The Rostock International Parkinson's Disease (ROPAD) Study: Protocol and Initial Findings

Abstract

Background Genetic stratification of Parkinson's disease (PD) patients facilitates gene‐tailored research studies and clinical trials. The objective of this study was to describe the design of and the initial data from the Rostock International Parkinson's Disease (ROPAD) study, an epidemiological observational study aiming to genetically characterize ~10,000 participants. Methods Recruitment criteria included (1) clinical diagnosis of PD, (2) relative of participant with a reportable LRRK2 variant, or (3) North African Berber or Ashkenazi Jew. DNA analysis involved up to 3 successive steps: (1) variant (LRRK2) and gene (GBA) screening, (2) panel sequencing of 68 PD‐linked genes, and (3) genome sequencing. Results Initial data based on the first 1360 participants indicated that the ROPAD enrollment strategy revealed a genetic diagnostic yield of ~14% among a PD cohort from tertiary referral centers. Conclusions The ROPAD screening protocol is feasible for high‐throughput genetic characterization of PD participants and subsequent prioritization for gene‐focused research efforts and clinical trials. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The Genetics of Parkinson’s Disease and Implications for Clinical Practice

“…With this increasing wealth of genetic knowledge, new strategies to assimilate the information and make it available to clinicians, researchers and patients are being created [ 218 , 219 , 220 ]. Whereas the treatment implications for different forms of monogenic diabetes have driven genetic testing into clinical practice, this is not yet the case for routine PD care, although examples of this are beginning to emerge [ 33 , 221 , 222 ]. While it is possible to provide some information to individual patients regarding risk of disease and prognosis, the range of predictions creates uncertainty.…”

“…Duplications and triplications of SNCA can also cause PD with evidence for a ‘dosage effect’, where greater expression of α-synuclein leads to more severe clinical features [ 30 , 31 ]. However, pathogenic SNCA variants only account for a tiny proportion of PD cases [ 32 , 33 , 34 ].…”

“…p.E326K (p.E365K) and p.T369M (p.T408M), found commonly in European populations, double PD risk compared to the general population, but do not cause Gaucher disease [ 108 , 111 , 112 , 113 ]. Collectively 10–15% of European PD patients carry a PD associated GBA variant, making it numerically the most significant PD genetic risk factor by some distance [ 33 ].…”

“…Heterozygous PRKN variants are common finding amongst those with PD. One large study found that some 1.2% of early onset/familial PD cases carry a PRKN variant [ 33 ]. The same study found that PRKN carriers had an age at onset some 12 years lower than PD cases without other genetic risk factors.…”

LIPAD (LRRK2/Luebeck International Parkinson's Disease) Study Protocol: Deep Phenotyping of an International Genetic Cohort

“…To identify LRRK2 pathogenic variant carriers among 10,000 PD patients from 15 countries and to establish a clinical trial-ready cohort, the ROPAD study was initiated ( 9 ). The ROPAD study performs genetic testing of pathogenic variants in the LRRK2 and GBA genes and, if negative, carries out genetic screening of 68 genes linked to PD or related movement disorders.…”