Socioeconomic disparities in health across the life-course are well-documented, long-standing, and consequential. Research suggests that a significant proportion of the social gradient in health is due to SES differences in health-risk behaviors. Scholarship investigating the underlying mechanisms whereby lower SES increases health-risk behavior points to the mediating role of risk-increasing (or ‘riskogenic’) psychosocial schemas. Specifically, evidence suggests that social context and experiences in development, which are patterned by one’s social position, calibrate psychosocial orientations, including impulsivity or self-control, sensation seeking, and hostile views of relationships, which influence health-risk behaviors and health outcomes. Although the past decade has seen a spate of published GE-health research, few studies have focused on the role of G-E interplay in shaping psychosocial schemas as mechanisms through which SES adversity shapes health disparities. This project will investigate the effects of SES adversity on changes in psychosocial schemas, conceived as socially-calibrated and genetically-influenced endophenotypes which link SES adversity to increased health risk-behaviors. Additionally, although we know that social experiences “get under the skin” to have enduring effects on health outcomes, we lack knowledge on the biological pathways through which such effects persist. Thus, second, and more innovatively, we will engage with the nascent field of social epigenetics to examine DNA methylation (DNAm) as a biological mechanism through which SES-adversity calibrates psychosocial schemas. In this project, we will investigate the DNAm patterns underlying psychosocial adaptations to SES adversity that increase health-risk behaviors, building on work that identifies DNAm as an important molecular underpinning of experience-dependent changes in cognitions, decision-making, and behavior.

There has been increasing research attention to the impact of in utero exposures to specific perinatal risk factors and their potential impact on diseases later in life. One of these is hypertensive disorders of pregnancy (HDP), a perinatal condition which affects up to 10% of pregnancies globally. Current evidence shows that HDP are associated with an increased risk of offspring cardiovascular, immune, metabolic disorders in later life. HDP are also responsible for various adverse perinatal outcomes such as preterm birth, low birth weight and intrauterine growth restriction, which are known risk factors for numerous mental health morbidities. In addition, HDP may also affect brain development via utero-placental vascular insufficiency and fetal malnutrition and lead to subsequent neurobehavioral difficulties. A lot of research has been conducted on the associations between HDP and cognitive functioning in offspring, however, evidence on the effect of intrauterine exposure to HDP on offspring mental and behavioural disorders is not well-established.
Two systematic reviews conducted by this team, one currently under review and the other one accepted by the British Journal of Psychiatry have shown that HDP had a negative impact for a range mental or behavioural disorders. Our finding showed that preeclampsia was associated with increased risk of offspring schizophrenia. The risk of Autism spectrum disorder was also 32% higher in offspring who had intrauterine exposure to preeclampsia as compared to those non-exposed. However, we found inconclusive finding on the effect of HDP and other mental and behavioural disorders, suggesting the need of further studies to progress this area of research. Following on from these findings, this PhD project aims to add to the existing evidence in a meaningful way by conducting a high quality, large sample, birth cohort study.

The proposal is to continue the collaborative work we have been doing with this Swiss group over the past few years. Ben Spycher was a Marie Curie Fellow who worked with ALSPAC data previously. Prof Kuehni leads eth Leicester Asthma Cohorts and has established the Swiss Paediatric Airway Cohort (SPAC). OUr joint objective is to discover influences that determine the onset and progression of asthma in children, how asthma varies between individuals in type and severity and whether we can predict the outcome of asthma using individuals' information. The data in eth Leicester adn Swiss cohorts is complementary to data held in ALSPAC and we have had joint publications where ALSPAC is able to replicate findings in the other cohorts run by the Swiss group.

Intimate Partner Violence (IPV) is defined as any violent behavior within an intimate relationship or any other controlling behavior that is conducted by a current or former partner. It is the most common form of violence in women which constitutes a major public health problem worldwide. The current explanatory theories of IPV perpetration can be summarized as feminist/sociocultural, social learning theory-based intergenerational transmission and psychological/psychosocial. According to the feminist/sociocultural theory, domestic violence is a consequence of “patriarchy”. From this view, violence is used as a form of power and control of women by men. The intergenerational transmission theory asserts that domestic violence is based on the exposure to, or observation of, violence in the family of origin. Psychological theories propose that there are psychological, psychiatric, behavioural and neurological risk factors for domestic violence perpetration. In the study of IPV perpetration, it is important to consider the variables addressed by such theories as a whole and from a developmental perspective and there is no study that simultaneously considers all the variables of these explanatory theories. The general aim of our study is to identify those etiological mechanisms linking risk factors for IPV perpetration across development. This study will be the first one that sheds light on which the origins of IPV perpetration are by knowing how IPV perpetration develops. Implications in terms of prevention and treatment will be of a great relevance for public health.

Growing evidence points to a role of epigenetic alterations in the development of psychiatric disorders. DNA methylation – an epigenetic mechanism sensitive to both genetic and environmental influences – has been linked to a wide range of emotional and behavioral problems in childhood, including anxiety, depression, conduct problems and attention-deficit hyperactivity. However, findings to date have been primarily drawn from candidate gene studies, or EWAS studies investigating single sites across the genome. As a result, how much of the variance in psychiatric phenotypes is collectively explained by the methylome as a whole is currently unknown.

Genome-wide association studies (GWAS) have been critical in identifying thousands of genetic variants associated with complex traits and diseases. For certain complex traits however, it may be the case that there is difficulty in phenotypic measurement and this can lead to issues of statistical power. This is particularly problematic for behavioural phenotypes that may be predominantly determined by the environment, as is the case for educational attainment and well-being (Okbay et al., 2016; Okbay et al., 2016; Rietveld et al., 2013). Genetic analyses of such phenotypes can be hindered by the fact that individual SNPs have limited explanatory power and any associations found may not be causal or may be mediated by many other intermediate phenotypes (Krapohl et al., 2014). However, such studies have enabled the description of common genetic contributions to complex behaviours. Taken together, these GWAS results form a pool of genetic variants which may then be used in Mendelian randomization (MR) analyses; both looking at the effect of these features on outcomes but also the effect of outcomes on them.

This project will use newly collected data in the Avon Longitudinal Study of Parents and Children cohort to analyse voting behaviour. Firstly, we aim to conduct a GWAS on voting behaviour to discover any genetic variants associated with this complex trait. Additionally, we plan on considering the potential of using MR analysis to look at this behavioural phenotype. Specifically, we aim look at the effect of well instrumented risk factors on voting behaviour itself, i.e. ‘backwards MR’.

References
Krapohl, E. et al. The high heritability of educational achievement reflects many genetically influenced traits, not just intelligence. Proc. Natl Acad. Sci. USA 111, 15273–15278 (2014).

Okbay, A. et al. Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses (vol 48, pg 624, 2016). Nature Genetics 48, 1591-1591 (2016).

Okbay, A. et al. Genome-wide association study identifies 74 loci associated with educational attainment. Nature 533, 539-+ (2016).

Rietveld, C.A. et al. GWAS of 126,559 Individuals Identifies Genetic Variants Associated with Educational Attainment. Science 340, 1467-1471 (2013).

Individuals exposed prenatally to cigarette smoke tend to have lower birthweight and have higher risks for a variety of detrimental health outcomes later in life. Cigarette smoke exposure is also associated with DNA methylation changes at gene GFI1, and recent evidence suggests that these changes may play a role in the lower birthweight of exposed infants. We would like to determine if there is evidence that these DNA methylation changes may also play a role in risk factors for other health outcomes of prenatal cigarette smoke exposure. We would specifically like to investigate factors related to cardiovascular and metabolic health.

Women who experience a hypertensive disorder of pregnancy are at greater risk for diseases of the heart and blood vessels. Breastfeeding may reduce this risk in women in general and particularly in those who have had a hypertensive disorder of pregnancy. This proposed study will examine if the duration/amount of breastfeeding has a beneficial effect on markers of heart health in later life in women who did and did not develop a hypertensive disorder of pregnancy.

Using two British cohort studies, the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Millennium Cohort Study (MCS), this fellowship will explore the longitudinal patterns and predictors of multiple cancer-risk behaviours (MCRB). MCRB are modifiable behaviours including tobacco smoking, alcohol consumption, physical inactivity, overweight and obesity, unhealthy diet and risky sexual behaviour that are associated with cancer incidence and mortality. Rather than focusing on specific cancers this research will cover a wide range of cancers that are associated with these behaviours.