published_or_final_version / Psychiatry / Doctoral / Doctor of Philosophy

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Diss. (sammanfattning) Uppsala : Uppsala universitet, 2005. / Härtill 5 uppsatser.

Thesis (Ph. D.)--Washington State University, May 2008. / Includes bibliographical references.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1967. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

No description available.

A population-based study in South East Wales (population 668,100) identified 69 families with 135 affected members with von Recklinghausen neurofibromatosis (NF-1), giving a disease prevalence of 20/105 of population. In these families penetrance of the NF-1 gene was 100% by the age of five years. 41/135 cases were judged to represent new disease mutations and the mutation rate was estimated to lie between 3.1x10-5 and 10.4x10-5. A parental age effect for new mutations was not demonstrated, nor was a maternal effect on disease severity. The clinical features and natural history of NF-1 in this cohort were used to derive data for genetic counselling and recommendations for the management of affected individuals. For counselling purposes the complications of NF-1 can be usefully divided into 4 categories (the frequency of each, based on this study, are shown in parentheses): intellectual handicap (33% overall, moderate/severe retardation 3.2%, minimal retardation/ learning difficulties 29.8%); complications developing in childhood and causing lifelong morbidity, e. g. facial plexiform neurofibromas, scoliosis, pseudoarthrosis (8.5%); 'treatable' complications which can develop at any age, e. g. benign disorders of the nervous system, visceral and endocrine tumours, renal artery stenosis (15.7%) and malignant or CNS tumours (4.4-5.2%). The study population indicates that sufferers are not being diagnosed sufficiently early, nor receiving appropriate follow-up and counselling. It is recommended that patients with NF-1 have regular clinical assessments to monitor for the development of complications, although none occur often enough to warrant biochemical or radiological screening. As many of the complications develop early in life, children should have biannual review; in adults, unless a particular complication indicates more frequent review,annual clinical examination is sufficient. Alongside the population survey, genetic linkage studies were undertaken in selected large families to determine the chromosomal localisation of the NF-1 gene. At the outset of this work, two families had been reported in which NF-1 and Myotonic Dystrophy (DM) appeared to co-segregate, suggesting that the two genes were closely linked and on chromosome 19. However, linkage studies of 3 chromosome 19 markers linked to DM showed significantly negative lod scores, therefore excluding this possibility. Other chromosomes were then studied using random unique sequence DNA probes and samples from the largest families were made available to collaborators in the USA for linkage studies using possible candidate genes (ß nerve growth factor and oncogenes). No marker studied showed evidence of linkage. The negative data were used to produce an exclusion map for NF-1, using the computer program 'EXCLUDE'. The presentation of this work was one of the factors which precipitated the formation of an international consortium for NF-1 linkage in February 1987; the first task of the consortium was to produce an expanded exclusion map. A small positive lod score for a marker on chromosome 17, taken with the exclusion data, showed that NF-1 was seven times more likely to be on chromosome 17 than any other chromosome; this was rapidly confirmed by two North American groups, one of which was using samples from the 5 largest families presented in the thesis. Subsequent linkage analysis of pericentromeric chromosome 17 markers in the Welsh family panel showed no evidence of non-allelic heterogeneity and identified closely linked flanking markers for the NF-1 gene suitable for prenatal/presymptomatic diagnosis. The chromosomal localisation of NF-1 represents a major step towards the eventual understanding of the disease pathogenesis and the development of possible treatments.

Etiological models of complex disease are elusive[46, 33, 9], as are consistently replicable findings for major genetic susceptibility loci[54, 14, 15, 24]. Commonly-cited explanations invoke low-frequency genomic variation[41], allelic heterogeneity at susceptibility loci[33, 30], variable etiological trajectories[18, 17], and epistatic effects between multiple loci; these represent among the most methodologically-challenging issues in molecular genetic studies of complex traits. The response has been con- sistently reactionary—hypotheses regarding the relative contributions of known func- tional elements, or emphasizing a greater role of rare variation[46, 33] have undergone periodic revision, driving increasingly collaborative efforts to ascertain greater numbers of participants and which assay a rapidly-expanding catalogue of human genetic variation. Major deep-sequencing initiatives, such as the 1,000 Genomes Project, are currently identifying human polymorphic sites at frequencies previously unassailable and, not ten years after publication of the first major genome-wide association find- ings, re-sequencing has already begun to displace GWAS as the standard for genetic analysis of complex traits. With studies of complex disease primed for an unprecedented survey of human genetic variation, it is essential that human geneticists address several prominent, problematic aspects of this research. Realizations regarding the boundaries of human traits previously considered to be effectively disparate in presentation[44, 39, 35, 27, 25, 12, 4, 13], as well as profound insight into the extent of human genetic diversity[23, 22] are not without consequence. Whereas the resolution of fine-mapping studies have undergone persistent refinement, recent polygenic findings suggest a less discriminant basis of genetic liability, raising the question of what a given, unitary association finding actually represents. Furthermore, realistic expectations regarding the pattern of findings for a particular genetic factor between or even within populations remain unclear. Of interest herein are methodologies which exploit the finite extent of genomic variability within human populations to distinguish single-point and cumulative group differences in liability to complex traits, the range of allele frequencies for which common association tests are appropriate, and the relevant dimensionality of common genetic variation within ethnically-concordant but differentially ascertained populations. Using high-density SNP genotype data, we consider both hypothesis-driven and agnostic (genome-wide) approaches to association analysis, and address specific issues pertaining to empirical significance and the statistical properties of commonly- applied tests. Lastly, we demonstrate a novel perspective of genome-wide genetic “background” through exhaustive evaluation of fundamental, stochastic genetic processes in a sample of matched affected and unaffected siblings selected from high- density schizophrenia families.