.......................................................................................................................................... ii Preface............................................................................................................................................ iv Table of contents ............................................................................................................................ vi List of tables ................................................................................................................................... ix List of figures ................................................................................................................................. xi List of abbreviations .................................................................................................................... xiii Glossary of terms ........................................................................................................................ xvii Acknowledgments........................................................................................................................ xix 1. Chapter 1: Introduction ....................................................................................................... 1 1.1. General features of Parkinson disease ........................................................................ 1 1.1.1. Motor features ..................................................................................................... 1 1.1.2. Non-motor features ............................................................................................. 2 1.1.3. Pathology ............................................................................................................ 2 1.2. Identification of genetic mutations in PD ................................................................... 3 1.2.1. Linkage analysis.................................................................................................. 3 1.2.2. Next generation sequencing ................................................................................ 4 1.2.3. Genome-wide case-control association............................................................... 5 1.3. Genes implicated in late-onset autosomal dominant PD ............................................ 6 1.3.1. SNCA .................................................................................................................. 6 1.3.2. LRRK2 ................................................................................................................ 7 1.3.3. MAPT ................................................................................................................. 8 1.3.4. EIF4G1 ................................................................................................................ 9 1.3.5. VPS35 and DNAJC13....................................................................................... 10 1.3.6. CHCHD2........................................................................................................... 11 1.3.7. Recessively inherited gene mutations ............................................................... 12 1.4. GWAS in PD............................................................................................................. 13 1.5. Neurobiological interactions: is there one pathway for PD? .................................... 20 1.6. Reduced penetrance .................................................................................................. 23 2. Chapter 2: Disease penetrance estimates of mutations in late-onset PD .......................... 25 2.