Genetic variants associated with progression in Parkinson’s disease, Manuela Tan, UCL
There are currently no treatments to stop or slow progression in Parkinson’s disease. In order to develop new disease modifying treatments and stratify patients, we need to better understand the biology of progression. Genome-wide association studies (GWASs) of Parkinson’s patients compared to controls have helped us to understand more about the pathways for disease risk, but not progression. In this talk I will present the results of GWASs for motor, cognitive, and cross-domain progression in Parkinson’s. I will also share early data from GWASs of progression to clinical milestones, including mortality and dementia.
A human single-cell atlas of the Substantia nigra reveals novel cell-specific pathways associated with the genetic risk of Parkinson’s disease and neuropsychiatric disorders, Violoa Volpato, Cardiff DRI
We sequenced ~ 17,000 nuclei from both the Cortex and Substantia Nigra (SN) of five human brains and generated the first human single-nuclei transcriptomic atlas of the SN, a region playing important roles in reward and movement. By mapping genetic variants associated with different human traits to SN cell-type-specific gene expression patterns, we demonstrate for the first time that Parkinson’s disease (PD) genetic risk, for which the symptoms are caused by loss of SN dopaminergic neurons (DaNs), is indeed associated with DaN-specific gene expression affecting pathways such as mitochondrial organisation and functioning, protein ubiquitination and vesicle transport. We also identify a distinct cell type association between PD risk and oligodendrocyte-specific gene expression. Unlike Alzheimer’s disease (AD), we find no association between PD risk and microglia or astrocytes, suggesting that neuroinflammation plays a less causal role in PD than AD. Beyond PD, we find other neuropsychiatric disorders, particularly schizophrenia (SCZ), to be associated to SN DaNs and GABAergic neurons. Nevertheless, we find that each neuropsychiatric disorder is associated with a distinct set of genes within those neuronal types. On the contrary, we find an overlapping component of risk between neuropsychiatric disorders in the association to glial cells, particularly oligo-precursor cells (OPCs). This atlas provides the first objective associations between genetic risk of multiple disorders and the midbrain cell types these risks likely manifest through, thereby directing our aetiological understanding.