Parkinson sjúka í Føroyum – ein langtíðar kanning
Maria Skaalum Petersen
Deildin fyri Arbeiðs- og Almannaheilsu
Matthew Farrer, Sofus Joensen, Gunhild Waldemar, Beate Ritz, Súsanna Crooks, Noomi O. Gregersen, Tórmóður Stórá, Guðrið Andorsdóttir
Stuðul úr Granskingargrunninum:
Parkinson’s disease (PD), best known as a movement disorder, is a multifaceted syndrome of trait components that include autonomic, cognitive, motor, psychiatric, sensory and sleep deficits, many of which are progressive. Current symptomatic treatments are of limited efficacy, even for the movement disorder, while the etiology of disease and its progression remain poorly defined. The increasing prevalence of PD in our aging society requires therapeutic strategies that slow or halt neurodegeneration.
The Faroe Islands is well suited to complex trait mapping given its isolation and reduced heterogeneity, excellent genealogic records and large pedigrees. Importantly, the prevalence of PD is 2-fold greater than neighboring countries, an excess not explained by environmental risk factors alone. Complex segregation analysis of PD on the islands, based on clinical diagnoses and genealogic data, is suggestive of a genetic contribution. However, our preliminary data largely excludes rare coding variability in loci genetically linked to PD. Still, in four of the multi-incident pedigrees comparative exome analyses are ongoing and may yet identify another novel genetic determinant for disease susceptibility.
Little is known about the joint genetic and environmental factors contributing to PD, or its specific clinical components (motor and non-motor symptoms), and more especially those which modify disease progression. Any ability to predict the decline of affected subjects would have profound benefits for newly diagnosed patients, their families, healthcare systems and for novel therapeutic development. The Faroese cohort represents a relatively small, pragmatic investment for the comprehensive longitudinal study sorely needed to advance our understanding of this complex disease process.
With complete ascertainment of existing and de novo PD patients in the Faroe Islands we plan a longitudinal familybased, cohort study, focused on progression. We intend to continue recruitment, obtain more clinical and environmental phenotyping (including progression), more detailed genealogical investigation of patients and control subjects free of neurologic disease, and their 1st-3rd degree pedigrees. We plan to integrate data from on-going screening of known PD genes, exome analysis and genome-wide SNP genotyping/copy number variants (CNV). With excellent genealogical data we propose a pedigree-based approach using linkage (identical-by-descent (IBD)) analyses to elucidate the contribution of: 1) known (and perhaps novel) genes on PD progression; 2) environmental factors that may enhance susceptibility to onset and progression phenotypes, and; 3) to assess their joint contribution. While genetic and environmental risk factors for PD etiology have been described, little is known about environmental predictors of motor and non-motor progression and different phenotypes of PD. We intend to look at potential environmental (inc. PCBs, mercury, β -HCH) behavioral (e.g. smoking, caffeine, physical activity), and medical (comorbidities, PD medications etc.) determinants of PD progression, also together with genetic factors.
Although a longitudinal cohort might be developed anywhere in the world, the Faroese population represents a unique opportunity as it is a geographic, environmental and genetic isolate. It has an ‘engaged’ patient network already committed to research, with relatively large pedigrees and superbly detailed genealogy, unfettered patient access to health care, traditionally high participation rates in research and low probability of losing subjects to followup, presents a unique opportunity to test the hypothesis that in multivariate modelling of multiple trait phenotypes, genetic and environmental factors will inform progression. Hence, we wish to rigorously pursue the following aims:
Aim 1 - Recruitment to a longitudinal study of PD in the Faroese population (new patients, current cohort members and 1st-3rd relatives) collecting blood samples, clinical, environmental and genealogical data. Ascertain clinical data/biospecimens and data on a similar set of pedigrees free from neurologic disease.
Aim 2 - To perform genetic analysis within Faroese pedigrees with multi-incident PD. Exome analysis will be performed to identify novel variants linked to PD and/or progression. Illumina genotyping and CNV analyses will be performed to define haplotypes, identity-by-descent vectors and inform genealogy. A similar dataset will be obtained for pedigrees of healthy subjects free from neurologic disease.
Aim 3 - To quantify the contribution of known (and perhaps novel) genes and environment influencing susceptibility and/or progression of PD or trait components, using multivariate statistical modelling. Assess the linkage of haplotype vectors, inherited identical-by-descent (IBD), with clinical phenotypes.
We anticipate the molecular, clinical and environmental knowledge gained from this research will improve diagnosis, prognosis and accelerate the development of novel treatments, e.g. aimed at slowing progression. Predicting progression is the most important issue for newly diagnosed patients. Genetic predictors can hopefully help identify those patients most vulnerable to rapid progression and clarify the biologic pathways most likely to be involved in the underlying mechanisms. Those patients with most rapid progression and/or destined to significant comorbidities including non-motor disease, may benefit from knowing. Hence, by exploring the contributions of genetic factors to complex progression phenotypes in PD, our work will help fill an important knowledge gap.