Mind-reading receptors: The role of the vasopressin receptor 1a gene (AVPR1A) in human empathy, social interaction and health Alyssa Rhiannon Morse June 2019 A thesis submitted for the degree of Doctor of Philosophy of The Australian National University. © Copyright by Alyssa Rhiannon Morse 2019 2 ! This page left intentionally blank. ! Student Statement This statement certifies that the following work entitled Mind-reading receptors: The role of the vasapressin receptor Ia gene (AVPRllt in human empathy, social interaction and health is the autlror's own original work, except where otherwise specified, complies with The AustralianNational University Award Rules and has not previously been accepted for awmd of a degree or diploma to any other university or institution of higher learning. This thesis was supported by an Australian Government Research Training Program (AGRTP) Scholarship. According to the Procedure: Higher degree research - submission and examination of theses, the word count of this thesis without appendices is 43733. Date'll Student signature: lo,, lbn 4 ! Acknowledgements The literature I’ve read over the years of this project has taught me about the importance of social support for health and wellbeing. My experience working on this project has certainly taught me the personal value of social support and of my social networks – it takes a village to raise a PhD Scholar! To my supervisory panel, thank you for your guidance and advice over the course of my candidature, I am grateful for all I have learned. To my Primary Supervisor, Simon Easteal, it has been a long journey to get here since my candidature commenced in 2012. Thank you for staying the course with me, through all its twists and turns. To Richard Burns, thank you for joining my panel in the later years of my candidature. Your support and the knowledge you imparted have been invaluable. I am grateful for the friendly working environment created by the staff and students at the John Curtin School of Medical Research who have shared parts of this journey with me. Particular thanks to Susan Tan, for always being happy to talk through a challenge, exchange knowledge, or just stop for a chat. To my wonderful colleagues at the Centre for Mental Health Research, since I joined the team in 2016 you have been a constant source of encouragement and inspiration. Working at CMHR has shown me how much I have learned through my PhD candidature and supported me to continue to grow my skills and confidence. A special thank you to Michelle Banfield, for that first opportunity you gave to me and all your support since then. To my friends, thank you for reminding me to engage in social interaction, not just study it. To my dear friend Liz Huxley, I will always be grateful for the support, understanding and much needed coffee breaks and crafternoons. Music has been another important part of this journey; this thesis was written to an instrumental soundtrack ranging from JS Bach to Dexter Gordon to Darren Korb. To my singing teacher, Dennis Brain, thank ! 5 ! you for encouraging me to continue pursuing my passion for music, it has been such an important creative outlet for me. Last, but certainly not least, I am so very grateful to my amazing family. Mum and Dad, I would not have made it here without your constant support, thank you for your patience and for creating the nurturing space I needed to complete this project. To my brothers, Callum and Elliott, thank you for taking my mind off work when things were tough and for always knowing how to make me smile. To the newest (and furriest) members of our family, Lily and Jasper, thank you for the schnauzer hugs, listening ears and reminders to get outside and take a walk. And to Nana and Papa Wilson, thank you for your love and prayers. Papa, although you couldn’t be here to see the end of this journey, I have kept you with me. Your fountain pen has helped me draft many of my chapters. Thank you to the village of people who have supported me throughout this process. I can’t wait to see what comes next. ! 6 ! Abstract Social support is beneficial for human mental and physical health, whereas experiencing social strain can be detrimental. The impact of social interaction varies between individuals and this variation may partly be driven by biological factors. Evidence suggests that variation in the 5’ promoter region of the vasopressin 1a receptor gene (AVPR1A) influences individual differences in human social behaviours, social cognition, and how a person responds to their social environment. The research described in this thesis aimed to determine whether variation in the short tandem repeat polymorphism AVPR1A RS3 was directly associated with individual differences in mental and physical health, and whether AVPR1A RS3 genotype moderated the impact of social support and social strain on health. The project also aimed to explore the relationship between AVPR1A RS3 variation and empathy, a trait that could provide a link between AVPR1A and health outcomes. Relationships between genetic variation and social and health phenotypes were explored. Two series of nested multi-level linear models found a significant association between AVPR1A RS3 genotype and women’s self-reported physical and mental health. Results indicate that women carrying one or two copies of the Short RS3 allele report better mental and physical health than women homozygous for the Long RS3 allele. There was some evidence of an interaction between genotype and social support and strain variables, but the overall pattern of interaction effects was unclear. No direct relationship between AVPR1A and health was found for men. Due to the limitations of the data set used, a population-based analysis and a twin-modelling analysis could not draw strong conclusions about the relationship between AVPR1A RS3 genotype and individual differences in empathy. However, within the context of existing literature, the results of this project support the hypothesis that genetic variation at the RS3 locus is associated with individual differences in tendency to empathise and cognitive empathy skill. ! 7 ! In this project, empathy was measured using three short-form versions of two common empathy measures, the Empathy Quotient and the Reading the Eyes in the Mind Test. The psychometric properties of these measures were explored to determine if they were appropriate for use in future research. A short-form of the Empathy Quotient, the EQ-17, was judged to be appropriate for future use. Two short-forms of the Reading the Mind in the Eyes test, the RMET-17 and RMET-14, were found to have similar psychometric properties to the full-length test, however, results indicated that they were inappropriate for future research use. The results of this project align with previous research linking AVPR1A RS3 variation with social traits and add new evidence indicating that this genetic variant is also associated with individual differences in women’s mental and physical health. The relationship between AVPR1A RS3 genotype and both mental and physical health emphasises the importance of continuing to improve our understanding of the vasopressin system in human social behaviour. ! 8 ! Table of Contents Student Statement .................................................................................................................... 3! Acknowledgements .................................................................................................................. 4! Abstract ..................................................................................................................................... 6! Table of Contents ..................................................................................................................... 8! Figures and Tables ................................................................................................................. 13! Chapter 1: Introduction ........................................................................................................ 16! Chapter 2: Literature Review and Aims ............................................................................. 21! Chapter Summary ................................................................................................................. 22! Social Support and Wellbeing .............................................................................................. 24! Social Neuropeptides: Oxytocin and Vasopressin ............................................................... 26! Candidate Gene Analysis ..................................................................................................... 29! Biological Function of AVPR1A Variation .......................................................................... 31! Evidence from Animal Studies ..................................................................................... 31! Evidence from Human Studies ..................................................................................... 35! Social Role of Vasopressin: Evidence from Exogenous Vasopressin Administration Studies .............................................................................................................................................. 37! Facial Emotional Expression Recognition ................................................................... 37! Cooperative Social Interaction ..................................................................................... 38! Response to Social Stressors .......................................................................................