Abstract
BackgroundParkinson’s disease (PD) is a neurodegenerative movement disorder affecting 1–5% of the general population for which neither effective cure nor early diagnostic tools are available that could tackle the pathology in the early phase. Here we report a multi-stage procedure to identify candidate genes likely involved in the etiopathogenesis of PD.MethodsThe study includes a discovery stage based on the analysis of whole exome data from 26 dominant late onset PD families, a validation analysis performed on 1542 independent PD patients and 706 controls from different cohorts and the assessment of polygenic variants load in the Italian cohort (394 unrelated patients and 203 controls).ResultsFamily-based approach identified 28 disrupting variants in 26 candidate genes for PD including PARK2, PINK1, DJ-1(PARK7), LRRK2, HTRA2, FBXO7, EIF4G1, DNAJC6, DNAJC13, SNCAIP, AIMP2, CHMP1A, GIPC1, HMOX2, HSPA8, IMMT, KIF21B, KIF24, MAN2C1, RHOT2, SLC25A39, SPTBN1, TMEM175, TOMM22, TVP23A and ZSCAN21. Sixteen of them have not been associated to PD before, were expressed in mesencephalon and were involved in pathways potentially deregulated in PD. Mutation analysis in independent cohorts disclosed a significant excess of highly deleterious variants in cases (p = 0.0001), supporting their role in PD.Moreover, we demonstrated that the co-inheritance of multiple rare variants (≥ 2) in the 26 genes may predict PD occurrence in about 20% of patients, both familial and sporadic cases, with high specificity (> 93%; p = 4.4 × 10− 5). Moreover, our data highlight the fact that the genetic landmarks of late onset PD does not systematically differ between sporadic and familial forms, especially in the case of small nuclear families and underline the importance of rare variants in the genetics of sporadic PD.Furthermore, patients carrying multiple rare variants showed higher risk of manifesting dyskinesia induced by levodopa treatment.ConclusionsBesides confirming the extreme genetic heterogeneity of PD, these data provide novel insights into the genetic of the disease and may be relevant for its prediction, diagnosis and treatment.
Highlights
Parkinson’s disease (PD) is a neurodegenerative movement disorder affecting 1–5% of the general population for which neither effective cure nor early diagnostic tools are available that could tackle the pathology in the early phase
Parkinson’s disease (PD) is a neurodegenerative movement disorder characterized by the loss of mesodiencephalic dopaminergic neurons of the substantia nigra pars compacta (SNpc), in association with the presence of Lewy bodies in some surviving neurons [1, 2]. mdDA neurons play a crucial role in the control of motor, sensory-motor and motivated behavior [3]
We first analysed the whole-exome sequencing (WES) data of the 53 PD patients belonging to 26 families to search for mutations in genes already known to be associated to dominant form of PD such as, SNCA, VPS35 and LRRK2
Summary
Parkinson’s disease (PD) is a neurodegenerative movement disorder affecting 1–5% of the general population for which neither effective cure nor early diagnostic tools are available that could tackle the pathology in the early phase. MdDA neurons play a crucial role in the control of motor, sensory-motor and motivated behavior [3]. Their degeneration causes the characteristic symptoms of PD, which include resting tremor, bradykinesia, rigidity, postural instability and a variety of other motor and non–motor symptoms [2]. The Generation Sequencing (NGS) methods are widespread in the diagnostic field, their application to PD is still limited to a small number of patients with a clear family history and to a small number of causative mutations, due to the high genetic heterogeneity associated with the disease and to the difficulty in interpreting test results
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