Search

My thesis considers the theme of comorbidity between cardiometabolic disorders and schizophrenia by focussing on three key aspects: the nature of association between cardiometabolic disorders and schizophrenia; the potential for common underlying biological mechanisms for the comorbidity; and the prediction of cardiometabolic risk in young adults with psychosis. On the nature of association between cardiometabolic disorders and schizophrenia, using longitudinal repeat measure data from a large birth cohort, I found that disruption to glucose-insulin homeostasis through childhood/adolescence is associated with increased risk of psychosis in early-adulthood; may not be fully explained by common sociodemographic and lifestyle factors; and may be specific to it. On the mechanisms of association between cardiometabolic disorders and schizophrenia, I used a range of genetic and observational epidemiological methods to examine whether inflammation and shared genetic liability may be common underlying biological mechanisms for the comorbidity. Using birth cohort data, I show that genetic risk for type 2 diabetes is associated with psychosis-risk in adulthood, and vice versa. I also show that genetic risk for type 2 diabetes may influence psychosis risk by increasing systemic inflammation. Using summary data from large genome-wide association studies (GWAS), I show a thread of evidence for shared genetic overlap between schizophrenia, cardiometabolic and inflammatory traits. Finally, using Mendelian randomization, I show evidence supporting that inflammation may be a common cause for insulin resistance and schizophrenia. On the prediction of cardiometabolic risk in young adults with psychosis, I performed a systematic review of cardiometabolic risk prediction algorithms and explored their predictive performance in a sample of young people at risk of developing psychosis. In doing so, I show that none are likely to be suitable for this population. Then, using patient data, I developed and externally validated the Psychosis Metabolic Risk Calculator (PsyMetRiC), the first cardiometabolic risk prediction algorithm specifically tailored for young people with psychosis. Together, my work suggests that cardiometabolic disorders and schizophrenia share aetiologic mechanisms, namely inflammation and shared genetic liability. I have shown that it is possible to accurately predict cardiometabolic risk in young people with psychosis using a tool tailored for the population. Such tools can in future become valuable resources for clinicians to reduce the risk of long-term cardiometabolic morbidity and mortality in people with schizophrenia.

Experimental animal models and observational studies suggest that maternal obesity in pregnancy influences the development of obesity in early infancy. As the trajectory of later adiposity is thought to be determined in early life; an understanding of potential contributing factors and associative mechanisms are essential to inform targeted interventions. The analyses reported in this thesis have sought to address these associations in mothers and their offspring from the UK Pregnancies Better Eating and Physical Activity Trial (UPBEAT), a randomised controlled trial of a behavioural intervention (diet and physical activity) in obese pregnant women. As the trial, did not show a reduction in the primary outcomes; incidence of gestational diabetes and delivery of a large for gestational age neonate, the dataset was treated as a cohort. Modifiable maternal risk factors including early pregnancy measures of maternal adiposity, were linearly associated with neonatal adiposity. An independent association with maternal birthweight and neonatal adiposity was also identified. Mode of early infant feeding (breast, formula and mixed feeding) and measures of general appetite influenced measures of infant growth and body composition at 6 months in offspring born to obese women from the UPBEAT cohort; providing evidence of a potential target for intervention within a sensitive window of opportunity. To address mechanistic pathways underpinning the associations between in-utero exposures and offspring adiposity, assessment of the cord blood metabolic profile was undertaken including measurement of candidate biomarkers and metabolome. A novel relationship between cord lysophosphatidylcholine with neonatal and infant anthropometry was identified, which was associated with maternal fasting glucose in late second trimester. Maternal fasting glucose in late second trimester was also found to partially mediate the effect of maternal parity and early pregnancy adiposity with neonatal adiposity. The UPBEAT intervention was associated with a reduction in a measure of offspring central adiposity, which was mediated through changes in antenatal diet and gestational weight gain instigated by the intervention. This provides evidence, within a randomised control trial setting that a behavioural intervention may potentially reduce offspring adiposity.

Epidemiological evidence suggests poor fetal growth is associated with poor later respiratory health, including the important childhood disorders asthma and wheeze. Factors creating a suboptimal early environment may persistently alter the structure and function of the immune and respiratory systems. This thesis explored the early life origins of paediatric asthma and wheeze in a large, prospective mother-child cohort. In particular, the contributions of maternal nutrition, and fetal and postnatal growth were assessed. The mothers of healthy, term infants had their body composition, lifestyle and diet characterised before and during pregnancy. Serum anti-oxidants, vitamin D and polyunsaturated fatty acids were measured in late pregnancy. Fetal growth was recorded by longitudinal ultrasound scans. 1548 children were followed to age 3 years and 469 were seen at 6 years. Wheeze was assessed by questionnaire and skin prick testing and detailed lung function measures were performed. Late pregnancy fetal growth faltering was associated with an increased risk of atopy and atopic wheeze at age 3 years, and greater weight and adiposity gain in the first year of life were associated with increased risk of wheeze. In those children seen at 6 years, greater maternal adiposity, before and during pregnancy, was associated with increased risk of non-atopic wheeze. Lower maternal pre-pregnancy vitamin D intake was associated with increased risk of childhood asthma, recent wheeze, and non-atopic wheeze. Lower maternal serum 25(OH) vitamin D in late pregnancy was also associated with childhood asthma and wheeze. Higher late pregnancy energy-adjusted vitamin A intake was associated with higher forced expiratory volumes but also greater bronchial hyperresponsiveness. Higher arachidonic acid status during pregnancy was associated with markers of atopy and greater risk of atopic wheeze. These results suggest early life factors contribute to paediatric asthma and wheeze. Optimising the early environment may reduce the burden of childhood wheeze