FOR 2488:  Reduced penetrance in hereditary movement disorders: Elucidating mechanisms of endogenous disease protection

• Subject Area: Medicine
• Term: since 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 287074911

In view of the identification of a surprisingly large number of carriers of allegedly pathogenicmutations who remain free of the disease in question, the importance of reduced penetrance appears to have been substantially underestimated. It, however, represents one of the most central questionsthat we currently face not only in the field of hereditary movement disorders, but in the entire realm of medical genetics and personalized medicine. In addition, there is a generalized preoccupationwith disease susceptibility, whereas the concepts of protection against disease have been largelyneglected in the genomic research community. In the first funding period, the Research Unit ‘ProtectMove’ has formed a closely interacting, interdisciplinary network and, after less than three years, already serves as a national and international hub for the study of reduced penetrance of movement disorders. It has attracted numerous new collaborators, students, cohorts, datasets, andbiomaterials and has built up a sustainable infrastructure, ranging from innovative data concepts tonew approaches of international team science, to platforms for induced Pluripotent Stem Cell (iPSC)technology, Genome Editing, and Third-generation Sequencing. The main hypotheses raised in thefirst grant proposal have been confirmed by a wealth of novel findings from all ProtectMove projects: i) Reduced penetrance and variable expressivity appear to represent a continuum across disease manifestation and expression and are not two completely distinct phenomena. ii) Pathogenic variantsin Parkinson’s disease (PD) and dystonia genes are more frequent in PD and dystonia patients thanin controls but also occur in the latter at a considerable frequency of ~8%. iii) It is possible with relatively limited numbers of mutation carriers to identify strong and biologically plausible modifiersof disease penetrance and expressivity. Multi-modal investigations at the phenotypic as well as at the functional level provide mechanistic insight into the involved pathways and mode of action ofthese modifiers. iv) Currently detected modifiers involve nuclear genetic factors including repeat expansions, the mitochondrial genome, gene-gene and gene-protein interactions, and inflammatoryresponse. v) These findings start impacting on patient counseling and hold translational potential fortargeted treatment. In the second funding period, we are planning to i) follow up on the mostpromising findings in large-scale replication studies and by functional validation; ii) leverage the full potential of longitudinal population-based and of new international cohorts of mutation carriers; iii)expand to a systems biomedicine approach; iv) add a strong mechanistic focus to that of modifieridentification; v) further establish ProtectMove as a hub of networking and career developmentaiming to lay the foundation for a Collaborative Research Center/Transregio (CRC/TR) following the second funding phase of ProtectMove. Two of the previous projects (P6 and P7) will be completed within the first funding period giving rise to two new projects (P9 and P10); also, there are four Coresproviding methodological service across ProtectMove. Z1 is the central coordination project, P1focuses on ‘Molecular mechanisms defining penetrance of LRRK2-associated PD’; P2 investigates‘Inflammation as a penetrance modifier in Parkin and PINK1 mutation carriers’; P3 identifies ‘Modifiers of Parkin and PINK1 mutation penetrance in PD using endogenous human models’; P4addresses ‘Modifiers of penetrance and expressivity in monogenic dystonia through insights from systems biology’; P5 continues to study ‘Mechanisms of penetrance and expressivity in X-linked dystonia-parkinsonism’; P8 exploits ‘Mendelian randomization and polygenic risk scores tounderstand reduced penetrance’; P9 builds on findings from the first funding period to explore the‘Relevance of genetic risk variants in reduced penetrance’; P10’s aim is ‘Identifying PD penetrancemodifying factors in the population-based CHRIS cohort’; Z2 combines ‘Data base, phenotyping and PD prodromal marker profile analyses, ethical, legal and social implications (ELSI) aspects, mutational analysis and iPSC core’; and INF is directed at ‘Maintenance and extension of the CentralProject Knowledge Base (CPKB), systems biomedicine and statistics pipeline’.

• DFG Programme: Research Units
• International Connection: Italy, Luxembourg

Projects

• Coordination Funds (Applicant Klein, Christine )
• Data base, phenotyping and prodromal signs, patient involvement and Ethical, Legal and Social Implications (ELSI) aspects, mutational analysis and induced Pluripotent Stem Cell (iPSC) Core (Applicants Berg, Daniela ;  Brüggemann, Norbert ;  Lohmann, Katja ;  Seibler, Philip )
• Identification of Penetrance- and Risk-Modifying Variants in Dystonia Using Different Genome-Wide Technologies (Applicants Bertram, Lars ;  Erdmann, Jeanette )
• Identifying determinants of reduced penetrance by analysis of mutation carriers and by age-at-onset analyses in Parkinson s disease (Applicants Koenig, Inke Regina ;  Lill, Christina )
• Identifying Parkinson’s disease penetrance-modifying factors in the population-based Cooperative Health Research in South Tyrol (CHRIS) cohort (Applicant Klein, Christine )
• Maintenance and Extension of a Central Project Knowledge Base (CPKB), systems biomedicine and statistics pipeline (Applicants Busch, Hauke ;  Erdmann, Jeanette ;  Koenig, Inke Regina ;  Krawczak, Michael )
• Mechanisms of penetrance and expressivity in X-linked dystonia-parkinsonism (Applicants Kaiser, Frank ;  Rakovic, Aleksandar ;  Westenberger, Ana )
• Mendelian randomization and polygenic risk scores to understand reduced penetrance in movement disorders (Applicants Caliebe, Amke ;  Koenig, Inke Regina )
• Modifiers of Parkin and PINK1 mutation penetrance in Parkinson’s disease: Endogenous human models (Applicant Rakovic, Aleksandar )
• Modifiers of penetrance and expressivity in monogenic dystonia: Insights from systems biology (Applicants Busch, Hauke ;  Lohmann, Katja )
• Molecular mechanisms defining penetrance of LRRK2-associated Parkinson’s disease (Applicants Grünewald, Anne ;  Kasten, Meike ;  Trinh, Ph.D., Joanne )
• Physiological relevance of genetic risk variants in reduced penetrance (Applicants Kaiser, Frank ;  Spielmann, Malte ;  Westenberger, Ana )
• Reduced penetrance in Parkin and PINK1 deficiency: Inflammation as a Parkinson’s disease penetrance modifier (Applicants Klein, Christine ;  Seibler, Philip )

• Spokesperson: Professorin Dr. Christine Klein