Genetic and experimental perspectives on anxiety development and treatment response

Abstract

Anxiety disorders are common and debilitating psychiatric conditions characterised by disproportionate and persistent experiences of heightened autonomic arousal and negative affect. Onset is typically in childhood and only 50% of those affected respond to treatment. Despite this, they remain under-researched relative to other psychiatric disorders. As a result, little is currently known about the aetiological factors that influence anxiety development, or differential treatment response. Understanding such mechanisms could help to identify individuals most at risk of an anxiety disorder and personalise treatment approaches. Identifying differences in genetic variation that are associated with variation in anxiety is a promising route to understanding its’ aetiology. This thesis presents two approaches to examining genetic influences on anxiety relevant processes. The first is a genome-wide association study of current high anxiety symptoms and lifetime disorder assessed in the UK Biobank, a large community-based sample. Chapter 2 describes this study, finding a substantial role for common genetic variation in anxiety; 26% of the variance in lifetime anxiety disorder and 31% of the variance in high current anxiety symptoms is due to measured common genetic variants. Five novel genetic loci were associated with lifetime anxiety, including a locus within the BDNF receptor gene, NTRK2 . The second approach involves experimentally modelling anxiety development and treatment response using fear conditioning. This experimental paradigm is a well-established model but is difficult to carry out in the large samples required for well-powered genetic investigations. Chapter 3 describes a series of feasibility work and studies that together resulted in the development and validation of a smartphone app for the remote delivery of a fear conditioning experiment (the FLARe app). In Chapter 4, over 2,000 members of the Twins Early Development Study (TEDS) underwent a fear conditioning task administered using the FLARe app. Both fear acquisition and extinction, models for anxiety development and treatment respectively, were found to be significantly influenced by genetic variation and the non-shared environment. Furthermore, fear acquisition and extinction share some, but not all, of the same underlying genetic influences. The implications of these findings and the novel app-based approach are addressed in the general discussion.

Date of Award	1 Dec 2019
Original language	English
Awarding Institution	King's College London
Supervisor	Thalia Eley (Supervisor) & Gerome Breen (Supervisor)