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Genetic inheritance is not the only way parents’ genes may affect children. It is also possible that parents’ genes are associated with investments into children’s development. We examined evidence for links between parental genetics and parental investments, from the prenatal period through to adulthood, using data from six population-based cohorts in the UK, US and New Zealand, together totalling 36,566 parents. Our findings revealed associations between parental genetics—summarized in a genome-wide polygenic score—and parental behaviour across development, from smoking in pregnancy, breastfeeding in infancy, parenting in childhood and adolescence, to leaving a wealth inheritance to adult children. Effect sizes tended to be small at any given time point, ranging from RR = 1.12 (95% confidence interval (95%CI) 1.09, 1.15) to RR = 0.76 (95%CI 0.72, 0.80) during the prenatal period and infancy; β = 0.07 (95%CI 0.04, 0.11) to β = 0.29 (95%CI 0.27, 0.32) in childhood and adolescence, and RR = 1.04 (95%CI 1.01, 1.06) to RR = 1.11 (95%CI 1.07, 1.15) in adulthood. There was evidence for accumulating effects across development, ranging from β = 0.15 (95%CI 0.11, 0.18) to β = 0.23 (95%CI 0.16, 0.29) depending on cohort. Our findings are consistent with the interpretation that parents pass on advantages to offspring not only via direct genetic transmission or purely environmental paths, but also via genetic associations with parental investment from conception to wealth inheritance.

Social interactions among animals can be complex, and abnormal social behaviours may result in negative fitness consequences for both the individual displaying them, and the entire group. To understand the neural basis of complex social behaviour, we can study simpler behaviours that precede and mediate them. Social spacing, the typical distance between individuals in a group, is an easily quantifiable behaviour in Drosophila melanogaster. Here, I investigated the neural circuitry underlying social spacing through the lens of Autism-candidate gene neuroligin 3. Based on the Nlg3 enrichment pattern in adult fly brains, I hypothesized that nlg3-expressing neurons, along with the mushroom bodies and protocerebral bridge, were involved in this behaviour. I determined that all the aforementioned structures are involved, and there is likely sexual dimorphism in this neural circuitry. This research contributes to understanding the role Nlg3 plays in social spacing and reveals more routes of neural connectivity to be investigated.

BACKGROUND: The philosophical debate about the roles of nature versus nurture in human flourishing is not new. But the rise of precision education—a growing field of research that encourages the use of genetic data to inform educational interventions to better meet student needs—has renewed historical and ethical concerns. A major worry is that “genetic hype” may skew public perceptions toward a deterministic perception of the child’s educational trajectory, regardless of the child’s capacities, and underestimation of environmental factors affecting educational outcomes. We tested this hypothesis with parents and adults from the general public in the US. METHODS: A newly developed computerized implicit association test (IAT) to assess automatic associations between genetics or environments and student behaviors that are associated with educational achievement was administered to samples of parents of children below 21 years old (n=450) and adults from the general public (n=419). The samples were representative of the adult US population and adjusted to oversample Black/African American participants. An overall D score for participants’ IATs (range: [−2, 2]) was calculated on the basis of the speed of participants’ responses. RESULTS: The mean IAT score for both samples indicated stronger association between the quality of being a good student and environment rather than genetics (parents: mean=−0.146, t=−6.56, p

Functional impairment is increasingly prevalent among middle-aged and older adults, with 2 in 5 adults over the age of 65 having some form of disability, the majority being limitations on mobility. Many older adults are able to maintain functional capacity well into later life, but the factors that contribute to high levels of function and the mechanisms by which they operate are unclear, although prior work has demonstrated the importance of social relationships for health. Guided by principles from the life course perspective and perspectives on social connectedness, this dissertation examined the role of social connectedness across the life course as a predictor of functional capacity in adulthood. I used existing longitudinal data from the national Midlife in the United States (MIDUS) study to pursue three central aims. First, Paper 1 compared theoretical and data-driven approaches to classifying life course relationships, including multiple dimensions of social connectedness at different time points across the life course. Results showed that the data-driven approach (i.e., latent profile analysis) was a stronger predictor of functional limitations than the theoretical approach and revealed relationship trajectories consistent with life course cumulative processes. Second, using the profiles obtained from Paper 1, Paper 2 probed the association between life-course social connectedness and functional limitations by examining the potential mediating role of candidate biological and behavioral mechanisms, and moderation by socioeconomic status (SES). Paper 2 findings suggested that observed differences in later-life functional limitations based on life-course social connectedness can be at least partially explained by physical activity, but do not vary by SES. Contrary to hypotheses, inflammation was not a significant mediator. Third, Paper 3 used monozygotic twin data and within-family analyses to sharpen the focus on potential causal associations between life-course social connectedness and adult functional status. Results suggested that the association is likely driven by genetic and/or shared environmental influences. Taken together, these results add to our understanding of social connectedness and health and address important gaps in the literature. These findings are used to generate theory- and intervention-relevant insights into the successful maintenance of health, independence, and function across the lifespan.

Indiana University-Purdue University Indianapolis (IUPUI), Tolerance is a diagnostic criterion for alcohol use disorder (AUD) and dependence and is often measured metabolically or behaviorally by comparing blood ethanol concentrations (BEC) or locomotor performance to an ethanol (EtOH) challenge before and after a drinking history, respectively. To explore another aspect of chronic behavioral tolerance in a family history positive (FH+) model of AUD, crossed High Alcohol Preferring (cHAP) mice were allowed to respond instrumentally for an EtOH reinforcer after either a five-week history of continuous home cage two-bottle choice (2BC) drinking or a concurrent five-week water-drinking period. Additionally, some of these animals were placed back into the operant box after home cage drinking histories to respond in extinction, allowing for the quantification of alcohol-motivated seeking alone in the absence of EtOH taking and its intoxicating effects. The results demonstrate that an alcohol history does not lead to a subsequent increase in active lever responding or inactive lever responding when compared to water-drinking controls. However, female cHAP mice with an EtOH-drinking history respond more on the inactive lever in extinction compared to water controls, suggesting that home cage EtOH history potentiates variation in responding in extinction. Overall, female mice responded more on the active lever and drank more alcohol in the reinforced condition, but again, there was not an effect of drinking history on this sex-specific effect. Together these results suggest that while female cHAPs, regardless of drinking history, are more motivated to work to drink EtOH, reinforced and non-reinforced instrumental responding are not reliable readouts for tolerance in cHAP mice compared to other endpoints such as drinking in the dark (DID) assays.

Summary The aim of this study is to investigate the role of gene-environment correlation (rGE) in the association between emotional symptoms and home chaos, parental feelings, discipline, monitoring and control and stressful life events using data from the Twins Early Development Study (TEDS). We will explore the role of rGE in emotional symptoms within age, at ages 4, 7, 9, 12, 16, and 21 using parent and twin reports. Firstly, phenotypic analyses will be conducted to assess the association between each environmental factor and emotional symptoms at each age. Secondly, to decompose the genetic and environmental influences, bivariate twin analyses will be conducted between emotional symptoms and each environmental factor. Background Emotional symptoms (e.g. low mood, tearfulness, fearfulness, and excessive worrying) in children and adolescents, have been identified as key vulnerability factors for developing emotional problems such as depression and anxiety (Birmaher et al., 1996; Goodman & Goodman, 2009), which in turn persist over time, conferring increased risk for later mental health problems (Gregory et al., 2007; Hannigan et al., 2017; Roza et al., 2003; Waszczuk et al., 2016). Depression and anxiety disorders are the two most common psychiatric conditions, with a global lifetime prevalence of 16-20% (Kessler et al., 2005, 2009). They onset in late childhood and adolescence (anxiety: 11 years old; Kessler 2005, depression: 18 years old; (Hankin et al., 1998; Kovacs & Devlin, 1998), making them two of the most prevalent disorders affecting youth (Merikangas et al., 2010). They are highly comorbid with other mental health illnesses and particularly with each other (Kessler et al., 2005). Evidence suggests that more than 75% of children diagnosed with depression, also express anxiety symptoms (Ghandour et al., 2019). Depression and anxiety disorders have complex and multifactorial aetiologies, with evidence from twin and genome-wide association studies suggesting that they are moderately heritable (Craske et al., 2017; Fernandez-Pujals et al., 2015; Howard et al., 2019; Polderman et al., 2015; Purves et al., 2020). Evidence suggests that depression and anxiety are genetically correlated in childhood and adolescence, potentially explaining their high comorbidity (Eley & Stevenson, 1999; Franić et al., 2010; Waszczuk et al., 2016; Waszczuk et al., 2014). Genetic factors are found to also explain the increased stability of the disorders (Hannigan et al., 2017; Nivard et al., 2015). Additionally, environmental factors such as the family environment and stressful life events are implicated in their development (Goodyer, 1990; Rapee et al., 2009) Family environment The family environment plays a key role in the development of children’s depression and anxiety, due to its relatively constant presence across development (Bronfenbrenner, 1986; Hannigan et al., 2017). Components of the family environment have been found to impact childrens’ depression and anxiety both concurrently and prospectively. For example, household chaos, defined as living in crowded, noisy and/or chaotic homes and lacking a routine, has been associated with symptoms of depression and anxiety in both children (Gregory et al., 2005; McAnally et al., 2019) and adolescents (Erickson & Newman, 2017; Evans et al., 2003). However, most of the evidence on the link between household chaos and depression and anxiety comes from studies in early childhood samples, and thus further research is required to further support this association in adolescence and early adulthood. Parenting style and the parent-child relationship have also been associated with the development and maintenance of depression and anxiety disorders in both childhood (Bögels & Brechman-Toussaint, 2006; McLeod et al., 2007; National Research Council (US) and Institute of Medicine (US) Committee on Depression et al., 2009; Rapee, 1997) and adolescence (Branje et al., 2010; Delay et al., 2013; National Research Council (US) and Institute of Medicine (US) Committee on Depression et al., 2009; Rapee et al., 2009). Parenting styles have been broadly grouped into two dimensions, namely, positive and negative parenting. Positive parenting includes behaviours such as increased responsiveness, acceptance and approval (Baumrind, 1991; McLeod et al., 2007) and is associated with increased autonomy and problem coping in children (Wolfradt et al., 2003). Negative parenting includes behaviours such as over controlling and critical parenting (Rapee, 1997) or demandingness (Oliver et al., 2014) and has been associated with poor emotion regulation and mental health outcomes and increased child dependence on the parent. Stressful life events Stressful life events have also been associated with the development of emotional problems and symptoms (Brown & Harris, 1978; Garber, 2010; Harland et al., 2002; National Research Council (US) and Institute of Medicine (US) Committee on Depression et al., 2009). Interestingly, most studies on young samples focus on depression (Goodyer, 2001) or on the association between traumatic life events (such as sexual abuse or neglect) and anxiety or depression (Cohen et al., 2001; Collishaw et al., 2007; Molnar et al., 2001). However, evidence from adult population (McLaughlin et al., 2010; Miloyan et al., 2018) and clinical (Francis et al., 2012; Taher et al., 2015) sample studies suggests that exposure to non-traumatic stressful life events is associated with the subsequent development of anxiety disorders and broader emotional problems (Kessler et al., 2010). At present there is limited evidence regarding the association between non-traumatic life events and the development of anxiety and broader emotional problems in young people. The evidence on the role of environmental factors as risk factors for emotional problems is strong. However, most cross sectional studies tend to assume a simple directionality of effects from the environment to children and adolescent behaviour and psychopathology, and do not consider the possibility of a bidirectional association which some studies have demonstrated (e.g. Hannigan et al., 2017; Hudson et al., 2009; Lewis et al., 2014). Additionally, the findings from cross sectional studies are limited by the presence of confounding variables such as genetic factors, which are known to influence environmental factors (Kendler & Baker, 2007) and may thus be underlying the bidirectional association. Gene-Environment correlation (rGE) One of the most interesting lessons learned from decades of twin studies is that these environmental factors do not occur independently of individuals’ behaviours, but instead, are shaped by individuals’ heritable characteristics (Bolinskey et al., 2004; Hanscombe et al., 2010; Jaffee & Price, 2007, 2007; Plomin, 1994; Plomin & Bergeman, 1991; Saudino et al., 1997; Silberg et al., 1999; Spotts et al., 2005). This is called gene-environment correlation (Plomin et al., 1977). Three rGE mechanisms have been identified, namely, passive, evocative and active (Plomin et al., 1977). Passive rGE refers to the correlation between the genotype inherited by a child and the environment provided by the parents, as influenced by their own heritable characteristics, and occurs independently of the child. Evocative rGE refers to the association between an individual’s behaviour that is genetically influenced and the response to this behaviour from others in the individual’s environment. Finally, active rGE refers to the association between the individual’s behaviour that is genetically influenced and the environmental situations into which the individual selects themself. Environmental factors are moderately heritable (Kendler & Baker, 2007). A meta analysis reported that genetic factors account for 18%-30% for family environment dimensions such as cohesion, conflict and organisation, for 35% of parenting behaviours (e.g. intrusiveness), and 28% of stressful life events (Kendler & Baker, 2007). Given the genetic influence on these aspects of the environment that are known to be associated with the development of depression, anxiety and emotional problems, which are also heritable, it is possible that underlying genetic factors influence their association. Several studies have conducted rGE analyses with depression and have explored the genetic covariation with home environment factors (e.g. Hannigan et al., 2017; Jaffee & Price, 2007; Lau & Eley, 2008; Neiderhiser et al., 1999; Pike et al., 1996; Wilkinson et al., 2013) and stressful life events (e.g. Lau & Eley, 2008; Rice et al., 2003; Silberg et al., 1999; Thapar et al., 1998). More analytically, a study (Wilkinson et al., 2013) exploring the genetic correlation between home chaos and parenting at age 9 and depression at age 12 reported that home chaos and parenting were genetically correlated with depression. These results suggest that the same genetic factors account for depression and home environment factors, which are also considered risk factors for developing depression. Moreover, another study (Lau & Eley, 2008) that investigated the rGE with depression and maternal discipline and dependent negative life events (i.e. events associated with an individual's behaviour e.g. break-up) in adolescents (mean age 15), found a significant genetic overlap between depression and both environmental factors. Furthermore, other studies exploring the genetic covariation between depression and family connectedness (e.g. parent-child relationship and parental warmth) (Jacobson & Rowe, 1999), parental hostility (Lewis et al., 2014), and parental negativity (Pike et al., 1996) in children in late childhood and adolescence have also supported these findings. Additionally, although the association is found to be weaker, there is evidence supporting the genetic covariation between total scores of negative life events (i.e. total number of the dependent and the independent stressful life events an individual has experienced) and depression in late childhood and adolescence (Rice et al., 2003; Silberg et al., 1999; Thapar et al., 1998). Surprisingly, very few studies have conducted rGE analyses with anxiety or with the broader category of emotional symptoms, which includes both anxiety and depression, suggesting this is a gap in the literature. One gene-environment correlation analysis with anxiety found that high levels of child anxiety were genetically correlated with over-controlling parenting (Eley et al., 2010), consistent with the presence of an evocative rGE. Based on these preliminary findings and evidence from research in depression, which has a similar genetic basis with anxiety (Eley & Stevenson, 1999), it is possible that the genetic factors contributing to the development of anxiety also influence the environmental factors associated with the development of anxiety. Furthermore, some studies that have explored the role of rGE in depression from a developmental perspective, suggest that the role of genetic and environmental factors changes during development and that genetic factors play a greater role as the child enters adolescence. For example, a study investigating developmental change in the association between the home environment (i.e. parental feelings and discipline and home chaos) and depression (Hannigan et al., 2017) found that the influence of genetic factors and non-shared environmental factors increased in the transition from childhood to adolescence, while the influence of shared environmental factors decreased. A study on the developmental change in the association between negative life events and depression suggested a similar pattern of change (Rice et al., 2003). These findings are consistent with the developmental perspective of rGE that was proposed by Scarr & McCartney (Scarr & McCartney, 1983), based on which the influence of the rGE mechanisms on behaviour and psychopathology changes over time. More analytically, they suggested that the influence of passive rGE is prominent in infancy and early childhood, when the child primarily attends to environmental stimuli that are shaped and provided by the parents, and declines as the child enters late childhood and adolescence. Adolescence is a period in which the child begins to explore other environments outside the family one, and constructs its own environments, and thus, active rGE has a greater influence on the child’s development. Evocative rGE exerts an influence throughout development, as children and adolescents evoke responses from people around them based on various characteristics that are influenced by their genotypes (e.g. personality). Taken together, these studies suggested that the increase in the role of genetic factors may explain the sharp increase in the onset of depression that comes with adolescence. It is again possible that similar developmental patterns of change influence the association between anxiety or broader emotional problems and environmental factors, however, at present, there are no studies that have investigated this. Additionally, there are no studies that have systematically explored the age-related change in the rGE, from early childhood to young adulthood. Most studies have been conducted on late-childhood and early adolescent samples, due to the critical role that the transition from childhood to adolescence plays in the development of psychopathology. However, it is equally important to understand the underlying mechanisms involved in the early years of development and the transition from adolescence to young adulthood and to identify the environmental factors that are most influential at each age. Evidence suggests that some anxiety disorders (e.g. separation anxiety and specific phobias) may start as early as 6-7 years old (Kessler et al., 2005), thus emphasising the need to understand the role of rGE in their development. Also, the transition to young adulthood is associated with important life changes, increased independence (Keller et al., 2007; Rimfeld et al., 2019) and the mean onset of depression (Hankin et al., 1998), stressing the importance of better understanding the role that genetic and environmental factors play in psychopathology. Gaps in the literature & the present study To date, studies on the role of rGE in depression and anxiety have emphasised the importance of disentangling the role of genetic and environmental effects in the development of psychopathology. However, as highlighted above, gaps exist in the literature. In summary, there is a need for more studies exploring the role of rGE in anxiety and broad emotional problems and a need for studies to adopt a developmental perspective and to systematically explore the age-related change in rGE in the association between depression, anxiety and broader emotional problems, and environmental factors. The present study aims to explore the role of rGE in emotional symptoms across development, in the Twins Early Development Study cohort, and specifically at ages 4, 7, 9, 12, 16, and 21. The TEDS cohort gives us the unique opportunity to cover these gaps in the literature and to improve our understanding of the rGE mechanisms involved in emotional symptoms across development. Exploring the role of rGE in the association between emotional symptoms, home chaos, parenting, and stressful life events, will allow us to disentangle the genetic and environmental effects influencing the emergence of depression and anxiety and broad emotional symptoms, and consequently, to better understand the aetiologies and maintenance mechanisms underlying them. Additionally, as the effects of specific environments may be more influential at certain time-points, the longitudinal design will allow us to identify the most influential factors at each age and consequently to inform prevention and treatment interventions.

Online questionnaire study to examine intra-couple correlations and similarity for a range of variables associated with Theory of Mind and Dark Triad personality traits.

Questionnaire and behavioural study to examine intra-couple similarity for a range of variables associated with autism spectrum conditions.

Behavioral disorders arise from environmental, lifestyle, and genetic factors. Past studies have shown evidence for the hereditability of several major behavioral neuropsychiatric disorders, such as schizophrenia, depression, and bipolar disorder. In these cases, certain genetic defects are passed down from parental generations and increase an offspring’s risk of inheriting a specific disorder. While neuropsychiatric disease susceptibility cannot be attributed solely to genetics, it is important to study how one’s genetic makeup can affect various facets of human behavior. Uncovering this link between genes and behavior could lead to the discovery of new biological factors involved in the development of highly prevalent neurological responses and disorders. A recent study in behavioral genetics has shown that there may be a genetic basis for irrational phobias. It highlights the possibility that phobias are a form of inherited defense mechanism passed down through familial genes. In this study, researchers Dias and Ressler from the Emory School of Medicine subjected mice to fear conditioning by exposing them to the scent of chemical acetophenone, which smells like cherry blossoms, before administering electric shocks to the mice. Offspring of these mice (which were not exposed to the same conditioning as their parents) showed fearful responses to the odor of acetophenone, even when smelling it for the first time. This demonstrated that they had acquired a phobia of the chemical odor. Structural abnormalities were also discovered in the olfactory bulbs of the offspring mice. Upon sequencing the mice’s sperm DNA, Dias found that the gene encoding M71, an odo receptor activated by acetophenone, was methylated in the conditioned parental and direct offspring generations. However, it is unknown whether this epigenetic alteration in sperm DNA was responsible for the offspring’s heightened odor sensitivity. It is possible that different biological mechanisms worked in conjunction to translate the inherited ancestral experiences to irrational phobias in the offspring. Other studies in behavioral genetics have shown that some neuropsychiatric disorders are less heritable—or have a weaker genetic component—than others. For example, while genes may account for more than half of the risk for certain neuropsychiatric disorders, such as schizophrenia or bipolar disorder, the hereditability of anxiety and depression appear to be lower. According to Dr. Pine at the Cold Spring Harbor Laboratory, approximately 30-50% of the risk for anxiety and depression is genetic, while the other 50% to 70% of the risk may be attributed to environmental factors, such as substance use, stress, diet, and childhood experiences. Anxiety disorders are the most common form of mental illness in the U.S., affecting 18% of the total population. Depression is also common, with around 10% of Americans experiencing a major depressive disorder at some point in their lives. Despite the high prevalence, genetic disposition for anxiety and depression is weak when compared to other neuropsychiatric disorders. As scientists, we must determine why this is the case. Is it due to a difference in the number of gene defects? For example, are there less genetic variations linked to anxiety and depression than to other more heritable diseases? Or are depression/anxiety genes less evolutionally conserved? Only by answering these questions can we get a firm understanding of the genetic root of these conditions and develop ways to prevent or fight the disorders. We must examine the gene defects themselves. Perhaps, in behavioral disorders with relatively low heritability, the gene variations only minimally disrupt the major pathways of the brain. In such cases, it would be wise to study non-genetic factors that trigger the behavioral response. In addition, a psychodynamic treatment approach – alleviating a patient’s mental tension with the help of a psychiatrist—may be more helpful than invasive medical procedures. On the other hand, personalized medicine, such as gene therapy, may be the best option for treating significantly inheritable disorders, like schizophrenia. Through advancements in gene testing, doctors are able to conduct pre-symptomatic diagnostic tests to see the risk for patients with a family history of inherited neurological disorders. Tests can detect abnormalities, which may include missing or heavily altered sections of a gene, or genes that are inactive or lost, in DNA or RNA samples of patients. In other cases, a test may detect excessive RNA from a single gene, indicating that it is overexpressed in the body. Identifying and fixing these problematic sequences in the genetic code requires extensive knowledge of the human genome. Physicians providing personalized medicine must take into account a patient’s genetic makeup to determine the best form of targeted treatment for an illness. Through genetic research, we are slowly beginning to unravel the biological basis for many neuropsychiatric disorders. Understanding the role of genes in highly prevalent neurological responses, like anxiety and phobias, is crucial for designing effective treatments tailored to patients who are suffering these conditions. Specifically, by identifying the genetic markers associated with inheritable neuropsychiatric diseases, we can analyze a patient’s risk of disease inheritance and responsiveness to existing medical treatment. This knowledge will make a powerful impact on the medical community and the future of medicine.

Children with psychopathology have an increased risk of continued psychopathology in adulthood compared to the general population. Therefore an understanding of the genetic underpinnings of such traits could be crucial in identifying children most at risk of adverse outcomes, as well as in developing intervention or prevention strategies that may prove useful to them. In this thesis, studies were performed with the aim of investigating genetic mechanisms underlying the persistence of psychiatric traits in children and adolescents, as well as understanding how they develop into adulthood. Chapter 1 of this thesis serves as an introduction to the topics covered, as well as providing an overview of the state of the field up to the point of this undertaking. In chapter 2 we performed a systematic review of studies that used statistical genetic methods to evaluate the contribution of common genetic variants to psychiatric disorders and traits. We showed that larger sample sizes facilitate the discovery of trait-associated genetic variants, as well as provide evidence of heritability based on measured genetic variants, known as SNP-based heritability. Importantly, we observed abundant cross-trait associations across psychopathology traits, suggesting a role for pleiotropic genetic effects in the aetiology of psychopathology across development. In chapter 3 we investigated genetic associations between repeated measures of childhood psychopathology, and polygenic scores (PGS) of adult traits including major depression, bipolar disorder, subjective wellbeing, neuroticism, insomnia, educational attainment, and BMI. We showed a consistent pattern of mostly stable genetic associations between adult trait PGS and childhood psychopathology across age, indicating the existence of a set of genetic factors that influence psychopathology and related traits across the lifespan. Additionally, we showed differential associations between educational attainment and BMI PGS, and types of childhood psychopathology, providing evidence for pleiotropy not just within psychopathology, but across related health and socioeconomic indicators. In chapter 4 we used structural equation modelling to investigate the extent to which the genetic associations observed between childhood psychopathology and adult traits are explained by correlations between the adult trait PGS, as well as correlations between the childhood measures. Again, we observed differential associations between educational attainment and BMI PGS, and childhood psychopathology, i.e. educational attainment PGS was associated with ADHD symptoms, while BMI PGS was associated with ADHD symptoms and social problems. Only major depression PGS remained associated with all three childhood psychopathology measures, suggesting that while shared genetic factors have a role in our understanding of psychopathology, unique genetic factors are likely also important. In chapter 5 we combined genetic, environmental and psychosocial (risk) factors to produce a model for the prediction of adolescent intentional self-harm, aggression, or a combination of both. Our results suggested that aggressive symptoms in mid-adolescence as well as PGS of psychiatric disorders were important predictors of aggression and/or self-harm. We also showed that a combination of different types of predictors, including both genetic, environmental and psychosocial factors, provided the best model for predicting our outcome. Finally, in chapter 6 we investigated the extent to which common variant and rare variant gene-set enrichment analyses converge to similar results for schizophrenia. Results implicated genes likely to be under stringent selection, and suggests partial convergence across common and (ultra-)rare variants, indicating that the same biological mechanisms are implicated across the allele frequency spectrum. Chapter 7 summarises the main findings of the thesis, as well as discussing their implications and future perspectives with regards to field at large. I conclude that a move from genetic variation to disease mechanisms and biological pathways is crucial to further our understanding. The integration of information across the allele frequency spectrum also likely offers the best avenue for significant progress.