Frach, Leonard Valentin; (2024) Intergenerational Transmission of Risk for Externalising Behaviours: Causal Inference and Genetically Informed Approaches. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Background: Within the broader externalising spectrum, early forms of conduct problems, inattention and hyperactivity are predictive of a range of later poor health and social outcomes, highlighting the societal costs of externalising, in addition to the impact of these problems on individuals and their families. Therefore, understanding the aetiology of early externalising problems is crucial for providing effective prevention and treatment options. Externalising problems run in families and are also influenced by genetics. Thus, research on early (parental) risk factors for externalising need to account for genetic effects to elucidate potential modifiable factors. In my PhD thesis, I examined the intergenerational transmission of risk for externalising behaviours in childhood and adolescence, namely conduct problems and attention deficit hyperactivity disorder (ADHD). Methods: To study the intergenerational transmission of externalising problems, I implemented and developed a number of genetically informed methods. In particular, I focused on genotyped mother-father-child trios to distinguish environmental from genetic routes of transmission. I also developed extensions of a statistical method for genetic sensitivity analyses. Objectives: I examined i) individual and parental predisposing factors for ADHD while controlling for genetic confounding, i.e., shared genetic effects on the (parental) predisposing factors and child ADHD. I further investigated ii) individual and familial genetic effects on ADHD and conduct problems, i.e., effects of children’s own genetics (measured by polygenic scores) and effects of parental genetics, independent of the child’s genetics. Finally, I tested iii) mediation of these genetic effects via epigenetic modifications, i.e., DNA methylation (DNAm). Results: Results revealed that i) associations between individual and parental factors and ADHD reflected substantial genetic confounding. However, residual associations between ADHD and individual characteristics of the child (lower birth weight and difficult temperament) remained significant. There was little evidence for residual associations between parental factors (maternal body mass index, smoking in pregnancy, education) and ADHD. ii) I found significant individual genetic effects for conduct problems and ADHD using several polygenic scores. Parental polygenic scores were associated with child outcomes via genetic transmission rather than reflecting familial genetic effects via the environment. iii) Lastly, I did not find robust associations between polygenic scores and DNAm, or between DNAm and ADHD, and no evidence that genetic effects on ADHD were mediated via DNAm. Discussion: My research underlines the role of genetic transmission in explaining large parts of the intergenerational transmission of externalising. The proposed methodological approaches will help researchers working with polygenic scores in developmental psychopathology and related fields. Conclusion: My results support previous findings of the role of genetics in intergenerational associations. I provided new insights into the nature of these genetic effects (that is, child versus parental genetic effects) and examined a novel mediation approach via DNAm. Lastly, my findings do not diminish the importance of parenting. Parental effects beyond genetics are not ruled out and my findings should be triangulated with other genetically informed and causal inference approaches.

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