Joint genome-wide association study of progressive supranuclear palsy identifies novel susceptibility loci and genetic correlation to neurodegenerative diseases.
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ABSTRACT:
SUBMITTER: Chen JA
PROVIDER: S-EPMC6083608 | biostudies-literature | 2018 Aug
REPOSITORIES: biostudies-literature
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Joint genome-wide association study of progressive supranuclear palsy identifies novel susceptibility loci and genetic correlation to neurodegenerative diseases.
Chen Jason A JA Chen Zhongbo Z Won Hyejung H Huang Alden Y AY Lowe Jennifer K JK Wojta Kevin K Yokoyama Jennifer S JS Bensimon Gilbert G Leigh P Nigel PN Payan Christine C Shatunov Aleksey A Jones Ashley R AR Lewis Cathryn M CM Deloukas Panagiotis P Amouyel Philippe P Tzourio Christophe C Dartigues Jean-Francois JF Ludolph Albert A Boxer Adam L AL Bronstein Jeff M JM Al-Chalabi Ammar A Geschwind Daniel H DH Coppola Giovanni G
Molecular neurodegeneration 20180808 1
<h4>Background</h4>Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease for which the genetic contribution is incompletely understood.<h4>Methods</h4>We conducted a joint analysis of 5,523,934 imputed SNPs in two newly-genotyped progressive supranuclear palsy cohorts, primarily derived from two clinical trials (Allon davunetide and NNIPPS riluzole trials in PSP) and a previously published genome-wide association study (GWAS), in total comprising 1646 cases and 10,662 controls ...[more]
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Project description:BackgroundProgressive supranuclear palsy (PSP) is a parkinsonian neurodegenerative tauopathy affecting brain regions involved in motor function, including the basal ganglia, diencephalon and brainstem. While PSP is largely considered to be a sporadic disorder, cases with suspected familial inheritance have been identified and the common MAPT H1haplotype is a major genetic risk factor. Due to the relatively low prevalence of PSP, large sample sizes can be difficult to achieve, and this has limited the ability to detect true genetic risk factors at the genome-wide statistical threshold for significance in GWAS data. With this in mind, in this study we genotyped the genetic variants that displayed the strongest degree of association with PSP (P<1E-4) in the previous GWAS in a new cohort of 533 pathologically-confirmed PSP cases and 1172 controls, and performed a combined analysis with the previous GWAS data.ResultsOur findings validate the known association of loci at MAPT, MOBP, EIF2AK3 and STX6 with risk of PSP, and uncover novel associations with SLCO1A2 (rs11568563) and DUSP10 (rs6687758) variants, both of which were classified as non-significant in the original GWAS.ConclusionsResolving the genetic architecture of PSP will provide mechanistic insights and nominate candidate genes and pathways for future therapeutic intervention strategies.
| S-EPMC6038352 | biostudies-literature
Project description:Progressive supranuclear palsy is characterised pathologically by the deposition of neurofibrillary tangles consisting of tau protein. Patients with the disease have been reported to have a more frequent occurrence of one allele of an intronic polymorphism of the tau gene. Other diseases which may involve tau deposition include frontotemporal dementia and corticobasal degeneration. This polymorphism has been studied in a series of subjects with progressive supranuclear palsy, corticobasal degeneration, frontotemporal dementia, idiopathic Parkinson's disease, and normal controls to (1) confirm this association in a large series and (2) to investigate a possible role for this association in other disorders which involve tau deposition. The results confirm the finding of an overrepresentation of the A0 allele and the A0/A0 genotype in patients with progressive supranuclear palsy, in the largest series reported to date. The A0 allele was found in 91% of patients with progressive supranuclear palsy as opposed to 73% of controls (p<0.001) and the A0/A0 genotype was seen in 84% of patients as compared with 53% of controls (p<0.01). There was no significant difference between patients with Parkinson's disease, frontotemporal dementia, or corticobasal degeneration, and controls. The A0 allele may have a direct effect on tau isoform expression in progressive supranuclear palsy or it may be in linkage disequilibrium with an adjacent determinant of tau gene expression. The explanation for this difference between a predisposition factor to progressive supranuclear palsy and the other conditions may lie in the molecular pathology of these diseases.
| S-EPMC1736363 | biostudies-other
Project description:BackgroundProgressive 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).MethodIn 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.ResultsOur 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.ConclusionsThrough WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.
| S-EPMC10793533 | biostudies-literature
Project description:BackgroundWe aimed to produce a detailed neuropathological analysis of pyramidal motor system pathology and provide its clinical pathological correlation in cases with definite progressive supranuclear palsy (PSP).MethodsPyramidal motor system pathologies were analyzed in 18 cases with neuropathologically confirmed PSP. Based on a retrospective clinical analysis, cases were subtyped according to Movement Disorder Society criteria for clinical diagnosis of PSP as probable, possible or suggestive of PSP with Richardson's syndrome (n = 10), PSP with predominant corticobasal syndrome (n = 3), PSP with predominant parkinsonism (n = 3), PSP with predominant speech/language disorder (n = 1), and PSP with progressive gait freezing (n = 1). Clinical manifestations of motor neuron involvement (pseudobulbar or bulbar signs and spasticity) were retrospectively assessed semiquantitatively. Neuropathologically, hyperphosphorylated tau-related pyramidal motor system neuronal, neuritic, and glial pathology using anti-tau AT8 clone immunohistochemistry, was also evaluated.ResultsClinical manifestations of pyramidal motor system involvement were found in patients with different PSP subtypes. A statistically significant higher load of tau pathology was found in the pyramidal system in PSP-Richardson's syndrome compared to other PSP subtypes (p = 0.016); however, there was no significant correlation between pyramidal system tau pathology and related motor clinical symptoms.ConclusionsTau pathology in the spinal cord and pyramidal motor system structures is very common in progressive supranuclear palsy and may neuropathologically supplement the distinction between classic Richardson's syndrome from other progressive supranuclear palsy subtypes.
| S-EPMC6425568 | biostudies-literature
Project description:To determine the effects of single nucleotide polymorphisms (SNPs) identified in a genome-wide association study of progressive supranuclear palsy (PSP), we tested their association with brain gene expression, CpG methylation and neuropathology. In 175 autopsied PSP subjects, we performed associations between seven PSP risk variants and temporal cortex levels of 20 genes in-cis, within ±100 kb. Methylation measures were collected using reduced representation bisulfite sequencing in 43 PSP brains. To determine whether SNP/expression associations are due to epigenetic modifications, CpG methylation levels of associated genes were tested against relevant variants. Quantitative neuropathology endophenotypes were tested for SNP associations in 422 PSP subjects. Brain levels of LRRC37A4 and ARL17B were associated with rs8070723; MOBP with rs1768208 and both ARL17A and ARL17B with rs242557. Expression associations for LRRC37A4 and MOBP were available in an additional 100 PSP subjects. Meta-analysis revealed highly significant associations for PSP risk alleles of rs8070723 and rs1768208 with higher LRRC37A4 and MOBP brain levels, respectively. Methylation levels of one CpG in the 3' region of ARL17B associated with rs242557 and rs8070723. Additionally, methylation levels of an intronic ARL17A CpG associated with rs242557 and that of an intronic MOBP CpG with rs1768208. MAPT and MOBP region risk alleles also associated with higher levels of neuropathology. Strongest associations were observed for rs242557/coiled bodies and tufted astrocytes; and for rs1768208/coiled bodies and tau threads. These findings suggest that PSP variants at MAPT and MOBP loci may confer PSP risk via influencing gene expression and tau neuropathology. MOBP, LRRC37A4, ARL17A and ARL17B warrant further assessment as candidate PSP risk genes. Our findings have implications for the mechanism of action of variants at some of the top PSP risk loci.
| S-EPMC4947429 | biostudies-literature
Project description:IntroductionThere is growing interest in using patient-reported outcomes as end points in clinical trials, such as the progressive supranuclear palsy quality of life (PSP-QoL) scale. However, this tool has not been widely validated and its correlation with validated motor scales has not been explored. To evaluate the potential utility of using PSP-QoL as an outcome, it is important to examine its relationship with a standard scale used to evaluate neurologic parameters, such as the PSP Rating Scale.MethodsPSP-QoL and PSP Rating Scale scores were gathered from 60 clinically diagnosed PSP patients, including patients with Richardson syndrome PSP (PSP-RS, n = 43) and those with non-RS PSP variants (n = 17). Linear regression analysis adjusted for age, sex, and disease duration was used to evaluate the cross-sectional relationship between the total and subscale scores of the 2 instruments.ResultsAmong 60 PSP patients, there was a significant correlation between total PSP-QoL and PSP Rating Scale scores. The physical and mentation subscales of each instrument also demonstrated significant correlations. Comparisons among PSP subtypes indicated that worsening PSP-QoL Total and Physical subscale scores correlated with worsening PSP Rating Scale gait subscale scores more strongly for the non-RS PSP variants than for PSP-RS.DiscussionThere is a significant association between the total scores and many of the subscale scores of the PSP-QoL and the PSP Rating Scale. Additionally, the relationship between these measures may differ for PSP-RS and non-RS variants. These findings suggest that the PSP-QoL may be useful in clinical trials as a patient-reported outcome measure. Large prospective multicenter studies utilizing the PSP-QoL are necessary to examine its relationship to disease evolution and changes in the PSP Rating Scale.
| S-EPMC8119324 | biostudies-literature
Project description:Progressive supranuclear palsy (PSP) is a neurodegenerative syndrome that is clinically characterized by progressive postural instability, supranuclear gaze palsy, parkinsonism and cognitive decline. Pathologically, diagnosis of PSP is based on characteristic features, such as neurofibrillary tangles, neutrophil threads, tau-positive astrocytes and their processes in basal ganglia and brainstem, and the accumulation of 4 repeat tau protein. PSP is generally recognized as a sporadic disorder; however, understanding of genetic background of PSP has been expanding rapidly. Here we review relevant publications to outline the genetics of PSP. Although only small number of familial PSP cases have been reported, the recognition of familial PSP has been increasing. In some familial cases of clinically probable PSP, PSP pathologies were confirmed based on NINDS neuropathological diagnostic criteria. Several mutations in MAPT, the gene that causes a form of familial frontotemporal lobar degeneration with tauopathy, have been identified in both sporadic and familial PSP cases. The H1 haplotype of MAPT is a risk haplotype for PSP, and within H1, a sub-haplotype (H1c) is associated with PSP. A recent genome-wide association study on autopsyproven PSP revealed additional PSP risk alleles in STX6 and EIF2AK3. Several heredodegenerative parkinsonian disorders are referred to as PSP-look-alikes because their clinical phenotype, but not their pathology, mimics PSP. Due to the fast development of genomics and bioinformatics, more genetic factors related to PSP are expected to be discovered. Undoubtedly, these studies will provide a better understanding of the pathogenesis of PSP and clues for developing therapeutic strategies.
| S-EPMC4572662 | biostudies-literature
Project description: Not available
| S-EPMC7011663 | biostudies-literature
Project description:Purpose of reviewProgressive supranuclear palsy (PSP) is a progressive adult-onset neurodegenerative disease. Abnormally, phosphorylated forms of the microtubule-associated protein tau containing four repeat domains (4R-tau) aggregate in neurons. Additionally, increasing evidence suggests that secretion and uptake of fragments of abnormal 4R-tau may play a role in disease progression. This extracellular tau is a natural target for immunotherapy.Recent findingsThree monoclonal antibodies targeting extracellular tau are in clinical stages of development. ABBV-8E12 and BIIB092 were safe in Phase 1, but both Phase two studies recently failed futility analyses. UCB0107 recently reported (in abstract form) Phase 1 safety results, and a Phase 2 study is under consideration. Stem cell therapy and the infusion of plasma are also being explored clinically.SummaryThe likely role of extracellular tau in the progression of PSP makes tau a natural target for targeted immunotherapy. Clinical trials are still in early stages, and although tau immunotherapy has largely been shown to be safe, efficacy has yet to be demonstrated.
| S-EPMC7722007 | biostudies-literature
Project description:IntroductionTremor is thought to be a rare feature of progressive supranuclear palsy (PSP).MethodsWe retrospectively reviewed the database of the CurePSP brain bank at Mayo Clinic Florida to retrieve all available clinical information for PSP patients. All patients underwent a standard neuropathological assessment and an immunohistochemical evaluation for tau and α-synuclein. DNA was genotyped for the MAPT H1/H2 haplotype.ResultsOf the 375 PSP patients identified, 344 had a documented presence or absence of tremor, which included 146 (42%) with tremor, including 29 (20%) with postural/action tremors, 16 (11%) with resting tremor, 7 (5%) with intention tremor, 20 (14%) with a combination of different types of tremor, and 74 (51%) patients who had tremor at some point during their illness, but details were unavailable. The tremor severity of 96% of the patients (54/55) who had this data was minimal to mild. The probability of observing a tremor during a neurological examination during the patient's illness was estimated to be ∼22%. PSP patients with postural/action tremors and PSP patients with resting tremor responded to carbidopa-levodopa therapy more frequently than PSP patients without tremor, although the therapy response was always transient. There were no significant differences in pathological findings between the tremor groups.ConclusionsTremor is an inconspicuous feature of PSP; however, 42% (146/344) of the PSP patients in our study presented some form of tremor. Because there is no curative therapy for PSP, carbidopa/levodopa therapy should be tried for patients with postural, action, and resting tremor.
| S-EPMC4887294 | biostudies-literature