Leveraging family data for complex trait genomics

Abstract

Fundamental questions about the roles of genes, environments, and their interplay in the development of complex behaviours have traditionally been the domain of twin and family study designs. More recently, the rapidly growing availability of large genomic datasets, comprised of unrelated individuals, has generated exciting novel insights. However, there are major stumbling blocks. It has been difficult to capture the full heritability of complex traits, as estimated from family data, with measured DNA. Moreover, the genetic influence identified using DNA may be confounded with environmental effects. A deeper integration of genomic research with family-based quantitative genetics helps to address these issues and push knowledge further. This thesis includes four empirical chapters. Each increases the accuracy of findings in complex trait genomics by using cutting-edge methods in combination with insights and data from twin and family studies. The first chapter demonstrates the utility of longitudinal twin data for defining a measure of emotional problems. This measure is more heritable and powerful for genomic research than individual time-specific assessments. The second chapter presents evidence that genomic data from families in the UK Biobank can be leveraged to capture additional genetic effects on neuroticism and educational attainment. The third chapter uses an adoption design to measure how polygenic scores for educational attainment pick up environmental effects provided by relatives. The fourth chapter uses genomic data on parent-offspring trios to show that environmental effects of parents on childhood emotional symptoms can be indexed using the parental genome. Limitations of these approaches, potential directions for future research, and overarching conclusions are presented in the final chapter. Overall, this thesis demonstrates that family-based quantitative genetic research is not only the foundation and justification for complex trait genomics. It is of enduring importance, especially when integrated with new genomic tools. Family-based genetic research charts the direction for complex trait genomics.

Date of Award	1 Jun 2020
Original language	English
Awarding Institution	King's College London
Supervisor	Thalia Eley (Supervisor) & Robert Plomin (Supervisor)