Consanguinity is the union of closely related individuals - which can have genetic implications on the health of offspring(s). Consanguineous families with disorders have been extensively analysed by geneticists and this has led to the identification of many autosomal recessive disorder causal variants and genes. Two copies of the 'inactivating' or loss of function (LoF) allele are required to cause an autosomal recessive disorder, one inherited from the mother and the other from the father. In outbreeding populations these LoF alleles very rarely meet their counterpart (as it requires both parents to possess the allele), thus are passed down the generations silently - sometimes for millennia. However, consanguineous and/ or endogamous offspring have elevated levels of homozygosity, which dramatically increases the probability of any allele to be in a homozygous (or more correctly autozygous) state. This increase in probability applies to LoF mutations also; and this elevation of levels of homozygosity is the main reason why extremely rare autosomal recessive disorders are usually only seen in populations where consanguinity (and/ or endogamy) levels are high.

No description available.

No description available.

No description available.

No description available.

No description available.

Mitochondrial DNA (mtDNA) point mutations clonally expand and result in focal respiratory chain deficiency in tissues of patients with mitochondrial disease and to a lesser extent in normal human ageing. The consequences of mtDNA point mutations upon cellular processes and the mechanisms involved in mitochondrial disease heterogeneity and progression as well as age-related tissue dysfunction, however still remain unknown. The aim of this thesis was to further our understanding of clonally expanded mtDNA point mutations in ageing and the mechanisms associated with disease heterogeneity, using mice that harbour mtDNA point mutations. Characterisation of mitochondrial dysfunction in the PolgA+/mut mouse colon provided evidence for a conserved mechanism for the clonal expansion of somatic mtDNA point mutations by random genetic drift, without any selective constraints, resulting in age-related respiratory chain deficiency in colonic crypts of both PolgA+/mut mice and ageing humans. Preliminary data examining the gene expression profile of respiratory chain deficient colonic crypts revealed potential alterations in processes concerning: the cell cycle and proliferation; DNA maintenance and repair; cell adhesion and tight junction formation; the adaptive immune response and energy metabolism. Such changes hold a number of potentially interesting associations with the development of colorectal cancer and the pathogenesis of inflammatory bowel disease. Using histochemical and mtDNA genome analysis, the m.5024C>T tRNAAla mouse was shown to be a fairly good model of a pathogenic mt-tRNA point mutation in disease. Results demonstrated that the m.5024C>T mutation was pathogenic; mice displayed phenotypic evidence of respiratory chain deficiency; aged mice displayed evidence of disease progression; different tissues showed different biochemical thresholds and there was a selective loss of the mutation in actively dividing cells. These observations have important implications for the role of mtDNA point mutations in ageing and potential mechanisms that govern mitochondrial disease presentation, progression and transmission.

Epigenome-wide association scans (EWAS) of human complex traits are a rapidly growing area of research, in part due to recent advances in technology that have allowed for a deeper coverage of the human methylome. One of the unique features of the human methylome is that it is dynamic and previous studies have shown that age can have a strong impact on DNA methylation patterns. The dynamic nature of DNA methylation also influences EWAS methodology, both from a statistical and biological perspective. In this thesis, I explored EWAS methods and applications to ageing and age-related phenotypes. Firstly, I estimated EWAS power under several simulation scenarios and study designs, and my results suggested that the majority of recent EWAS studies lack statistical power to detect small DNA methylation effect sizes. I then applied EWAS to identify differential methylation CpG sites associated with three phenotypes, including ageing, birth weight and smoking. One of the novel findings from this thesis was that hundreds of genome-wide significant ageing-related hypermethylated regions were identified across multiple tissues in twins. These findings confirm and extend previous work showing that ageing has a strong underlying effect on DNA methylation. Birth weight did not yield significant differential methylation sites, which may be partly explained by low power to detect modest methylation effects. Smoking is a well-known environmental risk factor for disease, and my analyses identified novel impacts of smoking on DNA methylation patterns in adipose tissue, which are of interest to cardiovascular and metabolic disease. I further explored the impacts of smoking by integrating DNA methylation and gene expression profiles in adipose tissue and in whole blood. In addition to identifying novel results, my findings also confirmed that the AHRR and F2RL3 genes showed stable and consistent changes related to smoking in both DNA methylation and gene expression profiles across tissues. My findings explored methodological issues in genome-wide methylation studies and showed that age and smoking have a strong and reproducible effect on DNA methylation across tissues in humans, which suggests that these factors should always be included as covariates in EWAS of human complex traits.

Psychological variables have been shown to be important in the experience of chronic pain. One such variable, pain catastrophizing, has repeatedly been demonstrated as a significant predictor of pain intensity. With the aim to explore the relationship between pain catastrophizing and pain intensity, a systematic review of published empirical research was undertaken. The results suggested that there is a significant relationship between pain intensity and pain catastrophizing on a cross-sectional basis. However this relationship becomes more complex when additional psychological factors are controlled for or considered as mediating or moderating variables. The limitations of the review and implications of findings are discussed. The second section of this thesis is an empirical study that considered the relationship between chronic pain-related outcomes and a more recently emerging psychological variable in the field of chronic pain, self-compassion. This took a cross-sectional self-report questionnaire design. Recruitment took place in NHS chronic pain clinics, community support groups, social media websites and online forums (N = 210). This research suggested that, while some aspects of self-compassion were significantly correlated with pain intensity and pain-related disability, together they could not explain a unique amount of variance in either outcome variable once other psychological variables were controlled for in hierarchical regression models. Limitations of the study and clinical implications are discussed. The third section of this thesis takes the form of a critical appraisal which further discusses the process of conducting the research element of this thesis.

No description available.