We aim to define new pathogenic mutations that cause Parkinson’s disease (PD) and other neurological disorders and to investigate the overlap between neurological disorders and risk / protection for infectious diseases. We will evaluate genetic, biomarker and clinical data regarding infectious disease history to investigate the link between rare variants in lysosomal and immune-related genes associated with neurological movement disorders, such as LRRK2 or GBA1 in Parkinson’s disease. The rationale for this research is that there are mutations that are protective against infectious diseases such as tuberculosis and leprosy, which may become common due to selective pressure to survive and reproduce in early life, could affect risk of developing neurological disorders later in life. Thus, genetic pleiotropy may apply to both common and rare variants. We propose the following research questions:
-What is the UK Biobank population prevalence and penetrance of known and novel genetic and biomarker (SOMASCAN / OLINK) risk factors for neurological diseases including Parkinson’s disease, PSP, and dementia – we will analyse this data in relation to data generated in the global Parkinson’s genetics programme and 100K genomes programme.
-Do carriers of these variants have a clinical history of infectious disease, including tuberculosis and mycobacterial infection (i.e. leprosy) in comparison to non-risk allele carriers (controls)
-What is the ancestry distribution of these carriers, and which infectious disease types and rare variants are more prevalent in each ancestry
-Is there an association between genetic ancestry, infectious disease risk, and lysosomal/immune gene rare variant type. Does this correlate with differences in neurological disease penetrance and outcomes (e.g. severity, duration)
