RESUMEN
BACKGROUND: Multiple system atrophy is a neurodegenerative disease with α-synuclein aggregation in glial cytoplasmic inclusions, leading to dysautonomia, parkinsonism, and cerebellar ataxia. OBJECTIVE: The aim of this study was to validate the accuracy of the International Parkinson and Movement Disorder Society Multiple System Atrophy clinical diagnostic criteria, particularly considering the impact of the newly introduced brain magnetic resonance imaging (MRI) markers. METHODS: Diagnostic accuracy of the clinical diagnostic criteria for multiple system atrophy was estimated retrospectively in autopsy-confirmed patients with multiple system atrophy, Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. RESULTS: We identified a total of 240 patients. Sensitivity of the clinically probable criteria was moderate at symptom onset but improved with disease duration (year 1: 9%, year 3: 39%, final ante mortem record: 77%), whereas their specificity remained consistently high (99%-100% throughout). Sensitivity of the clinically established criteria was low during the first 3 years (1%-9%), with mild improvement at the final ante mortem record (22%), whereas specificity remained high (99%-100% throughout). When MRI features were excluded from the clinically established criteria, their sensitivity increased considerably (year 1: 3%, year 3: 22%, final ante mortem record: 48%), and their specificity was not compromised (99%-100% throughout). CONCLUSIONS: The International Parkinson and Movement Disorder Society multiple system atrophy diagnostic criteria showed consistently high specificity and low to moderate sensitivity throughout the disease course. The MRI markers for the clinically established criteria reduced their sensitivity without improving specificity. Combining clinically probable and clinically established criteria, but disregarding MRI features, yielded the best sensitivity with excellent specificity and may be most appropriate to select patients for therapeutic trials. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
RESUMEN
Tremor, whether arising from neurological diseases, other conditions, or medication side effects, significantly impacts patients' lives. Treatment complexities necessitate clear algorithms and strategies. Levodopa remains pivotal for Parkinson's tremor, though response variability exists. Some dopamine agonists offer notable tremor reduction targeting D2 receptors. Propranolol effectively manages essential tremor and essential tremor plus (ET/ET +), sometimes with primidone for added benefits, albeit dose-dependent side effects. As reserve medications anticholinergics and clozapine are used for treatment of parkinsonian tremor, 1-Octanol and certain anticonvulsant drugs for tremor of other orign, especially ET. Therapies such as invasive deep brain stimulation and lesional focused ultrasound serve for resistant cases. A medication review is crucial for all forms of tremor, but it is particularly important if medication may have triggered the tremor. Sensor-based detection and non-drug interventions like wristbands and physical therapy broaden diagnostic and therapeutic horizons, promising future tremor care enhancements. Understanding treatment nuances is a key for tailored tremor management respecting patient needs and tolerability. Successful strategies integrate pharmacological, non-invasive, and technological modalities, aiming for optimal symptom control and improved quality of life.
RESUMEN
Essential tremor (ET) is the most common adult-onset movement disorder. In the present study, we performed whole exome sequencing of a large ET-affected family (10 affected and 6 un-affected family members) and identified a TUB p.V431I variant (rs75594955) segregating in a manner consistent with autosomal-dominant inheritance. Subsequent targeted re-sequencing of TUB in 820 unrelated individuals with sporadic ET and 630 controls revealed significant enrichment of rare nonsynonymous TUB variants (e.g. rs75594955: p.V431I, rs1241709665: p.Ile20Phe, rs55648406: p.Arg49Gln) in the ET cohort (SKAT-O test p-value = 6.20e-08). TUB encodes a transcription factor predominantly expressed in neuronal cells and has been previously implicated in obesity. ChIP-seq analyses of the TUB transcription factor across different regions of the mouse brain revealed that TUB regulates the pathways responsible for neurotransmitter production as well thyroid hormone signaling. Together, these results support the association of rare variants in TUB with ET.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Temblor Esencial/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Anciano , Anciano de 80 o más Años , Animales , Secuenciación de Inmunoprecipitación de Cromatina/métodos , Estudios de Cohortes , Exoma/genética , Familia , Femenino , Humanos , Masculino , Ratones Endogámicos C57BL , Persona de Mediana Edad , Linaje , Polimorfismo de Nucleótido Simple/genética , Factores de Transcripción/genética , Secuenciación del Exoma/métodosRESUMEN
BACKGROUND: Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome-wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease. OBJECTIVE: Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied only autopsy-confirmed cases. METHODS: We studied common genetic variations in Multiple System Atrophy cases (N = 731) and controls (N = 2898). RESULTS: The most strongly disease-associated markers were rs16859966 on chromosome 3, rs7013955 on chromosome 8, and rs116607983 on chromosome 4 with P-values below 5 × 10-6 , all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms. The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4). INTERPRETATION: Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4-immunoreactive neurons were significantly reduced inpatients with olivopontocerebellar atrophy. These findings point to a potential ZIC4-mediated vulnerability of neurons in Multiple System Atrophy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Asunto(s)
Atrofia de Múltiples Sistemas , Atrofias Olivopontocerebelosas , Degeneración Estriatonigral , Autoanticuerpos , Autopsia , Estudio de Asociación del Genoma Completo , Humanos , Atrofia de Múltiples Sistemas/genética , Atrofia de Múltiples Sistemas/patología , Proteínas del Tejido Nervioso/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , alfa-Sinucleína/metabolismoRESUMEN
Ataxia telangiectasia is a rare autosomal recessive multisystem disorder caused by mutations in the gene of ATM serine/threonine kinase. It is characterized by neurodegeneration, leading to severe ataxia, immunodeficiency, increased cancer susceptibility, and telangiectasia. Here, we discovered a co-segregation of two ATM gene variants with ataxia telangiectasia in an Egyptian family. While one of these variants (NM_000051.4(ATM_i001):p.(Val128*)) has previously been reported as pathogenic, the other one (NM_000051.4(ATM_i001):p.(Val1729Leu)) is regarded as a variant of uncertain significance. Our findings in this family provide additional evidence for causality of the second variant and argue that its status should be changed to pathogenic.
Asunto(s)
Ataxia Telangiectasia/genética , Mutación Missense , Mutación Puntual , Causalidad , Egipto , Femenino , Genotipo , Humanos , Masculino , Linaje , Fenotipo , Secuenciación del Exoma , alfa-Fetoproteínas/genéticaRESUMEN
BACKGROUND: Parkinson's disease is characterized by intraneuronal α-synuclein aggregation. Currently there is no α-synuclein-based blood test in clinical practice. OBJECTIVES: Our aim was to assess by means of further testing and analysis whether α-synuclein measurements in serum L1CAM-immunocaptured exosomes can differentiate Parkinson's disease from related movement disorders. METHODS: We used poly(carboxybetaine-methacrylate)-coated magnetic beads to isolate L1CAM-positive exosomes and triplexed electrochemiluminescence to measure exosomal α-synuclein, clusterin, and syntenin-1 from 267 serum samples. Combined analysis of our current and previously published data from the Oxford, Kiel, Brescia, and PROSPECT cohorts consisting of individuals (total n = 735) with Parkinson's disease (n = 290), multiple system atrophy (MSA, n = 50), progressive supranuclear palsy (n = 116), corticobasal syndrome (n = 88), and healthy controls (n = 191) was done using 2-stage (training vs validation) receiver operating characteristic analysis. RESULTS: We established that α-synuclein level in L1CAM-immunocaptured exosomes above 14 pg/mL is a robust biomarker across cohorts that distinguishes Parkinson's disease from MSA (AUC, 0.90 vs 0.98) or 4-repeat tauopathies (AUC, 0.93 vs 0.94). We confirmed that exosomal clusterin is elevated in subjects with 4-repeat tauopathy, and when combined with α-synuclein, it improved the performance of the assay in differentiating Parkinson's disease from 4-repeat tauopathies to AUC, 0.98 versus 0.99. Correction for the generic exosomal protein syntenin-1 did not consistently improve the performance of the assay. CONCLUSIONS: α-Synuclein and clusterin in L1CAM-immunocaptured serum exosomes is a validated blood test for the molecular stratification of neuronal α-synucleinopathy (ie, Lewy body pathology) versus phenotypically related neurodegenerative movement disorders. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Asunto(s)
Exosomas , Molécula L1 de Adhesión de Célula Nerviosa , Trastornos Parkinsonianos , Biomarcadores , Exosomas/metabolismo , Humanos , Molécula L1 de Adhesión de Célula Nerviosa/metabolismo , Trastornos Parkinsonianos/metabolismo , alfa-Sinucleína/metabolismoRESUMEN
OBJECTIVE: Parkinson's disease is characterised neuropathologically by α-synuclein aggregation. Currently, there is no blood test to predict the underlying pathology or distinguish Parkinson's from atypical parkinsonian syndromes. We assessed the clinical utility of serum neuronal exosomes as biomarkers across the spectrum of Parkinson's disease, multiple system atrophy and other proteinopathies. METHODS: We performed a cross-sectional study of 664 serum samples from the Oxford, Kiel and Brescia cohorts consisting of individuals with rapid eye movement sleep behavioural disorder, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, frontotemporal dementia, progressive supranuclear palsy, corticobasal syndrome and controls. Longitudinal samples were analysed from Parkinson's and control individuals. We developed poly(carboxybetaine-methacrylate) coated beads to isolate L1 cell adhesion molecule (L1CAM)-positive extracellular vesicles with characteristics of exosomes and used mass spectrometry or multiplexed electrochemiluminescence to measure exosomal proteins. RESULTS: Mean neuron-derived exosomal α-synuclein was increased by twofold in prodromal and clinical Parkinson's disease when compared with multiple system atrophy, controls or other neurodegenerative diseases. With 314 subjects in the training group and 105 in the validation group, exosomal α-synuclein exhibited a consistent performance (AUC=0.86) in separating clinical Parkinson's disease from controls across populations. Exosomal clusterin was elevated in subjects with non-α-synuclein proteinopathies. Combined neuron-derived exosomal α-synuclein and clusterin measurement predicted Parkinson's disease from other proteinopathies with AUC=0.98 and from multiple system atrophy with AUC=0.94. Longitudinal sample analysis showed that exosomal α-synuclein remains stably elevated with Parkinson's disease progression. CONCLUSIONS: Increased α-synuclein egress in serum neuronal exosomes precedes the diagnosis of Parkinson's disease, persists with disease progression and in combination with clusterin predicts and differentiates Parkinson's disease from atypical parkinsonism.
Asunto(s)
Exosomas/metabolismo , Atrofia de Múltiples Sistemas/diagnóstico , Neuronas/metabolismo , Enfermedad de Parkinson/diagnóstico , Trastornos Parkinsonianos/diagnóstico , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Estudios Transversales , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Atrofia de Múltiples Sistemas/sangre , Enfermedad de Parkinson/sangre , Trastornos Parkinsonianos/sangreRESUMEN
INTRODUCTION: The genetic factors and molecular mechanisms predisposing to essential tremor (ET) remains largely unknown. OBJECTIVE: The objective of this study was to identify pathways and genes relevant to ET by integrating multiomics approaches. METHODS: Case-control RNA sequencing of 2 cerebellar regions was done for 64 samples. A phenome-wide association study (pheWAS) of the differentially expressed genes was conducted, and a genome-wide gene association study (GWGAS) was done to identify pathways overlapping with the transcriptomic data. Finally, a transcriptome-wide association study (TWAS) was done to identify novel risk genes for ET. RESULTS: We identified several novel dysregulated genes, including CACNA1A and SHF. Pathways including axon guidance, olfactory loss, and calcium channel activity were significantly enriched. The ET GWGAS data found calcium ion-regulated exocytosis of neurotransmitters to be significantly enriched. The TWAS also found calcium and olfactory pathways enriched. The pheWAS identified that the underexpressed differentially expressed gene, SHF, is associated with a blood pressure medication (P = 9.3E-08), which is used to reduce tremor in ET patients. Treatment of cerebellar DAOY cells with the ET drug propranolol identified increases in SHF when treated, suggesting it may rescue the underexpression. CONCLUSION: We found that calcium-related pathways were enriched across the GWGAS, TWAS, and transcriptome. SHF was shown to have significantly decreased expression, and the pheWAS showed it was associated with blood pressure medication. The treatment of cells with propranolol showed that the drug restored levels of SHF. Overall, our findings highlight the power of integrating multiple different approaches to prioritize ET pathways and genes. © 2020 International Parkinson and Movement Disorder Society.
Asunto(s)
Temblor Esencial , Estudios de Casos y Controles , Temblor Esencial/tratamiento farmacológico , Temblor Esencial/genética , Estudio de Asociación del Genoma Completo , Humanos , TranscriptomaRESUMEN
OBJECTIVE: Impaired lysosomal degradation of α-synuclein and other cellular constituents may play an important role in Parkinson's disease (PD). Rare genetic variants in the glucocerebrosidase (GBA) gene were consistently associated with PD. Here we examine the association between rare variants in lysosomal candidate genes and PD. METHODS: We investigated the association between PD and rare genetic variants in 23 lysosomal candidate genes in 4096 patients with PD and an equal number of controls using pooled targeted next-generation DNA sequencing. Genewise association of rare variants in cases or controls was analyzed using the optimized sequence kernel association test with Bonferroni correction for the 23 tested genes. RESULTS: We confirm the association of rare variants in GBA with PD and report novel associations for rare variants in ATP13A2, LAMP1, TMEM175, and VPS13C. CONCLUSION: Rare variants in selected lysosomal genes, first and foremost GBA, are associated with PD. Rare variants in ATP13A2 and VPC13C previously linked to monogenic PD and more common variants in TMEM175 and VPS13C previously linked to sporadic PD in genome-wide association studies are associated with PD. © 2020 International Parkinson and Movement Disorder Society.
Asunto(s)
Enfermedad de Parkinson , Estudio de Asociación del Genoma Completo , Glucosilceramidasa/genética , Humanos , Lisosomas , Mutación , Enfermedad de Parkinson/genéticaRESUMEN
Despite intensive effort, biomarker research for the detection of prodromal stage, diagnosis and progression of Parkinson's disease (PD) falls short of expectations. This article reviews the attempts in the last 20 years to find a biomarker, addresses challenges along the biomarker search and suggests the steps that should be taken to overcome these challenges. Although several biomarkers are currently available, none of them is specific enough for diagnosis, prediction of future PD or disease progression. The main reason for the failure finding a strong biomarker seems to be drastic heterogeneity of PD, which exhibits itself in all domains; from the clinic to pathophysiology or genetics. The diversity in patient selection, assessment methods or outcomes in biomarker studies also limit the interpretation and generalizability of the data. In search of a reliable biomarker, consideration of novel approaches encompassing individual demographic, clinical, genetic, epigenetic and environmental differences, employment of strategies enabling marker combinations, designing multicenter studies with compatible assessment methods, integration of data from preclinical domains and utilization of novel technology-based assessments are necessary.
Asunto(s)
Biomarcadores , Enfermedad de Parkinson/diagnóstico , HumanosRESUMEN
We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quantitative trait loci database mining showed association between the protective minor allele of rs10937625 and reduced expression in cerebellar cortex. We found no expression differences related to disease status or marker genotype for the other two genes. Replication of two lead single nucleotide polymorphisms of previous small genome-wide association studies (rs3794087 in SLC1A2, rs9652490 in LINGO1) did not confirm the association with essential tremor.
Asunto(s)
Temblor Esencial/genética , Estudio de Asociación del Genoma Completo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Proteínas Serina-Treonina Quinasas/genética , alfa Catenina/genética , Humanos , Polimorfismo de Nucleótido SimpleRESUMEN
OBJECTIVE: Essential tremor is a very common disease defined by sparse clinical criteria. It is unlikely that essential tremor is an etiologically homogeneous disease. Stratifying broadly defined diseases using clinical characteristics has often aided the etiopathological understanding. Most studies of essential tremor show 2 distinct age at onset peaks: early and late. This study investigates phenotypical differences between early- and late-onset essential tremor patients. METHODS: We studied a sample of 1137 tremor patients. Of these patients, 978 suffered from definite or probable essential tremor. All of the patients underwent the same standardized examination encompassing, among other items, drawing of the Archimedes spiral and assessment of the Fahn-Tolosa-Marin scale. RESULTS: Two subgroups of early-onset (≤ 24 years of age, n = 317) and late-onset (≥ 46 years of age, n = 356) patients were selected based on the visual and mathematical analysis of the age-at-onset distribution. Tremor severity in both groups was comparable. Tremor progression measured as Archimedes spiral score and the Fahn-Tolosa-Marin subscales divided by the disease duration in 10-year bins was significantly faster in late-onset patients when compared with early-onset patients. Early-onset patients more frequently reported a positive family history and alcohol sensitivity of the tremor. CONCLUSIONS: The age-at-onset distribution suggests a distinction between early- and late-onset tremor. Early-onset and late-onset essential tremor differ in the progression rates and the frequencies of a positive family history and history of a positive effect of alcohol on tremor. © 2016 International Parkinson and Movement Disorder Society.
Asunto(s)
Progresión de la Enfermedad , Temblor Esencial/fisiopatología , Adolescente , Adulto , Edad de Inicio , Anciano , Temblor Esencial/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
OBJECTIVE: To explore the clinimetric attributes of the German version of the quality of life in essential tremor (ET) questionnaire (QUEST) as a tremor-specific measure of quality of life. METHODS: This was an observational, cross-sectional study. The QUEST German version was obtained by translation-back translation procedure. ET cases were diagnosed according to the tremor investigation group criteria. Assessments included Archimedes spirals rating, EQ-5D, Beck Depression Inventory (BDI-II) and QUEST German version. Missing data were imputed for those cases in which the loss of data for one domain of the QUEST was <30%. RESULTS: Ninety three patients out of 138 (67.4%) with definite or probable ET had complete QUEST data after 43 item imputations and they constituted the sample for this study. The QUEST summary index (QSI) displayed no floor or ceiling effects. QUEST internal consistency (Cronbach's alpha) ranged between 0.50 and 0.89. Item-total domain correlations ranged from 0.26 to 0.82 and the item homogeneity indexes were satisfactory (range: 0.28-0.60). The QSI correlated weakly with the EQ-5D (rS=0.20) and moderately with the BDI-II (rS = 0.31) and the QUEST self-evaluation of tremor severity (rS = 0.44). CONCLUSIONS: The QUEST German version has, despite recognized data quality problems, satisfactory acceptability and internal consistency as a whole. The correlation analysis showed that tremor in the head, voice and right hand was moderately associated with quality of life.
Asunto(s)
Temblor Esencial/psicología , Calidad de Vida/psicología , Encuestas y Cuestionarios , Adolescente , Adulto , Niño , Preescolar , Estudios Transversales , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Escalas de Valoración Psiquiátrica , Psicometría , Análisis de Regresión , Reproducibilidad de los Resultados , Traducción , Adulto JovenRESUMEN
OBJECTIVE: We analyzed the coding region of the Fused in Sarcoma (FUS) gene in familial essential tremor (ET) and reviewed previous studies assessing FUS variants in ET. BACKGROUND: ET is often a familial disorder with an autosomal dominant inheritance pattern. A potentially causative variant in FUS has been identified in one ET family. Subsequent studies described further putatively causal variants. METHODS: We performed DNA sequencing of FUS in 85 unrelated, familial German and French definite ET patients. RESULTS: We did not find novel variants affecting the protein sequence. Seven previously published studies and data from the exome variant server (EVS) showed that rare exonic variants in FUS are not more frequent in ET than in the general population. CONCLUSIONS: Our findings provide no evidence for a role of rare genetic variants in the pathogenesis of ET, apart from the initially published FUS mutation segregating in a large ET family.
Asunto(s)
Temblor Esencial/genética , Mutación/genética , Proteína FUS de Unión a ARN/genética , Adulto , Anciano , Anciano de 80 o más Años , Análisis Mutacional de ADN , Bases de Datos Bibliográficas/estadística & datos numéricos , Femenino , Francia , Alemania , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Importance: The chromosome 17q21.31 region, containing a 900 Kb inversion that defines H1 and H2 haplotypes, represents the strongest genetic risk locus in progressive supranuclear palsy (PSP). In addition to H1 and H2, various structural forms of 17q21.31, characterized by the copy number of α, ß, and γ duplications, have been identified. However, the specific effect of each structural form on the risk of PSP has never been evaluated in a large cohort study. Objective: To assess the association of different structural forms of 17q.21.31, defined by the copy numbers of α, ß, and γ duplications, with the risk of PSP and MAPT sub-haplotypes. Design setting and participants: Utilizing whole genome sequencing data of 1,684 (1,386 autopsy confirmed) individuals with PSP and 2,392 control subjects, a case-control study was conducted to investigate the association of copy numbers of α, ß, and γ duplications and structural forms of 17q21.31 with the risk of PSP. All study subjects were selected from the Alzheimer's Disease Sequencing Project (ADSP) Umbrella NG00067.v7. Data were analyzed between March 2022 and November 2023. Main outcomes and measures: The main outcomes were the risk (odds ratios [ORs]) for PSP with 95% CIs. Risks for PSP were evaluated by logistic regression models. Results: The copy numbers of α and ß were associated with the risk of PSP only due to their correlation with H1 and H2, while the copy number of γ was independently associated with the increased risk of PSP. Each additional duplication of γ was associated with 1.10 (95% CI, 1.04-1.17; P = 0.0018) fold of increased risk of PSP when conditioning H1 and H2. For the H1 haplotype, addition γ duplications displayed a higher odds ratio for PSP: the odds ratio increases from 1.21 (95%CI 1.10-1.33, P = 5.47 × 10-5) for H1ß1γ1 to 1.29 (95%CI 1.16-1.43, P = 1.35 × 10-6) for H1ß1γ2, 1.45 (95%CI 1.27-1.65, P = 3.94 × 10-8) for H1ß1γ3, and 1.57 (95%CI 1.10-2.26, P = 1.35 × 10-2) for H1ß1γ4. Moreover, H1ß1γ3 is in linkage disequilibrium with H1c (R2 = 0.31), a widely recognized MAPT sub-haplotype associated with increased risk of PSP. The proportion of MAPT sub-haplotypes associated with increased risk of PSP (i.e., H1c, H1d, H1g, H1o, and H1h) increased from 34% in H1ß1γ1 to 77% in H1ß1γ4. Conclusions and relevance: This study revealed that the copy number of γ was associated with the risk of PSP independently from H1 and H2. The H1 haplotype with more γ duplications showed a higher odds ratio for PSP and were associated with MAPT sub-haplotypes with increased risk of PSP. These findings expand our understanding of how the complex structure at 17q21.31 affect the risk of PSP.
RESUMEN
BACKGROUND: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs). METHOD: In this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed. RESULTS: Our analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer's disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73 × 10-3) in PSP. CONCLUSIONS: Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.
Asunto(s)
Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Parálisis Supranuclear Progresiva , Secuenciación Completa del Genoma , Humanos , Parálisis Supranuclear Progresiva/genética , Predisposición Genética a la Enfermedad/genética , Masculino , Femenino , Anciano , Polimorfismo de Nucleótido Simple/genética , Persona de Mediana Edad , Anciano de 80 o más AñosRESUMEN
Background: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs). Method: In this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed. Results: Our analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer's disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73×10-3) in PSP. Conclusions: Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.