Whole genome analysis of genetic susceptibility factors in psychotic disorders Lavinia Athanasiu Department of Medical Genetics Division of Mental Health and Addiction Oslo University Hospital Faculty of Medicine University of Oslo A thesis for the PhD degree, Oslo, 2011 © Lavinia Athanasiu, 2012 Series of dissertations submitted to the Faculty of Medicine, University of Oslo No. 1255 ISBN 978-82-8264-265-1 All rights reserved. No part of this publication may be reproduced or transmitted, in any form or by any means, without permission. Cover: Inger Sandved Anfinsen. Printed in Norway: AIT Oslo AS. Produced in co-operation with Unipub. The thesis is produced by Unipub merely in connection with the thesis defence. Kindly direct all inquiries regarding the thesis to the copyright holder or the unit which grants the doctorate. TABLE OF CONTENTS 1. PREFACE .................................................................................................................... 5 1.1 ACKNOWLEDGEMENTS ......................................................................................................... 5 1.2 ABBREVIATIONS .................................................................................................................. 6 1.3 GENETIC TERMS .................................................................................................................. 9 1.4 LIST OF PAPERS ................................................................................................................. 11 2. ABSTRACT ................................................................................................................ 13 3. GENERAL INTRODUCTION ......................................................................................... 14 3.1 SCHIZOPHRENIA ................................................................................................................ 14 3.1.1 Phenotype .............................................................................................................. 14 3.1.2 Aetiology and epidemiology .................................................................................. 14 3.1.3 Treatment .............................................................................................................. 15 3.1.4 Mortality ................................................................................................................ 16 3.1.5 Other psychotic disorders ...................................................................................... 17 3.2 HUMAN GENETICS AND INHERITANCE .................................................................................... 17 3.2.1 Genetic variation ................................................................................................... 18 3.2.2 Linkage disequilibrium ........................................................................................... 18 3.3 ASSOCIATION STUDY DESIGN ................................................................................................ 19 3.3.1 Candidate gene studies ......................................................................................... 21 3.3.2 Genome wide studies ............................................................................................. 21 3.3.3 Copy number variation studies .............................................................................. 23 3.4 THE SEARCH FOR SCHIZOPHRENIA GENES ................................................................................ 23 3.4.1 Heritability of schizophrenia .................................................................................. 23 3.4.2 Observations from linkage studies ........................................................................ 24 3.4.3 Candidate gene studies ......................................................................................... 25 3.4.4 Genome wide association studies ......................................................................... 25 3.4.5 Copy number variants ............................................................................................ 26 3.5 GENETIC OVERLAP OF MENTAL DISORDER ............................................................................... 27 3.6 GENETIC VARIATION AND ADVERSE EFFECTS OF TREATMENT ....................................................... 28 4. AIMS OF THE STUDY ................................................................................................. 29 5. MATERIALS AND METHODS ...................................................................................... 30 5.1 THE THEMATIC RESEARCH AREA PSYCHOSIS ............................................................................. 30 5.1.1 Subjects .................................................................................................................. 30 5.1.2 Measurements ....................................................................................................... 31 5.1.3 Genetic features of the TOP sample ...................................................................... 32 5.1.4 Sub-studies sampling procedures .......................................................................... 34 5.2 REPLICATION SAMPLE DESCRIPTION (SGENE-PLUS) ................................................................. 34 5.3 METHODS IN THE ASSOCIATION STUDIES ................................................................................ 34 5.3.1 Candidate gene study ............................................................................................ 35 5.3.2 Genome wide study ............................................................................................... 35 5.3.3 Linkage disequilibrium as a tool ............................................................................ 35 5.3.4 Genotyping technology and quality control .......................................................... 36 5.4 STATISTICS ....................................................................................................................... 36 5.4.1 Statistical analyses ................................................................................................ 36 5.4.1 Power considerations ............................................................................................ 38 5.4.2 Correction for multiple testing............................................................................... 38 5.4.3 The statistical software ......................................................................................... 39 6. RESULTS IN BRIEF ..................................................................................................... 40 6.1 PAPER I ........................................................................................................................... 40 6.2 PAPER II .......................................................................................................................... 41 6.3 PAPER III ......................................................................................................................... 41 7. GENERAL DISCUSSION .............................................................................................. 43 7.1 FINDINGS, INTERPRETATIONS AND CLINICAL IMPLICATIONS ......................................................... 43 7.1.1 Susceptibility genes for schizophrenia ................................................................... 43 7.1.2 Common genetics for mental disorders ................................................................ 44 7.1.3 Genetic variation and risk for adverse effects ....................................................... 44 7.1.4 Current large scale GWAS findings ........................................................................ 45 7.2 GENERAL METHODOLOGICAL ISSUES; STRENGTHS AND LIMITATIONS ............................................. 46 7.2.1 Materials ................................................................................................................ 46 7.2.2 Association; study design and analyses ................................................................. 48 7.2.3 Correction for multiple testing............................................................................... 49 7.3 IMPLICATIONS FOR FURTHER RESEARCH .................................................................................. 49 8. FUTURE PERSPECTIVES ............................................................................................. 50 9. CONCLUDING REMARKS ........................................................................................... 51 10. REFERENCES ........................................................................................................... 52 11. ORIGINAL ARTICLES ................................................................................................ 65 1. Preface 1.1 Acknowledgements This present work has been performed at the TOP study group Department of Mental Health and Addiction and Department of Medical Genetics, Oslo University Hospital-Ullevål and Institute of Clinical Medicine, University of Oslo during the period 2007 and 2011. The PhD fellowship was financed by the South East Health Authority of Norway. I am grateful for working under my supervisor Srdjan Djurovic, who with his supreme knowledge, enthusiasm and kindness has made it easy to thrive both scientifically and socially, and for giving me the opportunity to explore the interesting field of psychiatric genetics. I have also greatly appreciated the generously sharing of knowledge and experience of my co-supervisors