<p>Chiari Type I Malformation (CMI) is a developmental disorder characterized by displacement of the cerebellar tonsils below the base of the skull, resulting in significant neurologic morbidity. While there are multiple proposed mechanisms for tonsillar herniation, "classical" CMI is thought to occur due to a compromised posterior cranial fossa (PF). As CMI patients display a high degree of clinical variability, it is hypothesized that this heterogeneous disorder has a complex etiology influenced by multiple genetic and environmental factors. Despite the fact that multiple lines of evidence support a genetic contribution to disease, no genes have been identified to date. Thus, the primary goal of this dissertation is to begin to dissect the genetic etiology of this important disorder and gain a better understanding of what factors contribute to the observed disease heterogeneity.</p><p>In order to address these goals, two studies and three distinct analytic approaches were carried out. In the first study, 367 individuals from 66 nonsyndromic, CMI multiplex families provided the basis for a whole genome linkage screen to identify genomic regions likely to harbor CMI susceptibility genes. Results from the linkage screen using the complete collection of families yielded limited evidence for linkage, likely due to genetic heterogeneity. Thus, two separate analytic approaches were applied to the data to reduce phenotypic and hopefully genetic heterogeneity, thereby increasing power to identify disease genes. In the first approach, families were stratified based on the presence or absence of connective tissue disorder (CTD) related conditions as hereditary CTDs are commonly associated with CMI and the presumed mechanism for tonsillar herniation differs between CMI patients with CTDs and "classical" CMI patients. Stratified analyses resulted in increased evidence for linkage to multiple genomic regions. Of particular interest were two regions located on chromosomes 8 and 12, both of which harbor growth differentiation factors, GDF6 and GDF3, which have been implicated in Klippel-Feil syndrome (KFS). In the second approach, a comprehensive evaluation of the genetic contribution to the PF was performed, followed by ordered subset analysis (OSA) using heritable, disease-relevant PF traits to identify increased evidence for linkage within subsets of families that were similar with respect to cranial base morphological traits. Much of the PF was found to be heritable and results from OSA identified multiple genomic regions showing increased evidence for linkage, including regions on chromosomes 1 and 22 which implicated several strong biological candidates for disease. </p><p>In the second study, 44 pediatric, surgical CMI patients were ascertained in order to establish disease subtypes using whole genome expression profiles generated from patient blood and dura mater samples and radiological data consisting of PF morphometrics. Sparse k-means clustering as well as a modified version were used to cluster patients using the biological and radiological data both separately and collectively. The most significant patient classes were identified from the pure biological clustering analyses. Further characterization of these classes implicated strong biological candidates involved in endochondral ossification from the dura analysis and a blood gene expression profile exhibiting a global down-regulation in protein synthesis and related pathways that may be associated with comorbid conditions. </p><p>Collectively, these studies established several strong biological disease candidates, as well as emphasized the need to better understand and account for disease heterogeneity, re-evaluate the current diagnostic criteria for CMI, and continue to investigate the use of endophenotypes, such as cranial base morphometrics, when conducting genetic studies.</p> / Dissertation

Late-onset Alzheimer’s disease (LOAD) is the most common form of dementia, with an incidence of up to 50% in western populations over the age of 85 and a high heritability (up to 80%). The identification of risk factors for the development of LOAD is imperative for improving our understanding of this disease and for identifying therapeutic targets for treatment or prevention. Currently, the major known risk factors for the development of LOAD are age and the ApoE ε4 genotype. Previous studies have implicated plasma levels of the amyloid beta (Aß) peptide as a LOAD-associated quantitative trait and identification of loci influencing this trait could provide new insights into LOAD. In this thesis, plasma levels of the Aß peptides Aß40 and Aß42 have been measured in two isolated populations and genome-wide linkage and association analyses were performed. The genome-wide association analyses identified a number of promising quantitative trait loci; highlighting both novel and previously reported LOAD genes for further study, whilst also providing an excellent resource for genetic convergence studies with other LOAD related traits. Several studies have reported an association between levels of oxidative stress and levels of Aß such that increasing levels of Aß appear to increase markers for oxidative stress and vice versa. The role of oxidative stress in LOAD and aging was therefore also investigated through analysis of mitochondrial mutational burden and DNA damage respectively, using DNA isolated from both blood and the brain and by carrying out a candidate gene association study of loci involved in mitochondrial function in LOAD cases and controls. Approaches to the investigation of mitochondrial genetics for the study of LOAD are comprehensively reviewed, adapted and tested and the results indicate a need for additional research in this aspect of the disease. This thesis therefore presents a focus on two aspects of genetic research into LOAD, a complex disease with multiple environmental and genetic influences which aims to advance our understanding of the disease and bring us closer to treatment and prevention strategies.

Thesis (M. Phil.)--University of Hong Kong, 2007. / Title proper from title frame. Also available in printed format.

Thesis (Ph. D. in Neuroscience)--Vanderbilt University, Dec. 2006. / Title from title screen. Includes bibliographical references.

Monogenic autoimmune diseases are highly variable syndromes that usually have onset in the first year of life and are often fatal in early childhood. Identifying monogenic autoimmune diabetes is important as it can have implications for medical management of patients, informs families and clinicians of prognosis and recurrence risk, and gives insights into beta-cell autoimmunity and immune tolerance. The first section of this thesis introduces monogenic autoimmune disease, with focus on the conditions that have autoimmune endocrine disorders as part of their clinical phenotype. The following section details the methodologies used throughout this thesis. In chapter 1, we used a type 1 diabetes genetic risk score (T1D-GRS) based on the top 10 risk alleles for T1D to identify patients with monogenic autoimmunity from patients with early-onset polygenic diabetes and additional autoimmunity. We showed that the T1D-GRS was highly discriminatory of monogenic autoimmunity, especially when combined with age of onset (ROC-AUC 0.88). We also identified 16 families for gene discovery studies. Furthermore, this work shows that polygenic risk for the development of T1D does not affect the development of diabetes in monogenic autoimmunity. Chapter 2 describes the genetic and phenotypic information for the largest cohort of patients with IPEX syndrome, caused by hemizygous mutations in FOXP3, reported to date (n=48). We analysed this data to determine if there were any genotypic or clinical characteristics of IPEX syndrome that could predict prognosis. We did not find evidence of phenotype-genotype relationships and showed that presenting feature did not predict prognosis. Medical management of IPEX syndrome cannot, therefore, be based on genotype or presentation. In chapter 3 we employed whole exome sequencing to look for causal variant(s) in a patient with diabetes (diagnosed aged 7 weeks) and autoimmune lymphoproliferative disease. This identified recessively inherited causative variants in LRBA. We then used targeted next generation sequencing (NGS) to screen a large cohort of patients (n=169) and identified an additional 8 probands and an affected family member. This confirms the role of LRBA as a neonatal diabetes gene, bringing the total number of genes to 25. In chapter 4, we assessed if immunoglobulin E (IgE) could be useful to identify patients with early-onset multisystem autoimmune disease caused by gain of function (GOF) STAT3 mutations. We showed that serum IgE was below the lower limit of the normal reference range (2KU/L) in all patients with STAT3 GOF (n=6), giving this threshold a sensitivity of 100% (95% CI: 54.1 – 100) and specificity 97.2% (95% CI: 96.2-97.9). We also found that IgE in patients with IPEX (n=16) was significantly higher than those with STAT3 GOF (p=0.002) suggesting it could be useful to identify IPEX from STAT3 GOF in non-consanguineous males with early-onset autoimmunity. The final concluding section summarises the key findings of each chapter, the impact of these findings and suggests future avenues for research. Identifying monogenic autoimmunity has enabled prenatal diagnoses, given families and clinicians knowledge on recurrence risk, and could enable targeted therapies to be employed. This body of work will enable better discrimination of monogenic autoimmunity from polygenic clustering of early-onset autoimmunity, and gives insights into the factors that determine disease phenotype and clinical course in monogenic autoimmunity. Gene discovery on the remaining patients will give new insights into the mechanisms of beta-cell autoimmunity and the regulation of the adaptive immune system and maintenance of immune tolerance.

Lower respiratory tract infections (LRTIs) are one of the most common infectious diseases in Europe and worldwide. Very little is known about the genetic factors associated with susceptibility to LRTI and so far studies have only analysed candidate gene loci. This work aimed to find genetic loci associated with susceptibility to severe and mild LRTI. To analyse severe LRTI, a European cohort of community acquired pneumonia (CAP) sepsis patients was used. To analyse mild LRTI, patients attending primary care with a cough were recruited across Europe. Two important candidate genes for susceptibility to severe and mild LRTI were studied. None of the four functional polymorphisms analysed in MBL2 were associated individually or when combined with susceptibility to LRTI or survival from severe LRTI. Rare homozygotes for rs12252 in the IFITM3 gene were found to associate with susceptibility to mild and severe viral LRTI, particularly influenza infection. Using a combination of genome-wide and candidate gene methods, 93 single nucleotide polymorphisms (SNPs) were chosen to genotype and analyse for susceptibility to mild LRTI. A gene region containing the MPHOSPH8, TPTE2, PSPC1 and ZMYM5 genes was found to associate with susceptibility to rhinovirus infection. A functional promoter SNP in the IL6 gene and a gene region containing the SAP18, MRP63 and SKA3 genes were associated with susceptibility to mild LRTI in smokers. A GWAS was performed for susceptibility to CAP sepsis in Europe. Genotypes were imputed for eight GWAS data sets comprising over 1000 CAP sepsis cases and over 4000 controls. Preliminary analysis results suggest an association in a chromosome 1 region containing the genes VASH2, ANGEL2 and RPS6KC1. This thesis presents results of the largest known genetic association study for susceptibility to CAP sepsis, and the only known genetic association study for mild LRTI. These novel findings will facilitate further research which may lead to better treatment and outcome for LRTI.

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 4 uppsatser.

Thesis (M. Phil.)--University of Hong Kong, 2008. / Includes bibliographical references (leaf 83-101) Also available in print.

Thesis (M. Phil.)--University of Hong Kong, 2008. / Includes bibliographical references (leaf 83-101) Also available online.

We present a 56-year-old patient suffering from frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). The history included a three-generation pedigree and the patient was found to be a mutation carrier. The diagnosis was hindered by late appearance of the hypokinetic movement disorder. For clinicians, it is important to consider rare neurodegenerative disease variants in early-onset familial dementia syndromes with behavioral, cognitive, and motor symptoms