Resolving complex genetic causes of Movement Disorders

Genetic studies within families has been used to identify genetic causes of disease. Modifiers of disease risk have been identified by comparing genetic markers between groups of patients and control invididuals. Genetic risk factors have a modest effect and seldom increase the disease risk by more than 50%. Therefore, such risk factors must 'work in concert' with other genetic or environmental risk factors in order to cause the disase in an individual. Genetic causes of inherited familial disease may be rare, but they have a strong biological effect and a single mutation may be enough to cause the disease. Disease causing variants that are more common, i.e. they have a frequency of about 1-5% in the population, may not always lead to disease and the disease may therefore 'skip generations' in a family. This phenomenon is called reduced penetrance. In this project, we have investigated whether the a mutation in the HTRA2 gene [p.G399S] increases the risk of movement disorders such as Parkinsons disease, tremor or cervical dystonia. This does not appear to be the case. We have also investigated a number of genes that have been nominated as candidate genes for tremor or dystonia. We have identified a novel candidate mutation for tremor-dystonia and we are now finalizing our analysis of this gene. Importantly, this grant has enabled us to set up cutting edge genetic and epigenetic analysis pipelines for future research.

The genetic basis of disease has been elucidated through the identification of genetic risk factors and through the identification of rare mutations with Mendelian inheritance. Genome wide association studies (GWAS) have identified risk alleles that are common in the population (>5.0% minor allele frequency; MAF) and are associated with a modest increase in disease risk, e.g. odds ratio (OR) < 2.0. Mendelian mutations may be rare, but they exert a significant biological effect and may be the sole cause of disease. Linkage studies, and more recently next-generation sequencing (NGS) has been applied to identify Mendelian disease genes. Non-rare pathogenic variants with reduced penetrance may or may not cause disease in an individual and represents the unexplored intermediate between common and rare genetic variants. The objective of this proposal is to identify genetic causes of cervical dystonia (CD) and essential tremor (ET) in a unique patient and control material from western Norway. I plan to address the complex genetics of these disorders by identifying both low-penetrance mutations and high-penetrance mutations by combining SNP-chip based indentity-by-descent (IBD) mapping and large scale exome sequencing in this homogeneous population. Verification of identified common genetic causes of cervical dystonia and essential tremor by targeted re-sequencing of genes containing candidate mutations in further patient samples.