Investigation into the consequences of study participation and measurement in psychiatric genetics research

Abstract

The role that genetics plays in influencing human traits and behaviours has been widely studied, and new techniques have been developed in recent years to investigate these factors at a molecular level. Some of these approaches involve studying the ‘heritability’ of a trait – which refers to the proportion of variation across a population that is attributable to genetic variation – while some others, such as genome wide association studies (GWAS), aim to identify specific genetic variants that are associated with variation in these traits. However, this research also requires various considerations: in how to sample participants for studies, in measuring complex traits and genetic variants, and in analysing and interpreting the relationships between them. In psychiatric genetics research, these considerations may be particularly important because psychological constructs are difficult to measure. This thesis examines these factors and how they can influence the results of research in psychiatric genetics. In the introductory chapter, I review the methods to measure complex psychiatric traits and genetic variants, with a focus on rare genetic variation, and review methods used to sample participants for studies. In the following chapters, I investigate these further – first, in a jointly-written review article that examines each of these challenges, explores how they may result in consistent or inconsistent results between different studies, and describes how they may be addressed to uncover whether there are underlying similarities or differences in the effects of genetic variation between studies. Following this, I investigate several challenges in greater detail in jointly-written research articles using data from mental health questionnaires. I focus on the measurement of latent psychiatric traits and of common and rare genetic variation and look at their potential impacts on parameters such as heritability estimates. I then focus on participation bias and item missingness in a depression questionnaire in a cohort study, explore the relationship between them, and how they may influence the performance of depression polygenic scores in predicting lifetime depression in the dataset. In the final discussion chapter, I bring together these threads and discuss the importance of careful study design and interpretation in psychiatric genetic research, and finally discuss the remaining gaps in the literature and future research that is needed in this area.