The genetics of sporadic Parkinson's disease - Refining the insights from genome-wide association studies

Abstract

Parkinson's disease is a common neurological disorder where the prevalence increases with age. The diagnosis is based on motor symptoms, namely slowness of movements, rigidity, tremor and balance problems, yet patients also suffer a range of other complaints, including cognitive decline and dementia. We may currently offer therapy that effectively alleviates some of the symptoms of Parkinson's disease, but without available treatment to target the cause of the disease, the condition typically follows a progressive course, severely affecting the quality of life of patients and their families. An improved understanding of the disease mechanisms on a molecular level is crucial for the development of new therapeutic strategies in the future. Mapping the genetic causes of the disease represents a key aspect of this effort. In recent years, a number of gene regions affecting the risk of Parkinson's disease have been identified through large-scale genetic investigations known as genome-wide association studies. This has represented a significant breakthrough, yet many open questions remain to be addressed before clinical medicine can take advantage of the results from these studies. The work presented in this thesis aims to shed further light on the genetic causes of Parkinson's disease by building upon the findings from genome-wide association studies. We first examined genetic risk-variants in patients and healthy controls in a material of more than 2500 participants from Norway and Sweden and found supportive evidence for an association with disease risk for 11 different gene regions. Next, we presented an effective study design for investigating such gene regions in detail in large sample sets by modern sequencing technologies. We then used this method as part of a study where we explored in depth a susceptibility region on chromosome 1, called PARK16. In the final study we investigated the relation between genetic risk variants in the SNCA gene and methylation, an epigenetic modification of the DNA molecule that regulates gene expression. We found evidence indicating that genetic susceptibility may be mediated through epigenetic mechanisms. Taken together, the studies presented in this thesis involve a broad range of methods and topics that are expected to become increasingly important in the genetic study of Parkinson disease, as well as other common diseases, in the years to come.