatric disorders. We found that these "psych SNPs" are enriched in cREs active in brain tissue and likely target genes involved in neural development pathways. We also demonstrated that psych SNPs overlap binding sites for TFs involved in neural and immune pathways. Finally, by identifying psych SNPs with allele imbalance in chromatin accessibility, we highlighted specific cases of psych SNPs altering TF binding motifs resulting in the disruption of TF binding. Overall, we demonstrated our collection of putative regulatory regions, the Registry of cREs, can be used to understand the potential biological function of noncoding variation and develop hypotheses for future testing.
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Ichikawa, Shoji. "The molecular genetic analysis of three human neurological disorders." free online free to MU campus, others may purchase, 2002. http://wwwlib.umi.com/cr/mo/preview?3074409.
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Zhang, Qiuping. "Genetic variants of lipid transport genes, dyslipidaemia and coronary heart disease." Thesis, Queen Mary, University of London, 1997. http://qmro.qmul.ac.uk/xmlui/handle/123456789/1642.
Full textAbstract:
Coronary heart disease (CHD) is one of the most common causes of death in Western Countries. Genetic factors playa major role in the aetiology of CHD, however, the primary defects responsible for the disease have not been identified in most cases. With the application of recombinant DNA technology, it is possible to analyse the putative aetiological role of candidate genes. The role of the Lipoprotein Lipase (LPL) gene and the Apolipoprotein AI-CIII-AIV gene cluster were examined in German and Chinese controls, dyslipidaemics and arteriopaths (coronary artery disease and/or peripheral artery disease). Analyses of four allelic distributions (HindIlI-RFLP, Ser447_Ter, Asp9-Asn and Asn291_Ser mutations) of the LPL gene in German and Chinese populations with or without arterial disease did not show any significant frequency differences. In the German group, plasma triglycerides and VLDL-triglycerides were lower in subjects possessing the Ser447_Ter mutation (p=0.06 and < 0.05 respectively), this mutation was also significantly less frequent in the highest tertiles for triglycerides (p<0.02) and VLDL(P<0.04). The Ser447_Ter variant was found at lower frequencies in the Chinese lipaemic subjects. In addition, two disease related genetic variants (Asp9-Asn and Asn291 _Ser) in Europeans were not found in the Chinese group (P<0.03). Analyses of four genotypic distributions (the ApoAI PstI, MspI, XmnI RFLPs and the ApoCIII G3175_C variant) of the ApoAI-CIII-AIV gene cluster in German and Chinese populations with or without arterial disease did not show any significant differences. However, significant associations between high triglyceride, VLDL, TGIHDL ratio and the PstI RFLP at the ApoAI gene were shown in the German group (p=O.OOl, p<0.02 and p<0.04). In the Chinese group, the rare alleles of the Apo CIII G3175 -C variant and the Apo AI MspI polymorphic variant were both found more frequently in the upper tertile distributions for apo CIII levels and plasma triglyceride/HDL ratios (p<0.05 and p<0.04 respectively). The frequencies of two disease related RFLPs of the ApoAI gene (detected Pane 2 b with Mspl and Xmnl) and the ApoC1I1 G3175 -C variant were significantly different (p<0.0006, p<0.004 and p<0.003 respectively) between Chinese and German control groups. Out of eighteen French patients with diabetes m., obesity and severe hypertriglyceridaemia, eight subjects were found to possess mutations at the LPL gene locus by direct DNA sequencing. Three of these: Argl92_Ter (C829_ T); Phe351 _Leu (C1308_ G) and Thr361 -Thr (C1338 _ A) had not previously been described. Thr361_ Thr appears to be a common population polymorphism whose allele frequency in normolipidaemic diabetics was found to be 0.120 (162 chromosomes studied). The others are all rare at frequencies of <0.01 and may contribute to the phenotype by impairi~g clearance of plasma triglycerides. In eleven of the most lipaemic Chinese subjects, Thr361_Thr (C1338_A) was observed, additionally, the previously published mutations, Ala261_ Thr and Ser447 -Ter, were also noticed. Finally, a Finnish kindred, with premature coronary heart disease and decreased HDL cholesterol levels, was identified having an ApoAI variant (Lys107 ~~) by Single-Strand Conformation Polymorphisms (SSCP) and direct DNA sequencing. This variant was caused by a 3 bp deletion of nucleotides 1396 through 1398 in exon 4 of the ApoAI gene. Ten family members were heterozygous for this mutation. Mean serum apoAI and apoAII levels in heterozygotes were reduced by 18% and 220/0, and cholesteryl ester transfer protein activity (CETP) was reduced by 25% compared with unaffected family members (both p<0.05) respectively, while the plasma lecithin:cholesterol acyltransferase (LCAT) activity did not show any difference between heterozygotes and unaffected family members. The ability of the isolated apoAI variant to serve as a co-factor for LCAT in vitro did not differ from that of normal apoAI.
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Taylor, Kay M. "Characterisation of Potential Fungal Disease Resistance Genes in Banana." Queensland University of Technology, 2005. http://eprints.qut.edu.au/16105/.
Full textAbstract:
Bananas are an extremely important crop, serving as both a staple food in developing countries and as a dessert fruit in Western society. Two of the most devastating pathogens currently affecting both commercial and subsistence banana production are Fusarium oxysporum (Foc; causal agent of Fusarium wilt) and Mycosphaerella species (causal agent of black and yellow Sigatoka). Conventional breeding programs designed to improve the disease resistance characteristics of the commercially elite Cavendish cultivar have, thus far, been largely unsuccessful. Genetic engineering is now regarded as the most promising method to generate enhanced disease resistance in banana. In other crops and model species, strategies to enhance disease resistance have included the transgenic expression of defense-related genes such as; disease resistance genes (R genes), downstream signaling genes (eg. NPR1, non-pathogenesis related) and antimicrobial peptides (AMPs). The overall aims of this research were to amplify and compare the nucleotide binding site (NBS) domains of potential disease resistance genes from disease resistant and disease susceptible banana cultivars. To isolate and compare complete R gene sequences from these cultivars. To generate transgenic Lady Finger banana plants expressing the D4E1 antimicrobial peptide under the control of two different promoters and finally to assess extracts from these plants for their ability to inhibit the growth of Foc Race1. Using degenerate primers, the NBS domains of six resistance gene candidate (RGC) sequences were amplified from the disease resistant cultivar Calcutta 4 (C4) and the disease susceptible cultivar Cavendish (Cav). The RGC 1, 2, 5 and 6 sequences showed similarity to previously characterized R gene sequences isolated from monocotyledonous plant species, while RGCs 3 and 4 showed similarity to R genes which form part of the Fusarium wilt resistance locus isolated from the dicotyledonous species, Lycopersicon esculentum; as well as other monocotyledonous R genes. RGCs 1-4 and 6 were present and transcriptionally active in both C4 and Cav, whereas RGC-5 was present in Cav only and was not transcribed. The transcripts could not be detected by Northern analysis, which is consistent with previous reports that R genes are constitutively transcriptionally active at only low levels. The NBS domains of RGCs 1-6 showed less than 65% similarity (amino acid level) to one another but when each individual RGC isolated from the C4 and Cav gDNA and cDNA templates was compared the sequences showed greater than 97% similarity (amino acid level). Comparative sequence analysis revealed amino acid positions that were consistently different between the C4 and Cav clones. Southern analysis revealed that RGC 1-5 were present in both the C4 and Cav genomes in only low copy number (1-2 gene copies with 1-3 alleles), whereas RGC-6 showed high copy number in both cultivars. Complete RGC sequences were subsequently amplified by RNA-ligase-mediated (RLM) -RACE and 3'-RACE using specific primers designed to each of the RGC 1-4 NBS domains. Amplicons for each RGC were assembled to form potentially complete RGC sequences. Analysis of the sequences revealed the presence of coiled coil (CC) motifs in two of the amino terminal sequences while leucine rich repeats (LRRs) were identified at the carboxy terminal of all sequences. Multiple 3'-RACE products were amplified for each RGC sequence. Although the polyadenylated products were of different lengths, the sequences were greater than 98% identical at the amino acid level (except an RGC 3 clone which was 91-95% identical to the other RGC 3 clones due to a 37 amino acid deletion). Specific primers used to amplify each complete RGC sequence from both C4 and Cav DNA revealed that: RGC 1 (3.53 kbp) could be amplified from both C4 and Cav; RGCs 2 (2.99 kbp) and 4 (4.44 kbp) could be amplified from only Cav, however, the proposed truncations of these sequences (RGC 2: 1.3 kbp, RGC 4: 2.8 kbp and 2.9 kbp) could be amplified from both cultivars; RGC 3 (4.57 kbp) could not be amplified from either C4 or Cav, however, the three shorter sequences (1.96 kbp, 1.34 kbp and 1.28 kbp) could be amplified from both templates. The functional significance of the truncated sequences is currently unknown, however, truncated sequences have been detected in a number of R gene families isolated from other crops. No major sequence differences, such as deletions/insertions or early stop codons, were identified between the RGC sequences amplified from C4 as compared to Cav (greater than 91% amino acid similarity) and no sequence was identified as being present in the susceptible but absent from the resistant cultivar. However, comparative analysis of multiple clones isolated from C4 and Cav did reveal amino acid residues that were consistently different between the two cultivars. These differences may result in differing resistance capabilities, functional genomics studies would need to be undertaken to determine this. It has been proposed that CC-NBS-LRR type R genes employ NDR1/HIN1-like (NHL) proteins, after pathogen invasion is detected, in the signaling process that ultimately leads to the elaboration of a defense response. A NHL partial sequence (420 bp) was amplified from the C4 banana cultivar. The complete sequence of this gene (termed NHL-1) was isolated using RLM and 3'-RACE technologies (576 bp and 535 bp amplicons, respectively) and subsequently the 1.106 kbp sequence was PCR amplified from both the C4 and Cav cultivars. The banana NHL-1 gene contained conserved motifs/domains previously identified within other NHL-type gene sequences. These included a signal peptide motif, a transmembrane domain and three previously identified conserved motifs. Based on current research into NHL type genes, the banana NHL-1 sequence may not be useful as a transgene to enhance disease resistance in elite cultivars. However, it potentially plays an important role in the defense response signal transduction pathway and therefore will further our understanding of plant-pathogen interactions in banana. Transgenic Lady Finger banana plants expressing the D4E1 antimicrobial peptide under the control of either the maize polyubiquitin (Ubi) or banana bunchy top virus (BBTV) DNA-6 (Bt6.1) promoters were generated. These plants were subsequently assessed for the ability of their crude protein extracts to inhibit the germination of Fusarium oxysporum f.sp. cubense Race1 conidia in vitro. These anti-fungal bioassays revealed that fungal colony growth was reduced by 37-100% using extracts from the pUbi-D4E1 transgenic lines and 89-99% using extracts from the pBt6.1-D4E1 transgenic lines. The transgenic lines are currently undergoing multiplication in preparation for glasshouse and small plant challenge trials for resistance to Fusarium wilt. These preliminary results suggest that D4E1 may be useful in enhancing disease resistance in banana.
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Tajouri, Lotfi, and n/a. "Gene Expression Analysis and Genetic Studies in Multiple Sclerosis." Griffith University. School of Health Science, 2005. http://www4.gu.edu.au:8080/adt-root/public/adt-QGU20060111.123933.
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Multiple Sclerosis (MS) is a neurodegenerative disease of the central nervous system (CNS). As part of this disorder the myelin sheath undergoes degeneration, leading to alterations in the conductivity of axons, and impaired function. The onset of the disease occurs in young adults and clinical pathology is characterised by varying severity. These include i) Relapsing Remitting MS (RR-MS), ii) Secondary Progressive MS (SP-MS) and iii) Primary Progressive MS (PP-MS). MS is more prevalent in women and accounts for more than two thirds of all MS sufferers. MS is considered to be a multifactorial disorder with both genetic and environmental components. The prevalence of MS is dependent on geographical localisation, with lower sunlight exposure linked to higher prevalence. Also, studies show an increased risk in close relatives, or in identical twins, indicating a significant genetic component to the disorder. There are a number of genes that may plausibly be involved in MS pathophysiology. These include myelin-related genes, such as the myelin basic protein (MBP), immune-related genes, such FC receptor and osteopontin, and heat shock proteins such as xb crystallin. These candidate genes have been implicated in a variety of ways but usually through immunological and/or genetic studies. One of the most consistent findings in recent years has been the association of disease with alterations in the specific major histocompatibility complex (MHC) localised to chromosome 6p21.3, and includes MHC I, II, III. Genome wide screens have permitted the identification of loci in the genome, which are associated with MS susceptibility. The number of genes involved in MS is unknown and several case-control association studies have been undertaken to reveal the involvement of potential candidate genes. In general terms, current research is aimed at determining allelic variation of candidate genes. Such genes have been implicated in MS because they reside within susceptible regions of the chromosome associated with MS or they have a plausible potential pathophysiological role in MS. Candidate loci investigated in this study, for association with MS susceptibility, include members of the nitric oxide synthase family of metabolic proteins (inducible NOS, iNOS/NOS2A and neuronal NOS, nNOS), methylenetetrahydrofolate reductase (MTHFR), catechol-O-methyl transferase (COMT), and vitamin D receptor (VDR). The MS population used in all studies consisted of over 100 MS cases and gender, age and ethnicity matched controls. In our study of inducible and neuronal NOS genes, PCR based assays were developed to amplify a region of both promoters that contained known microsatellite variation. Supporting phyisological data suggests that the neuroinflammatory aspects of MS are associated with aberrant NO production, which may be due to aberrant regulation of NOS activity. Specific amplified products were identified by fluorescent capillary electrophoresis and allele frequencies were statistically compared using chi-squared analysis. In the nNOS and iNOS study, no association was identified with allele frequency variation and MS susceptibility (nNOS: ?2=5.63, P=0.962; iNOS: ?2=3.4; P=0.082). Similarly, no differences in allele frequencies were observed for gender or clinical course for both markers (Pvalue greater than 0.05). In short, results from this study indicate that the NOS promoter variations studied do not play a significant role in determining susceptibility to MS in the tested population. The COMT and MTHFR genes are localised at 22q12-13 and 1p36.3 respectively, regions of the genome that have been found to be positively associated with MS susceptibility. In our research, we set out to examine the G158A change in the 4th exon of the COMT gene. This functional mutation leads to an amino acid change (valine to methionine) that is directly associated with changes in the activity of COMT. The MTHFR enzyme plays a role in folate metabolism, and can be implicated in the turnover of homocysteine. Previous investigations have shown that high levels of homocysteine are encountered in MS patients, where it is also linked to demyelination in the CNS. In our study the aim was to examine the C677T variation (alanine to valine amino acid change) in the exon 4 coding region of the MTHFR gene and the G158A variation in the COMT gene. Restriction fragment length polymorphism (RFLP) analysis and gel electrophoresis was used to identify specific alleles for both COMT and MTHFR. However, as with the NOS study, no specific association was identified between MS susceptibility and variation for either of the tested COMT or MTHFR (Pvalue greater than 0.05) variants. In a final genomic investigation of the MS population, three variations in the VDR gene were analysed for association with MS susceptibility and pathology. Using RFLP analysis, three VDR variants were investigated with genotypes detected using the Taq I, Apa I and Fok I restriction enzymes. In contrast to previous genotypic analyses, this study did show a positive association, specifically between the functional variation in exon 9 of the VDR gene and MS (Taq I, 2= 7.22, P= 0.0072). Interestingly, the Apa I variant of VDR was also found to be associated with MS ( 2=4.2, P=0.04). The Taq I and Apa I variants were also found to be in very strong and significant linkage disequilibrium (D'=0.96, Pvalue less than 0.0001) and their associations were more prominent with the progressive forms of MS (SP-MS and PP-MS). In addition to genotypic analysis of a clinical population, additional research was undertaken to identify novel targets for MS susceptibility studies. Global gene expression analysis was undertaken using comparative subtractive fluorescent microarray technology to examine differences in gene activity (expression) in age and sex matched MS plaque tissue and anatomically matched normal white matter (NWM). MS plaques were obtained post mortem from MS sufferers with no drug history in the last two months before death and matched anatomically to healthy white matter from donors with no previous neurological disorders. Target arrays consisted of 5000 cDNAs and analysis was conducted using the Affymetrix 428 scanner. In this way, 139 genes were shown to be differentially regulated in MS plaque tissue compared to NWM. Of these, 69 genes showed a common pattern of expression in the chronic active and acute plaque tissues investigated (Pvalue less than 0.0001, a=0.73); while 70 transcripts were uniquely differentially expressed ( 1.5-fold) in either acute or chronic active lesions. To validate the gene expression profile results, quantitative real time reverse transcriptase (RT) PCR (Q-PCR) analysis was performed. 12 genes were selected because they were shown to be differentially expressed by array analysis in this study, or because of their involvement in MS pathology. These included transferrin (TF), superoxide dismutase 1 (SOD1), glutathione peroxidase 1 (GPX1), glutathione S-transferase pi (GSTP1), crystallin, alpha-B (CRYAB), phosphomannomutase 1 (PMM1), tubulin beta-5 (TBB5), inositol 1,4,5-trisphosphate 3-kinase B (ITPKB), calpain 1 (CAPNS1), osteopontin (SPP1 or OPN), as well as the signal transducer and activator of transcription 1 (STAT1) and protein inhibitor of activated STAT1 (PIAS1). Both absolute (copy number) and comparative differences in the relative levels of expression in MS lesions and NWM were determined for each gene. The results from this study revealed a significant correlation of real time PCR results with the microarray data, while a significant correlation was also found between comparative and absolute determinations of fold. As with the results of array analysis, a significant difference in gene expression patterning was identified between chronic active and acute plaque pathologies. For example, a up to 50-fold increase in SPP1 and ITPKB levels in acute plaques contrasted with the 5-fold or less increase in chronic active plaques (P less than 0.0.1, unpaired t-Test). Of particular note, gamma-amino butyric acid receptor ?2 (GABG2), integrin ?5 (ITGB5), complement component 4B (C4B), parathyroid hormone receptor 1 (PTHR1) were found up-regulated in MS and glial derived neurotropic factor ?2 (GDNFA2), insulin receptor (INSR), thyroid hormone receptor ZAKI4 (ZAKI4) were found down-regulated in MS. Data also revealed a decreased expression of the immune related genes STAT1 and PIAS1 in acute plaques. In conclusion, this research used both genomic analysis and technologies in gene expression to investigate both known and novel markers of MS pathology and susceptibility. The study developed tools that may be used for further investigation of clinical pathology in MS and have provided interesting initial expression data to further investigate the genes that play a role in MS development and progression.
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Ying, Dingge, and 应鼎阁. "Identification of shared extended haplotypes in both population-based studies of complex disease and family-based studies of Mendelian disorders." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/205837.
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Recent founder mutations may play important roles in complex diseases and Mendelian disorders. Detecting shared haplotypes of identity by descent (IBD) could facilitate discovery of these mutations. Several programs address this such as threshold-based methods on genetic distance and probabilistic model-based methods, but they are usually limited to only detecting pair-wise shared haplotypes and not providing a comparison between cases and controls.
In this study, a novel algorithm and a applied software package (HaploShare)is developed to detect extended haplotypes that are shared by multiple individuals, which also allows comparisons between cases and controls. A catalog of haplotypes is firstly generated from healthy controls from the same population and used for phasing genotypes in cases. By accounting for all possible haplotype pairs that could explain the genotypes for each individual in a given haplotype block and possible transitions between blocks, the effect of phase uncertainty on detection power is minimized. In cases, haplotypes shared by pairs are identified and used to detect sharing of these haplotypes by different pairs. A likelihood ratio of a shared haplotype due to IBD or chance is estimated for each extended haplotype. Controls are used similarly through many rounds of simulations to obtain an empirical null distribution of the largest likelihood ratios of shared haplotypes, to give statistical estimates of shared haplotypes detected in cases that may be associated with an underlying disease.
Series of tests were performed to investigate the performance of HaploShare. Simulations of shared haplotypes demonstrated that HaploShare has better power not only on the detection of pair-wise shared haplotypes but multiple shared haplotypes in most of the simulation scenarios, comparing with other four commonly used programs. False positive rate (FPR) and the false discovery rate (FDR) were also evaluated by statistical calculation. According to the result, both of the two values were extremely low (FPR = 6.28x10-6 , FDR = 0.006), indicating that very few randomly shared haplotypes can be wrongly reported as IBD by HaploShare.
HaploShare was also tested on real cases on population data and family linkage analysis. 14 out of 173 Hirschsprung's disease cases were reported by HaploShare of carrying a common haplotype of 250 kb in length, which was consistent with previous findings by direct genotyping and candidate approach. Another testing case is an affected family with 8 cases and 9 unaffected individuals. Disease linked region can be correctly identified by traditional methods if all the data and the entire pedigree were provided. HaploShare showed the ability to locate the shared region even when very limited cases are available, which is clearly beyond the detection power of traditional methods.
The results from empirical simulations and real case applications indicate that HaploShare could effectively make use of population genotype information to improve the power of detection of shared haplotypes. The method may extend the findings in human genetics of both complex and single gene diseases.published_or_final_version
Psychiatry
Doctoral
Doctor of Philosophy
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Tam, Hoi-lam Elizabeth, and 譚凱琳. "FBI-1 amplification in gestational trophoblastic disease." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/206493.
Full textAbstract:
Gestational Trophoblastic Disease (GTD) encompasses a spectrum of disease that involves abnormal trophoblastic proliferation. It includes hydatidiform mole (HM), placental site trophoblastic tumor (PSTT), epithelioid trophoblastic tumor (ETT) and choriocarcinoma (CCA). While HMs are abnormal pregnancies with limited invasive potential, CCAs are true malignancies requiring chemotherapy. Although the majority of HM is resolved by surgical intervention, approximately 8-30% of them would develop into persistent GTD. In addition to that, being the most aggressive neoplasm in GTD, choriocarcinoma is a frankly malignant gestational trophoblastic neoplasm (GTN) that could be arisen from HM and could be fetal when widespread metastasis is developed. However, the underlying mechanisms of this disease progression are still unclear.
FBI-1 (Factor that Binds to Inducer of Short Transcripts (IST) protein 1) is a transcription factor that has been observed to be overexpressed in various types of human cancers. Recently, overexpression of FBI-1 is also reported in GTD and also in association with GTN development. However, the causes of FBI-1 overexpression in GTD are still unclear. This study aims to investigate gene amplification as a possible cause of FBI-1 overexpression in GTD. A quantitative real time PCR (qPCR) assay was established and was used to investigate ZBTB7A (the gene encoding FBI-1) amplification in GTD cell lines and clinical samples.
Using our qPCR assay, we demonstrated that ZBTB7A is not amplified in the CCA cell lines JEG-3 and JAR, in comparison with an immortalized trophoblast cell line HTR-8/SVneo. Testing ZBTB7A amplification in clinical samples also obtained similar findings although overexpression of FBI-1 was demonstrated in our previous studies. This is the first report illustrating absence of ZBTB7A amplification in cells with FBI-1 overexpression. There are other techniques that can detect gene amplification and/or other genetic and epigenetic mechanisms that may govern FBI-1 expression in GTD. Further studies will be worthwhile to pursue as FBI-1 is a potential target for cancer therapy.published_or_final_version
Pathology
Master
Master of Medical Sciences
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Luo, Liping. "A genetic study on familial breast cancer predisposing genes /." Stockholm, 2002. http://diss.kib.ki.se/2002/91-628-5184-5.
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McCallion, Andrew Smyth. "Characterisation and genetic mapping of genes with potential relevance to neurodegenerative disease." Thesis, University of Glasgow, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.241836.
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McGregor, Johanne Angelette. "Genetic and functional characterisation of iron metabolism genes, in health and disease." Thesis, King's College London (University of London), 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.428668.
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Nukaga, Yoshio. "A genealogy of genealogical practices : the development and use of medical pedigrees in the case of Huntington's disease." Thesis, McGill University, 2000. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=37800.
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The purpose of this dissertation is to examine the use, role and function of medical pedigrees as part of extended networks of genetic practices. Integral to my argument is a description of geneticisation (i.e., the redefinition of family problems as genetic in origin), grounded in a set of detailed case studies of the development and use of visual tools in genetic practices.In recent years, medical sociologists have tended to link geneticisation to medicalisation (i.e., the social control by doctors over patients accompanied by the translation of social problems into medical issues). I argue that the twin notions of geneticisation and medicalisation are problematic, insofar as they embody a simplistic and negative understanding of medical activities and they prevent a sociological inquiry into the technical content of genetic practices.
Medical pedigrees are visual tools used to translate family problems into visual inscriptions, in order to show the genetic nature of a given disease. The use of medical pedigrees in genetic counselling and research rests on a chain of genetic practices including the inscription of family trees, the standardisation of medical pedigrees, the combination of specialised forms of medical pedigrees with other diagnostic inscriptions, and the circulation of published pedigrees. The analysis is based on a genealogical approach, as built on a combination of historical and ethnographic methods. The genealogical approach was applied to the analysis of a long network of genetic practices centred on Huntington's disease. The analysis spans over 120 years and compares two different international settings (North America and Japan).
The thesis examines how lay support group members and family members collect family narratives, family inscriptions and family trees, which were first translated by genetic counsellors into various forms of medical pedigrees, and then circulated as educational material among lay and medical practitioners. On the basis of these case studies, the conclusion is reached that the notion of geneticisation should be understood as a specific process resulting from an emerging cooperative practice between medical practitioners and lay support group members, rather than as a process of medicalisation.
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Foster, Robert Graham. "Development of a modular in vivo reporter system for CRISPR-mediated genome editing and its therapeutic applications for rare genetic respiratory diseases." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/33040.
Full textAbstract:
Rare diseases, when considered as a whole, affect up to 7% of the population, which would represent 3.5 million individuals in the United Kingdom alone. However, while 'personalised medicine' is now yielding remarkable results using recent sequencing technologies in terms of diagnosing genetic conditions, we have made much less headway in translating this patient information into therapies and effective treatments. Even with recent calls for greater research into personalised treatments for those affected by a rare disease, progress in this area is still severely lacking, in part due to the astronomical cost and time involved in bringing treatments to the clinic. Gene correction using the recently-described genome editing technology CRISPR/Cas9, which allows precise editing of DNA, offers an exciting new avenue of treatment, if not cure, for rare diseases; up to 80% of which have a genetic component. This system allows the researcher to target any locus in the genome for cleavage with a short guide-RNA, as long as it precedes a highly ubiquitous NGG sequence motif. If a repair sequence is then also provided, such as a wild-type copy of the mutated gene, it can be incorporated by homology-directed repair (HDR), leading to gene correction. As both guide-RNA and repair template are easily generated, whilst the machinery for editing and delivery remain the same, this system could usher in the era of 'personalised medicine' and offer hope to those with rare genetic diseases. However, currently it is difficult to test the efficacy of CRISPR/Cas9 for gene correction, especially in vivo. Therefore, in my PhD I have developed a novel fluorescent reporter system which provides a rapid, visual read-out of both non-homologous end joining (NHEJ) and homology-directed repair (HDR) driven by CRISPR/Cas9. This system is built upon a cassette which is stably and heterozygously integrated into a ubiquitously expressed locus in the mouse genome. This cassette contains a strong hybrid promoter driving expression of membrane-tagged tdTomato, followed by a strong stop sequence, and then membrane-tagged EGFP. Unedited, this system drives strong expression of membrane-tdTomato in all cell types in the embryo and adult mouse. However, following the addition of CRISPR/Cas9 components, and upon cleavage, the tdTomato is rapidly excised, resulting via NHEJ either in cells without fluorescence (due to imperfect deletions) or with membrane-EGFP. If a repair template containing nuclear tagged-EGFP is also supplied, the editing machinery may then use the precise HDR pathway, which results in a rapid transition from membrane-tdTomato to nuclear- EGFP. Thereby this system allows the kinetics of editing to be visualised in real time and allows simple scoring of the proportion of cells which have been edited by NHEJ or corrected by HDR. It therefore provides a simple, fast and scalable manner to optimise reagents and protocols for gene correction by CRISPR/Cas9, especially compared to sequencing approaches, and will prove broadly useful to many researchers in the field. Further to this, I have shown that methods which lead to gene correction in our reporter system are also able to partially repair mutations found in the disease-causing gene, Zmynd10; which is implicated in the respiratory disorder primary ciliary dyskinesia (PCD), for which there is no effective treatment. PCD is an autosomal-recessive rare disorder affecting motile cilia (MIM:244400), which results in impaired mucociliary clearance leading to neonatal respiratory distress and recurrent airway infections, often progressing to lung failure. Clinically, PCD is a chronic airway disease, similar to CF, with progressive deterioration of lung function and lower airway bacterial colonization. However, unlike CF which is monogenic, over 40 genes are known to cause PCD. The high genetic heterogeneity of this rare disease makes it well suited to such a genome editing strategy, which can be tailored for the correction of any mutated locus.
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Poursaeed, Nasim. "Genetic diagnosis and identification of novel genes in neuromuscular disorders using next generation sequencing." Thesis, Strasbourg, 2012. http://www.theses.fr/2012STRAJ055/document.
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Les maladies neuromusculaires sont des maladies souvent très sévères et très handicapantes, et un fardeau pour les patients, leurs familles, ainsi que pour le système de santé. Le but de ce projet était de mettre au point et de valider une approche de capture de séquence et de séquençage haut débit pour identifier les mutations en cause chez les patients atteints de maladies neuromusculaires et également trouver les nouveaux gènes qui sont impliqués dans une sous-classe de myopathies, les myopathies centronucléaires. Nous avons montré que l’approche de capture de séquence et de séquençage haut débit peux être utile dans le domaine des maladies neuromusculaires car elle est moins coûteuse que les approches conventionnelles « gène par gène » mise en oeuvre dans les laboratoires de diagnostics génétiques.Cette stratégie devrait élargir les spectres cliniques connus et identifier de nouvelles maladies alléliques (des mutations dans un gène causant différentes maladies). De plus, cela sera utile pour l’élargissement des connaissances sur les corrélations génotypes-phénotypes qui sont nécessaires à une prise en charge plus adaptée et au développement de stratégies thérapeutiquesNeuromuscular disorders (NMD) are genetic diseases affecting muscles, nerves and neuromuscular junctions. They are rare and often severe with different age of onset from childhood to adulthood with significant burden to the patients, their families and public health system. For testing the possibility of using massively parallel sequencing as a routine technique in molecular diagnosis of neuromuscular disorders, the first aim of my PhD project was to use massively parallel sequencing technique in patients with different NMDs for disease-causing mutation detection. The second aim of my PhD project was to find novel gene(s) implicated in centronuclear myopathies (CNM). CNM are inherited neuromuscular disorders and a type of congenital myopathies, characterized mainly by presence of central and one or more internalized nuclei in muscle fibers with different severities and age of onset, using massively parallel sequencing. About 20% of CNM patients don’t have any mutations in four implicated genes. Disease- causing mutation(s)/ gene(s) in these patients need to be identified. We could show that next generation sequencing is a robust technique for gene identification if a homogenous cohort of patients is available and also is useful to use as a routine technique in molecular diagnosis as it istime and cost effective technique
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Li, Yan. "Genetic analysis of Alzheimer's disease associated genes : a perspective from abnormal cholesterol metabolism /." View the Table of Contents & Abstract, 2008. http://sunzi.lib.hku.hk/hkuto/record/B39711663.
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Xiang, Fengqing. "Genetic studies of neurological disorders : Rett syndrome and HD-like familial prion disease /." Stockholm, 2001. http://diss.kib.ki.se/2001/91-628-4882-8/.
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McCarthy, Shane. "Comparative sequencing of candidate genes in complex disease /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-663-8/.
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Whitmore, Scott Anthony. "Positional cloning of genes associated with human disease /." Title page, contents and summary only, 1999. http://web4.library.adelaide.edu.au/theses/09PH/09phw616.pdf.
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Thesis (Ph.D.) -- University of Adelaide, Dept. of Cytogenetics and Molecular Genetics, 1999.Copies of author's previously published articles inserted. Amendments pasted onto back-end paper. Bibliography: leaves 255-286.
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Marchione, Wesley A. "Pathogen resistance genes and proteins in orchids." Virtual Press, 2003. http://liblink.bsu.edu/uhtbin/catkey/1260625.
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To study resistance (R) genes that are expressed when Sophrolaeliacattleya Ginny Champion 'Riverbend' orchid tissue was infected with the tobacco mosaic virus (TMV0), a subtraction library of cDNA clones was previously constructed using mRNA isolated before and after infection (Shuck, unpublished). From 200 clones collected, 5 clones were randomly selected, DNA was isolated, and the cDNA insert was sequenced. These sequences were imported into BLAST to search for homology to other R genes. This search revealed clone 4A to have an 84% homology to a 54 nucleotide region from the Arabidopsis thaliana oligouridylate binding protein which is highly expressed and known to bind RNA Polymerase III transcripts and adenovirus associated RNAs. Further bioinformatics analysis was performed utilizing databases and analysis packages available on the Internet, software such as Vector NTI (Informax, Bethesda, MD), and manual searches. However, no additional domains or motifs indicative of pathogen resistance genes were located in any of the 5 clones. Subsequently, total proteins expressed at various time points following infection were examined on denaturing 5-20% gradient polyacrylamide gels stained with the ProteoSilver Plus TM silver stain kit (Sigma, St. Louis, MO) in order to examine the timing and duration of expression of proteins involved in TMV-O resistance. One protein of-18 kDa was highly expressed at 4 hr after infection that was not seen in the negative control. By 8 hr the band was no longer expressed, it was expressed again from 30 - 48 hr, but was not seen again in later time points. Finally, total mRNA isolated from pooled time points and subjected to in vitro translation indicated a reduction in translation products after infection, providing evidence of posttranscriptional gene silencing (PTGS) following TMV-O infection.Department of Biology
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Spataro, Nino 1984. "Human genetic disorders: Mendelian and complex diseases." Doctoral thesis, Universitat Pompeu Fabra, 2016. http://hdl.handle.net/10803/482220.
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From Darwin’s “On the Origin of Species”, many years elapsed before human diseases were considered in an evolutionary framework. Besides theoretical and empirical advances, we are far from the complete understanding of disease aetiology. Highly penetrant disorders with Mendelian inheritance are mostly explained by the mutation-selection balance model, which is insufficient to describe the selective pressures acting on the full set of alleles related to diseases. We show in the first two papers that Next Generation Sequencing (NGS) technologies provide a unique opportunity to investigate variation and contribute to the understanding of the genetic architecture of disease. Besides exploring the role of rare and copy number variants in Parkinson’s disease (PD), we demonstrate the functional relation between Mendelian and idiopathic PD. In the last paper, we report that variation in genes previously related to Mendelian disorders has a more important role in driving complex disease susceptibility than genes associated only to complex diseases.Des de l'Origen de les Espècies de Darwin van passar molts anys abans que les malalties humanes fossin considerades sota un marc evolutiu. Tanmateix, tot i els darrers avenços teòrics i empírics, estem molt lluny de tenir una comprensió completa de l'etiologia de les malalties humanes. Mentre els trastorns altament penetrants amb herència mendeliana poden explicar-se sota un model d’equilibri mutació-selecció, aquest és insuficient per descriure les pressions selectives que actuen sobre tot el conjunt d'al·lels associats a malalties. Mostrem en els dos primers treballs que les noves tecnologies de seqüenciació proporcionen una oportunitat única per investigar la variació i contribuir a la comprensió de l'arquitectura genètica de la malaltia. A més d'explorar el paper de les variants rares i en el nombre de còpies en la malaltia de Parkinson (PD), demostrem la relació funcional entre les formes mendelianes i idiopàtiques d’aquesta malaltia. En el darrer treball, mostrem sota una perspectiva evolutiva i funcional que, en comparació amb la variació genètica en gens associats només a malalties complexes, la variació en gens prèviament relacionats amb trastorns Mendelians sembla tenir un paper clarament més important en la susceptibilitat a la malaltia complexa.
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Baker, John Summers. "The function of innate immune genes in Crohn's disease." Thesis, University of Oxford, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.560924.
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Crohn's Disease (CD) is a debilitating condition characterised by chronic intermittent intestinal inflammation. More than 90 genetic polymorphisms are associated with CD susceptibility, including several in genes of the innate immune system. Here I present a series of experiments designed to enhance our knowledge of the roles of CD-associated polymorphisms in pathogenesis. Many therapeutic regimens are employed in CD treatment, but patients' responses to treatment and disease progression vary widely. There is great interest in studying whether analysis of patients' genotype at CD-associated polymorphisms can be used to predict their disease course, and guide clinical decision-making. To answer these questions, it is essential to be able routinely and cost- effectively to genotype patients at the full range of known CD-associated polymorphisms. The first project presented here describes the design and initial successful testing of a CD-specific genotyping microarray for use in genotype-phenotype studies. The polymorphism most strongly associated with CD susceptibility is in the pattern recognition receptor NOD2; the remaining experiments presented here study the function of NOD2 in primary human monocyte-derived Dendritic Cells (DCs). First, a microarray study is presented which characterises global transcriptional responses to NOD2 stimulation in DCs. NOD2 stimulation is shown to enhance transcriptional changes induced by Toll-Like Receptor 2 stimulation, and NOD2-mediated transcriptional regulation is shown to be lost in DCs expressing CD-associated NOD2 variants. Second, experiments are presented which describe development of a new protocol for proteomic analysis of post-translational protein modifications, and which identify a number of novel candidate targets of NOD2 signalling in DCs. Finally, a project is presented which demonstrates for the first time that NOD2 stimulation induces autophagy in DCs, in an NF-kB and RIPK2-dependent pathway. CD-associated polymorphisms in NOD2 and ATG 16Ll abolish NOD2-mediated autophagy induction, resulting in impaired bacterial handling and antigen presentation.
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McGregor, Nathaniel Wade. "The identification of novel susceptibility genes involved in anxiety disorders." Thesis, Stellenbosch : Stellenbosch University, 2014. http://hdl.handle.net/10019.1/95859.
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Thesis (PhD)--Stellenbosch University, 2014.ENGLISH ABSTRACT: The etiology of anxiety disorders remains incompletely understood. Clear evidence for a genetic component has been proposed; however, there is also an increasing focus on environmental factors and the interaction between these and the genetic components that may mediate (anxiety) disorder pathogenesis. No single gene or genetic component has been explicitly identified as being involved in the development of anxiety disorders. This is most likely due to a number of reasons, which include, for example, the heterogeneity of anxiety disorders, the contribution of environmental factors and methodological limitations (e.g. small sample size) of research studies. Until now, genetic association studies usually focused on one particular psychiatric disorder at a time. However, with the difficulty in identifying susceptibility genes and/or loci in heterogeneous disorders like obsessive-compulsive disorder and other conditions in the anxiety spectrum, it is perhaps timely to consider multivariate genetics and epidemiological studies in a number of disorders sharing a core characteristic – such as anxiety. In addition to genetic underpinnings, a number of environmental variables have also been identified as risk factors for pathological anxiety, including adverse life events like childhood physical and sexual abuse. The hypothesis for this project is that a pre-existing genetic vulnerability (or genetic risk) interacts with the impact of adverse life events to result in the development of one or more anxiety disorder(s). Considering phenotypic overlap amongst the anxiety disorders, it is likely that diverse networks of genes and/ or interacting pathways are responsible for the phenotypic manifestations observed. Sprague Dawley rats exhibiting behaviours indicative of anxiety in the context of environmental stressors (maternal separation and restraint stress) were used as model for the identification of novel susceptibility genes for anxiety disorders in humans. The striatum has previously been implicated as a candidate in the brain architecture of anxiety pathogenicity, and is also a site exhibiting a high degree of synaptic plasticity. The synaptic plasticity pathway was investigated using the dorsal striatum of the rat brain and several genes were identified to be aberrantly expressed in “anxious” rats relative to controls (Mmp9, Bdnf, Ntf4, Egr2, Egr4, Grm2 and Arc). In humans, it was found that the severity of early adversity was significantly and positively associated with the presence of an anxiety disorder in adulthood. When the human homologues of the susceptibility candidate genes that were identified using the animal model were screened in a human cohort of patients with obsessive-compulsive disorder (OCD), panic disorder (PD) or social anxiety disorder (SAD) (relative to controls), five single nucleotide polymorphisms (SNPs) were found to be significantly associated with these conditions. Four of these SNPs were also found to significantly interact with the severity of childhood trauma. Haplotype analysis of variants within the identified susceptibility candidates revealed novel haplotype associations, four of which are located in the MMP9 gene. Notably, this the first study to link these particular mutations in the MMP9 gene with anxiety disorders and this finding is consistent with previous work suggesting that MMP9 is involved in conditions like cardiovascular disease and cancer which have been associated with increased prevalence of anxiety disorders. In conclusion, this project yielded important findings pertaining to the etiology of anxiety disorders. The use of a combined anxiety disorders cohort (OCD, PD and SAD) may suggest that the associations found here may hold true for anxiety disorders in general and not only for a particular clinically delineated condition. Childhood trauma was confirmed as an increased susceptibility risk for anxiety disorders. Also, this research contributed several novel susceptibility genes (MMP9, EGR2, EGR4, NTF4, and ARC), five significant SNP associations, four significant SNP-environment interactions and five haplotype associations (within MMP9 and BDNF) as candidates for anxiety pathogenicity. The identified polymorphisms and haplotypes were demonstrated to be associated with susceptibility to anxiety disorders in a gene-environment correlation and gene-environment interaction.
AFRIKAANSE OPSOMMING: Die oorsake van angssteurings word steeds nie volledig verstaan nie. Daar is duidelike bewyse vir 'n genetiese komponent, maar daar is ook toenemende fokus op omgewingsfaktore en die interaksie tussen hierdie omgewingsfaktore en genetiese komponente by angssteurings. Geen enkele geen of genetiese komponent is al geïdentifiseer as diè wat betrokke is by die ontwikkeling van angssteurings nie. Dit is waarskynlik weens 'n aantal redes, wat byvoorbeeld, die heterogeneïteit van angssteurings, die bydrae van omgewingsfaktore en metodologiese beperkings (bv. klein steekproef) van die navorsingstudies, insluit. Verder het genetiese assosiasiestudies tot nou toe gewoonlik net op een spesifieke psigiatriese versteuring op 'n slag gefokus. Maar, gegewe die uitdaging om vatbaarheidsgene en / of loci in heterogene steurings soos obsessief – kompulsiewe steuring (OKV) en ander toestande op die angsspektrum te identifiseer, is dit tyd om genetiese en kliniese studies in ‘n aantal steurings - met ‘n oorvleuende kern-element soos angs -, gesamentlik te oorweeg. Bykomend tot die genetiese boustene, is ‘n aantal omgewingsveranderlikes soos traumatiese lewenservarings tydens die kinderjare as risikofaktore vir patologiese angs geidentifiseer. Die hipotese vir hierdie projek is dat daar 'n interaksie tussen genetiese kwesbaarheid (of genetiese risiko) en traumatiese lewensevarings is en dat dit tot die ontwikkeling van 'n / veelvoudige angssteuring(s) kan lei. Inaggenome die fenotipiese oorvleueling tussen die angssteurings, is dit waarskynlik dat diverse netwerke van gene en / of interaktiewe geen-paaie vir die manifestasie van hierdie toestande verantwoordelik is. Sprague Dawley-rotte met gedragswyses aanduidend van angs, in die konteks van omgewingstressore (d.i. skeiding van die ma-rot en bedwang-stres [restraint stress]), is as model gebruik vir die identifisering van nuwe vatbaarheidsgene vir angssteurings in mense. Die striatum is voorheen as ‘n kandidaat in die brein-argitektuur van patologiese angs voorgehou, en is ook ‘n plek met ‘n hoë mate van sinaptiese plastisiteit. Die sinaptiese plastisiteit is ondersoek deur te fokus op die dorsale striatum van die rotbrein en daar is verskeie gene gevind wat anders is in “angstige” rotte in vergelyking met kontroles (Mmp9, Bdnf, Ntf4, Egr2, Egr4, Grm2 en Arc). In mense is daar gevind dat die ernstigheidsgraad van vroeë trauma beduidend en positief met die teenwoordigheid van ‘n angssteuring tydens volwassenheid verband hou. Toe die menslike ekwivalente van die vatbaarheidsgene wat met die dieremodel geïdentifiseer is in ‘n mens-kohort met obsessief-kompulsiewe steuring (OKS), panieksteuring (PS) en sosiale angssteuring (SAS) ondersoek is, is gevind dat daar 5 enkele nukleotied polimorfismes (ENPs) is wat met die toestande verband hou. Daar is ook gevind dat vier van hierdie ENPs beduidend verband hou met die ernstigheidsgraad van trauma tydens die kinderjare. Haplotipe analise van variante binne die geïdentifiseerde vatbaarheidsgene het op nuwe haplotipe assosiasies – waarvan 4 op die MMP9-geen geleë is – gedui. Hierdie is dus die eerste studie wat gevind het dat dié spesifieke mutasies van die MMP9-geen met angssteurings verband hou. Hierdie bevinding strook met vorige werk wat daarop dui dat die MMP9-geen by toestande soos kardiovaskulêre siekte en kanker wat ook met verhoogde voorkoms van angssteurings verband hou, betrokke is. Ter afsluiting kan ons sê dat hierdie projek belangrike bevindinge oor die oorsake van angssteurings gemaak het. Die gebruik van ‘n gekombineerde angssteurings-kohort (OKS. PS en SAS) kan moontlik suggereer dat die assosiasies wat ons hier gevind het, waar is vir alle angssteurings en nie net vir ‘n spesifieke afgebakende toestand nie. Traumatiese ervarings tydens die kinderjare is ook bevestig as ‘n risiko vir die ontwikkeling van angssteurings. Hierdie navorsing het ook verskeie nuwe vatbaarheidsgene (MMP9, EGR2, EGR4, NTF4, en ARC), 5 beduidende ENP assosiasies, 4 beduidende ENP-omgewings-interaksies en 5 haplotipe assosiasies (by MMP9 en BDNF) geïdentifiseer as moontlike kandidate wat ‘n rol speel by die ontstaan van patologiese angs. Daar is ook gevind dat die geïdentifiseerde polimorfismes en haplotipes met vatbaarheid vir angssteurings in ‘n geen-omgewing- korrelasie en geen-omgewing- interaksie verband hou. Stellenbosch University http://scholar.sun.ac.za
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Klar, Joakim. "Positional Cloning of Disease Causing Genes : A Genetic Study of Obesity, Ichthyosis Prematurity Syndrome and Meniere's Disease." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4783.
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Boag, Alisdair Matthew. "An immunological and genetic investigation of canine hypoadrenocorticism (Addison's Disease)." Thesis, Royal Veterinary College (University of London), 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.618317.
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Feuk, Lars. "SNP based strategies to study candidate genes for Alzheimer's disease /." Stockholm, 2002. http://diss.kib.ki.se/2002/91-7349-334-1.
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Li, Yan, and 李艷. "Genetic analysis of Alzheimer's disease associated genes: a perspective from abnormal cholesterol metabolism." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B39793758.
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