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  • Stefanis, Leonidas  (7)
  • Medizin  (7)
  • 1
    Online-Ressource
    Online-Ressource
    Investigation of Shared Genetic Risk Factors Between Parkinson's Disease and Cancers
    Wiley ; 2023
    In:  Movement Disorders Vol. 38, No. 4 ( 2023-04), p. 604-615
    Details
    In: Movement Disorders, Wiley, Vol. 38, No. 4 ( 2023-04), p. 604-615
    Kurzfassung: Epidemiological studies that examined the association between Parkinson's disease (PD) and cancers led to inconsistent results, but they face a number of methodological difficulties. Objective We used results from genome‐wide association studies (GWASs) to study the genetic correlation between PD and different cancers to identify common genetic risk factors. Methods We used individual data for participants of European ancestry from the Courage‐PD (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease; PD, N = 16,519) and EPITHYR (differentiated thyroid cancer, N = 3527) consortia and summary statistics of GWASs from iPDGC (International Parkinson Disease Genomics Consortium; PD, N = 482,730), Melanoma Meta‐Analysis Consortium (MMAC), Breast Cancer Association Consortium (breast cancer), the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (prostate cancer), International Lung Cancer Consortium (lung cancer), and Ovarian Cancer Association Consortium (ovarian cancer) (N comprised between 36,017 and 228,951 for cancer GWASs). We estimated the genetic correlation between PD and cancers using linkage disequilibrium score regression. We studied the association between PD and polymorphisms associated with cancers, and vice versa, using cross‐phenotypes polygenic risk score (PRS) analyses. Results We confirmed a previously reported positive genetic correlation of PD with melanoma (G corr = 0.16 [0.04; 0.28]) and reported an additional significant positive correlation of PD with prostate cancer (G corr = 0.11 [0.03; 0.19]). There was a significant inverse association between the PRS for ovarian cancer and PD (odds ratio [OR] = 0.89 [0.84; 0.94]). Conversely, the PRS of PD was positively associated with breast cancer (OR = 1.08 [1.06; 1.10] ) and inversely associated with ovarian cancer (OR = 0.95 [0.91; 0.99]). The association between PD and ovarian cancer was mostly driven by rs183211 located in an intron of the NSF gene (17q21.31). Conclusions We show evidence in favor of a contribution of pleiotropic genes to the association between PD and specific cancers. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
    Materialart: Online-Ressource
    ISSN: 0885-3185 , 1531-8257
    URL: Issue
    URL: Article
    DOI: 10.1002/mds.v38.4
    DOI: 10.1002/mds.29337
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: Wiley
    Publikationsdatum: 2023
    ZDB Id: 2041249-6
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 2
    Online-Ressource
    Online-Ressource
    Genome-wide Association and Meta-analysis of Age at Onset in Parkinson Disease : Evidence From the COURAGE-PD Consortium
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Neurology Vol. 99, No. 7 ( 2022-08-16), p. e698-e710
    Details
    In: Neurology, Ovid Technologies (Wolters Kluwer Health), Vol. 99, No. 7 ( 2022-08-16), p. e698-e710
    Kurzfassung: Considerable heterogeneity exists in the literature concerning genetic determinants of the age at onset (AAO) of Parkinson disease (PD), which could be attributed to a lack of well-powered replication cohorts. The previous largest genome-wide association studies (GWAS) identified SNCA and TMEM175 loci on chromosome (Chr) 4 with a significant influence on the AAO of PD; these have not been independently replicated. This study aims to conduct a meta-analysis of GWAS of PD AAO and validate previously observed findings in worldwide populations. Methods A meta-analysis was performed on PD AAO GWAS of 30 populations of predominantly European ancestry from the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease (COURAGE-PD) Consortium. This was followed by combining our study with the largest publicly available European ancestry dataset compiled by the International Parkinson Disease Genomics Consortium (IPDGC). Results The COURAGE-PD Consortium included a cohort of 8,535 patients with PD (91.9%: Europeans and 9.1%: East Asians). The average AAO in the COURAGE-PD dataset was 58.9 years (SD = 11.6), with an underrepresentation of females (40.2%). The heritability estimate for AAO in COURAGE-PD was 0.083 (SE = 0.057). None of the loci reached genome-wide significance ( p 〈 5 × 10 −8 ). Nevertheless, the COURAGE-PD dataset confirmed the role of the previously published TMEM175 variant as a genetic determinant of the AAO of PD with Bonferroni-corrected nominal levels of significance ( p 〈 0.025): (rs34311866: β(SE) COURAGE = 0.477(0.203), p COURAGE = 0.0185). The subsequent meta-analysis of COURAGE-PD and IPDGC datasets (N total = 25,950) led to the identification of 2 genome-wide significant association signals on Chr 4, including the previously reported SNCA locus (rs983361: β(SE) COURAGE+IPDGC = 0.720(0.122), p COURAGE+IPDGC = 3.13 × 10 −9 ) and a novel BST1 locus (rs4698412: β(SE) COURAGE+IPDGC = −0.526(0.096), p COURAGE+IPDGC = 4.41 × 10 −8 ). Discussion Our study further refines the genetic architecture of Chr 4 underlying the AAO of the PD phenotype through the identification of BST1 as a novel AAO PD locus. These findings open a new direction for the development of treatments to delay the onset of PD.
    Materialart: Online-Ressource
    ISSN: 0028-3878 , 1526-632X
    URL: Article
    DOI: 10.1212/WNL.0000000000200699
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: Ovid Technologies (Wolters Kluwer Health)
    Publikationsdatum: 2022
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 3
    Online-Ressource
    Online-Ressource
    The Interaction between HLA‐DRB1 and Smoking in Parkinson's Disease Revisited
    Wiley ; 2022
    In:  Movement Disorders Vol. 37, No. 9 ( 2022-09), p. 1929-1937
    Details
    In: Movement Disorders, Wiley, Vol. 37, No. 9 ( 2022-09), p. 1929-1937
    Kurzfassung: Two studies that examined the interaction between HLA‐DRB1 and smoking in Parkinson's disease (PD) yielded findings in opposite directions. Objective To perform a large‐scale independent replication of the HLA‐DRB1  × smoking interaction. Methods We genotyped 182 single nucleotide polymorphism (SNPs) associated with smoking initiation in 12 424 cases and 9480 controls to perform a Mendelian randomization (MR) analysis in strata defined by HLA‐DRB1 . Results At the amino acid level, a valine at position 11 (V11) in HLA‐DRB1 displayed the strongest association with PD. MR showed an inverse association between genetically predicted smoking initiation and PD only in absence of V11 (odds ratio, 0.74, 95% confidence interval, 0.59–0.93, P Interaction  = 0.028). In silico predictions of the influence of V11 and smoking‐induced modifications of α‐synuclein on binding affinity showed findings consistent with this interaction pattern. Conclusions Despite being one of the most robust findings in PD research, the mechanisms underlying the inverse association between smoking and PD remain unknown. Our findings may help better understand this association. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
    Materialart: Online-Ressource
    ISSN: 0885-3185 , 1531-8257
    URL: Issue
    URL: Article
    DOI: 10.1002/mds.v37.9
    DOI: 10.1002/mds.29133
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: Wiley
    Publikationsdatum: 2022
    ZDB Id: 2041249-6
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 4
    Online-Ressource
    Online-Ressource
    Embracing Monogenic Parkinson's Disease: The MJFF Global Genetic PD Cohort
    Wiley ; 2023
    In:  Movement Disorders Vol. 38, No. 2 ( 2023-02), p. 286-303
    Details
    In: Movement Disorders, Wiley, Vol. 38, No. 2 ( 2023-02), p. 286-303
    Kurzfassung: As gene‐targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial‐ready cohorts is limited. Objective The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD‐linked variants; (2) provide harmonized and quality‐controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD. Methods We conducted a worldwide, systematic online survey to collect individual‐level data on individuals with PD‐linked variants in SNCA , LRRK2 , VPS35 , PRKN , PINK1 , DJ‐1 , as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype–phenotype relationships were analyzed. Results We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2 , 115 SNCA , 23 VPS35 , 429 PRKN , 75 PINK1 , 13 DJ‐1 , and 1224 GBA ) and 703 were unaffected (ie, 328 LRRK2 , 32 SNCA , 3 VPS35 , 1 PRKN , 1 PINK1 , and 338 GBA ). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published. Conclusions Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD‐linked variants; (2) provide harmonized and quality‐controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene‐targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
    Materialart: Online-Ressource
    ISSN: 0885-3185 , 1531-8257
    URL: Issue
    URL: Article
    DOI: 10.1002/mds.v38.2
    DOI: 10.1002/mds.29288
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: Wiley
    Publikationsdatum: 2023
    ZDB Id: 2041249-6
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 5
    Online-Ressource
    Online-Ressource
    Defining the Riddle in Order to Solve It: There Is More Than One “Parkinson's Disease”
    Wiley ; 2023
    In:  Movement Disorders Vol. 38, No. 7 ( 2023-07), p. 1127-1142
    Details
    In: Movement Disorders, Wiley, Vol. 38, No. 7 ( 2023-07), p. 1127-1142
    Kurzfassung: More than 200 years after James Parkinsondescribed a clinical syndrome based on his astute observations, Parkinson's disease (PD) has evolved into a complex entity, akin to the heterogeneity of other complex human syndromes of the central nervous system such as dementia, motor neuron disease, multiple sclerosis, and epilepsy. Clinicians, pathologists, and basic science researchers evolved arrange of concepts andcriteria for the clinical, genetic, mechanistic, and neuropathological characterization of what, in their best judgment, constitutes PD. However, these specialists have generated and used criteria that are not necessarily aligned between their different operational definitions, which may hinder progress in solving the riddle of the distinct forms of PD and ultimately how to treat them. Objective This task force has identified current in consistencies between the definitions of PD and its diverse variants in different domains: clinical criteria, neuropathological classification, genetic subtyping, biomarker signatures, and mechanisms of disease. This initial effort for “defining the riddle” will lay the foundation for future attempts to better define the range of PD and its variants, as has been done and implemented for other heterogeneous neurological syndromes, such as stroke and peripheral neuropathy. We strongly advocate for a more systematic and evidence‐based integration of our diverse disciplines by looking at well‐defined variants of the syndrome of PD. Conclusion Accuracy in defining endophenotypes of “typical PD” across these different but interrelated disciplines will enable better definition of variants and their stratification in therapeutic trials, a prerequisite for breakthroughs in the era of precision medicine. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
    Materialart: Online-Ressource
    ISSN: 0885-3185 , 1531-8257
    URL: Issue
    URL: Article
    DOI: 10.1002/mds.v38.7
    DOI: 10.1002/mds.29419
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: Wiley
    Publikationsdatum: 2023
    ZDB Id: 2041249-6
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 6
    Online-Ressource
    Online-Ressource
    Dairy Intake and Parkinson's Disease: A Mendelian Randomization Study
    Wiley ; 2022
    In:  Movement Disorders Vol. 37, No. 4 ( 2022-04), p. 857-864
    Details
    In: Movement Disorders, Wiley, Vol. 37, No. 4 ( 2022-04), p. 857-864
    Kurzfassung: Previous prospective studies highlighted dairy intake as a risk factor for Parkinson's disease (PD), particularly in men. It is unclear whether this association is causal or explained by reverse causation or confounding. Objective The aim is to examine the association between genetically predicted dairy intake and PD using two‐sample Mendelian randomization (MR). Methods We genotyped a well‐established instrumental variable for dairy intake located in the lactase gene (rs4988235) within the Courage‐PD consortium (23 studies; 9823 patients and 8376 controls of European ancestry). Results Based on a dominant model, there was an association between genetic predisposition toward higher dairy intake and PD (odds ratio [OR] per one serving per day = 1.70, 95% confidence interval = 1.12–2.60, P  = 0.013) that was restricted to men (OR = 2.50 [1.37–4.56], P  = 0.003; P ‐difference with women = 0.029). Conclusions Using MR, our findings provide further support for a causal relationship between dairy intake and higher PD risk, not biased by confounding or reverse causation. Further studies are needed to elucidate the underlying mechanisms. © 2022 International Parkinson and Movement Disorder Society
    Materialart: Online-Ressource
    ISSN: 0885-3185 , 1531-8257
    URL: Issue
    URL: Article
    DOI: 10.1002/mds.v37.4
    DOI: 10.1002/mds.28902
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: Wiley
    Publikationsdatum: 2022
    ZDB Id: 2041249-6
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 7
    Online-Ressource
    Online-Ressource
    Clinical rating scale for pantothenate kinase‐associated neurodegeneration: A pilot study
    Wiley ; 2017
    In:  Movement Disorders Vol. 32, No. 11 ( 2017-11), p. 1620-1630
    Details
    In: Movement Disorders, Wiley, Vol. 32, No. 11 ( 2017-11), p. 1620-1630
    Kurzfassung: Pantothenate kinase‐associated neurodegeneration is a progressive neurological disorder occurring in both childhood and adulthood. The objective of this study was to design and pilot‐test a disease‐specific clinical rating scale for the assessment of patients with pantothenate kinase‐associated neurodegeneration. Methods In this international cross‐sectional study, patients were examined at the referral centers following a standardized protocol. The motor examination was filmed, allowing 3 independent specialists in movement disorders to analyze 28 patients for interrater reliability assessment. The scale included 34 items (maximal score, 135) encompassing 6 subscales for cognition, behavior, disability, parkinsonism, dystonia, and other neurological signs. Results Forty‐seven genetically confirmed patients (30 ± 17 years; range, 6‐77 years) were examined with the scale (mean score, 62 ± 21; range, 20‐106). Dystonia with prominent cranial involvement and atypical parkinsonian features were present in all patients. Other common signs were cognitive impairment, psychiatric features, and slow and hypometric saccades. Dystonia, parkinsonism, and other neurological features had a moderate to strong correlation with disability. The scale showed good internal consistency for the total scale (Cronbach's α = 0.87). On interrater analysis, weighted kappa values (0.30‐0.93) showed substantial or excellent agreement in 85% of the items. The scale also discriminated a subgroup of homozygous c.1583C 〉 T patients with lower scores, supporting construct validity for the scale. Conclusions The proposed scale seems to be a reliable and valid instrument for the assessment of pediatric and adult patients with pantothenate kinase‐associated neurodegeneration. Additional validation studies with a larger sample size will be required to confirm the present results and to complete the scale validation testing. © 2017 International Parkinson and Movement Disorder Society
    Materialart: Online-Ressource
    ISSN: 0885-3185 , 1531-8257
    URL: Issue
    URL: Article
    DOI: 10.1002/mds.v32.11
    DOI: 10.1002/mds.27129
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: Wiley
    Publikationsdatum: 2017
    ZDB Id: 2041249-6
    Standort Signatur Einschränkungen Verfügbarkeit
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