The impact of rare variants in lysosomal genes in the pathogenesis of Parkinson disease

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Parkinson disease (PD) is one of the commonest and most serious neurodegenerative disorders. A causative therapy for PD does not exist. PD is a genetically complex disorder in most patients and monogenic in a minority.GWAS studies are limited to a relatively small number of common variants per gene. Recent large exome sequencing projects have demonstrated that the majority of protein coding rare variants have frequencies in the range of 1:1000 to <1:10.000 alleles. The best method to assess the role of rare variants is DNA sequencing. GWAS findings explain only a small part of the estimated heritability of Parkinson disease. Part of the remaining missing heritability will be due to rare variants. The impact of rare variants has already been shown for numerous disorders including Alzheimers disease. However, the impact of rare variants has not been systematically assessed in large patient and control samples due to the high cost of Sanger sequencing. Next-Generation-Sequencing (NGS) now offers a much more economic means to obtain very large amounts of DNA-sequence data.Lysosomes play an extremely important role in the pathogenesis of PD. Alpha-Synuclein (a-syn) is the key pathogenic protein in sporadic PD. Alpha-syn aggregates spontaneously and is a major constituent of the pathognomonic intraneuronal inclusions termed Lewy bodies. Lysosomes degrade soluble and aggregated a-syn using different pathways. Aggregated or otherwise pathologically altered a-syn impairs lysosomal function. Large studies showed that rare heterozygous variants in the gene encoding the lysosomal enzyme glucocerebrosidase (GBA) are strongly associated with Parkinson disease. These mutations interfere with a-syn degradation. Lysosomes are involved in the removal of defective mitochondria and this function is also disturbed in PD. In addition, a number of genes causing monogenic PD are implied in lysosomal function (e.g. LRRK2, VPS35, PINK1, PARK2, ATP13A2).We propose to sequence 18 carefully selected lysosomal candidate genes in 2500 PD patients and the same number of controls. An already tested DNA pooling strategy guarantees a very economic, yet thorough sequence analysis. These data will not only allow us to obtain a detailed view of the role of rare variants in lysosomal genes in PD but will also provide a unique dataset to test and establish novel statistical tools for the analysis or rare variant associations. Since rare variants are more likely to have a large impact on gene function the findings might also enable us to improve biological studies of lysosomal gene malfunction in PD. Kiel University is an ideal location for such a study because the applicants dispose of expertise in Parkinson disease (G. Deuschl), neurogenetics (G. Kuhlenbäumer), NGS (A. Franke) and statistical genetics (M. Krawcak). In addition we have one of the largest NGS facilities in Germany.