The OPDC will focus on understanding the earliest pathological pathways in Parkinson's disease (PD). Scientists with strengths in genetics and genomics, transgenic rodent PD models, in vivo neuroanatomy and neuropharmacology of the basal ganglia, magnetic resonance imaging (MRI), and analysis of protein biomarkers, will work closely with experts in clinical epidemiology and neurology of PD. We will identify causal genetic variants within pathways leading to PD from bioinformatics analyses of large-scale genomics projects. Variants will be characterised by resequencing genes in a clinical cohort of 2000 PD patients, 300 at-risk individuals and 300 age-matched controls. Induced pluripotent stem cells generated from individuals harbouring susceptibility variants will be differentiated into dopaminergic neurones. Genetic variant effects on genome-wide transcription/cellular dopamine homeostasis will identify best candidates to use in improved rodent models. BAC transgenesis will be used to express causal variants at physiologically-relevant levels preserving temporal and spatial expression. New models will be analysed for earliest changes of dopamine neuropharmacology compared to midbrain MRI. Biomarker studies on microRNAs/proteins will correlate blood/CSF findings with neuroanatomical alterations. This will lead to improved methods of earlier diagnosis of PD, identify new molecular targets for therapy, and generate improved models for testing neuroprotective treatments.