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The development of whole exome sequencing has transformed the study of disease predisposition. The sequencing of both large disease sets and smaller rare disease families enables the identification of new predisposition variants and potentially provide clinical insight into disease management. There is no standard protocol for analysing exome sequencing data. Outside of extremely large sequencing studies including thousands of individuals, statistical approaches are often underpowered to detect rare disease associated variants. Aggregation of variants into functionally related regions, including genes, gene clusters, and pathways, allows for the detection of biological processes that, when interrupted, may impact disease risk. In silico functional studies can also be utilised to further understand how variants disrupt biological processes and identify genotype-phenotype relationships. This study describes the exploration of sequencing datasets from cancers and benign tumour diseases including: i) hereditary diffuse gastric cancer, ii) sweat duct proliferation tumours, iii) adrenocortical carcinoma, and iv) breast cancer. Each set underwent germline whole exome sequencing followed by additional tumour or targeted sequencing to identify associated predisposition genes. Variants within a cluster of risk genes that are involved in double strand break repair were identified as associated with hereditary diffuse gastric cancer risk via gene ontology enrichment analysis. This cluster included PALB2 within which, using externally collated data, loss of function variants were identified as significantly associated with hereditary diffuse gastric cancer risk. Germline protein-affecting variants in the myosin gene MYH9 were identified in all individuals with a rare sweat duct proliferative syndrome, suggesting a role for MYH9 in skin development, regulation and tumorigenesis. These MYH9 variants were analysed in silico to identify a genotype-phenotype relationship between the clinical presentation and variants in the ATP binding pocket of the protein. Tumour matched normal sequence data from adrenocortical carcinoma cases was used to elucidate the role of Lynch syndrome genes in disease pathogenesis. Within the breast cancer set, candidate genes were selected to undergo targeted sequencing in a larger set of cases to further explore their role in breast cancer risk. Risk associated genes identified within this study may ultimately aid in diagnosis and management of disease. This thesis has also generated multiple novel tools and sequencing analysis techniques that may be of use for further studies by aiding in the prioritisation of candidate variants. The described techniques will provide support to researchers working on rare, statistically underpowered datasets and to provide standard analysis pipelines for a range of dataset sizes and types, including familial data and unrelated individuals.

Introduction: In the UK, the number of comorbidities seen in children has increased along with the worsening obesity rate. These comorbidities worsen into adulthood. Genome-wide association studies have highlighted single nucleotide polymorphisms associated with the weight status of adults and offspring individually. To date, in the UK, parental genetic, lifestyle, and social determinants of health have not been investigated alongside one another as influencers of offspring weight status. A comprehensive obesity prevention scheme would commence prior to conception and involve parental intervention including all known risk factors. This current study aims to identify the proportion of overweight that can be explained by known parental risk factors, including genetic, lifestyle, and social determinants of health with offspring weight status in the UK. Methods: A cross-sectional study was carried out on 123 parents. Parental and offspring anthropometric data and parental lifestyle and social determinants of health data were self-reported. Parental genetic data were collected by use of GeneFiX saliva collection vials and genotype were assessed for brain-derived neurotrophic factor (BDNF) gene rs6265, melanocortin 4 receptor (MC4R) gene rs17782313, transmembrane protein 18 (TMEM18) gene rs2867125, and serine/threonine-protein kinase (TNN13K) gene rs1514175. Associations were assessed between parental data and the weight status of offspring. Results: Maternal body mass index modestly predicted child weight status (p < 0.015; R2 = 0.15). More mothers of overweight children carried the MC4R rs17782313 risk allele (77.8%; p = 0.007) compared to mothers of normal-weight children. Additionally, fathers who were not Caucasian and parents who slept for

Violent offending and injecting drug use (IDU) are highly comorbid, serious behaviours. Despite extensive empirical investigation, the mechanisms underpinning this comorbidity remain unclear, which is, in part, due to a widespread assumption that drug use causes violence. In an effort to better understand the liability to violent offending among IDU, this thesis aimed to answer three major unresolved issues: (i) Does drug use cause violence or do underlying factors predispose individuals to drug use and violence? (ii) Is there heterogeneity in the nature of, and risk profiles for, violent offending? (iii) Are risks for violent offending specific to IDU? Addressing these issues was possible through quantitative examination of two large epidemiological datasets: one of community-based IDU (N=300) and a large treatment-based case-control sample (N=1,927). Analyses were structured according to a developmental framework that has not previously been used in this area. This framework focuses on the impact of early life predisposing factors on long term adverse behavioural outcomes. Violent offending was found to be highly prevalent among IDU, with a significant minority (approximately one-third) having committed a serious, injurious violent act. Findings regarding the risks for the likelihood (Chapter Two), severity (Chapter Three), stability (Chapter Four) and specificity (Chapter Five) of violent offending were remarkably consistent across the Chapters. Childhood psychopathology, higher scores on aggressive and impulsive trait measures, and childhood maltreatment were found to be strongly, positively correlated with the initial liability to violent offending. Substance use, on the other hand, appeared to play a greater role in the maintenance of violent behaviour. The findings further indicated that heterogeneity in violent patterns was best explained by the extent of cumulative exposure to early-life and substance use risks, such that IDU with greater early-life risk exposure engaged in more stable, serious violent behaviour. The antisocial markers noted among violent IDU were absent in a matched Control group, supporting a hypothesis of risk specificity for violence. This thesis provides new information to a growing literature regarding the substance use-violent offending association, and has implications for the early identification and intervention in individuals at high risk for an adverse developmental course

Firelighting behaviour amongst children and adolescents poses a significant concern for the well-being of the young person and their wider communities. Often difficult to detect, young firelighters account for a fifth of the fires lit in Australia. The focus of this study was to explore the characteristics and profiles of young firelighters in an Australian sample and to determine the rate of recidivism and identify variables that may predict firelighting recidivism risk.

Sport related burnout has become a concern for many athletes, coaches, and sport psychologists. Although burnout in sport is receiving more attention, the research still remains relatively limited (Capel, 1986; Dale & Weinberg, 1990; Fender, 1989; Gould, Udry, Tuffey, & Loehr, 1996). Dale and Weinberg (1990) indicated a need for future research concerning the identification of characteristics that may predispose athletes to burnout. No past research was found that investigated the relationship between optimism/pessimism and sport burnout. The primary purpose of this investigation was to examine the relationships between optimism and pessimism with burnout. A secondary purpose was to determine whether optimism, pessimism, and burnout differ between gender, race, age, aspects of soccer involvement, and participation in other sports. The Life Orientation Test-Revised (Scheier, Carver, & Bridges, 1994) and Burnout Inventory for Athletes (VanYperen, 1997) were completed by 100 youth athletes (42 boys, 58 girls) participating in premier/select (n_= 100) and high school (n = 55) soccer leagues, with 55 soccer players participating in both leagues. A Sport Questionnaire was also administered to obtain demographics information including gender, age, race, specific soccer involvement, and other sport participation. Results revealed statistically significant negative correlations between optimism and burnout (r = -.271, a < .01) as well as between optimism and intent to quit (r = -.308, a < .01). A significant positive correlation was found between age and burnout (r = .315, a < .01). No significant correlation was discovered between pessimism and burnout. Results revealed that youth soccer players classified as optimistic exhibited less burnout and showed less intent to quit soccer within one year.