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Parkinson's disease (PD) is a common neurodegenerative disorder with a significant risk proportion driven by genetics. While much progress has been made, most of the heritability remains unknown. This is in-part because previous genetic studies have focused on the contribution of single nucleotide variants. More complex forms of variation, such as structural variants and tandem repeats, are already associated with several synucleinopathies. However, because more sophisticated sequencing methods are usually required to detect these regions, little is understood regarding their contribution to PD. One example is a polymorphic CT-rich region in intron 4 of the SNCA gene. This haplotype has been suggested to be associated with risk of Lewy Body (LB) pathology in Alzheimer's Disease and SNCA gene expression, but is yet to be investigated in PD. Here, we attempt to resolve this CT-rich haplotype and investigate its role in PD. We performed targeted PacBio HiFi sequencing of the region in 1375 PD cases and 959 controls. We replicate the previously reported associations and a novel association between two PD risk SNVs (rs356182 and rs5019538) and haplotype 4, the largest haplotype. Through quantitative trait locus analyzes we identify a significant haplotype 4 association with alternative CAGE transcriptional start site usage, not leading to significant differential SNCA gene expression in post-mortem frontal cortex brain tissue. Therefore, disease association in this locus might not be biologically driven by this CT-rich repeat region. Our data demonstrates the complexity of this SNCA region and highlights that further follow up functional studies are warranted.
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A biallelic (AAGGG) expansion in the poly(A) tail of an AluSx3 transposable element within the gene RFC1 is a frequent cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS), and more recently, has been reported as a rare cause of Parkinson's disease (PD) in the Finnish population. Here, we investigate the prevalence of RFC1 (AAGGG) expansions in PD patients of non-Finnish European ancestry in 1609 individuals from the Parkinson's Progression Markers Initiative study. We identified four PD patients carrying the biallelic RFC1 (AAGGG) expansion and did not identify any carriers in controls.
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Sex influences the prevalence and symptoms of Lewy body dementia (LBD). However, genome-wide association studies typically focus on autosomal variants and exclude sex-specific risk factors. We addressed this gap by performing an X chromosome-wide association study using whole-genome sequence data from 2591 LBD cases and 4391 controls. We identified a significant risk locus within intron 1 of MAP3K15 (rs141773145, odds ratio = 2.42, 95% confidence interval = 1.65-3.56, p-value = 7.0 × 10-6) in female LBD cases conditioned for APOE ε4 dosage. The locus includes an enhancer region that regulates MAP3K15 expression in ganglionic eminence cells derived from primary cultured neurospheres. Rare variant burden testing showed differential enrichment of missense mutations in TEX13A in female LBD cases, that did not reach significance (p-value = 1.34 × 10-4). These findings support the sex-specific effects of genetic factors and a potential role of Alzheimer's-related risk for females with LBD.
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INTRODUCTION: Musculoskeletal injuries (MSKIs) are common during military and other occupational physical training programmes, and employers have a duty of care to mitigate this injury risk. MSKIs account for a high number of working days lost during initial military training, contribute to training attrition and impact training costs. Poorer movement quality may be associated with increased MSKI risk. METHODS: The present study evaluated the relationship between the Functional Movement Screen (FMS) Score, as a measure of movement quality, and injury risk in Royal Navy (RN) recruits. A cohort of 957 recruits was assessed using the FMS prior to the 10-week phase I training programme. Injury occurrence, time, type and severity were recorded prospectively during the training period. RESULTS: Total FMS Score was associated with injury risk (p≤0.001), where recruits scoring ≥13 were 2.6 times more likely to sustain an injury during training. However, FMS Score accounted for only 10% of the variance in injury risk (R2=0.1). Sex was the only additional variable to significantly affect the regression model. Mean FMS Scores for men (14.6±2.3) and women (14.4±2.4) were similar, but injury occurrence in women was 1.7 times greater than in men. Examining the influence of individual FMS movement tests on injury prediction did not improve the model, where those movements that significantly contributed to injury prediction only accounted for a small amount of the variance (R2=0.01). CONCLUSION: There was a weak relationship between FMS and injury risk in RN recruits. Evidence is provided that FMS score alone would not be appropriate to use as an injury prediction tool in military recruits.
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BACKGROUND: Parkin RBR E3 ubiquitin-protein ligase (PRKN) mutations are the most common cause of young onset and autosomal recessive Parkinson's disease (PD). PRKN is located in FRA6E, which is one of the common fragile sites in the human genome, making this region prone to structural variants. However, complex structural variants such as inversions of PRKN are seldom reported, suggesting that there are potentially unrevealed complex pathogenic PRKN structural variants. OBJECTIVES: To identify complex structural variants in PRKN using long-read sequencing. METHODS: We investigated the genetic cause of monozygotic twins presenting with a young onset dystonia-parkinsonism using targeted sequencing, whole exome sequencing, multiple ligation probe amplification, and long-read sequencing. We assessed the presence and frequency of complex inversions overlapping PRKN using whole-genome sequencing data of Accelerating Medicines Partnership Parkinson's disease (AMP-PD) and United Kingdom (UK)-Biobank datasets. RESULTS: Multiple ligation probe amplification identified a heterozygous exon three deletion in PRKN and long-read sequencing identified a large novel inversion spanning over 7 Mb, including a large part of the coding DNA sequence of PRKN. We could diagnose the affected subjects as compound heterozygous carriers of PRKN. We analyzed whole genome sequencing data of 43,538 participants of the UK-Biobank and 4941 participants of the AMP-PD datasets. Nine inversions in the UK-Biobank and two in AMP PD were identified and were considered potentially damaging and likely to affect PRKN expression. CONCLUSIONS: This is the first report describing a large 7 Mb inversion involving breakpoints outside of PRKN. This study highlights the importance of using long-read sequencing for structural variant analysis in unresolved young-onset PD cases. © 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.
Subject(s)
Parkinson Disease , Parkinsonian Disorders , Humans , Heterozygote , Mutation/genetics , Parkinson Disease/genetics , Parkinsonian Disorders/genetics , Ubiquitin-Protein Ligases/geneticsABSTRACT
Background: PRKN mutations are the most common cause of young onset and autosomal recessive Parkinson's disease (PD). PRKN is located in FRA6E which is one of the common fragile sites in the human genome, making this region prone to structural variants. However, complex structural variants such as inversions of PRKN are seldom reported, suggesting that there are potentially unrevealed complex pathogenic PRKN structural variants. Objectives: To identify complex structural variants in PRKN using long-read sequencing. Methods: We investigated the genetic cause of monozygotic twins presenting with a young onset dystonia-parkinsonism using targeted sequencing, whole exome sequencing, multiple ligation probe amplification, and long-read. We assessed the presence and frequency of complex inversions overlapping PRKN using whole-genome sequencing data of AMP-PD and UK-Biobank datasets. Results: Multiple ligation probe amplification identified a heterozygous exon 3 deletion in PRKN and long-read sequencing identified a large novel inversion spanning over 7Mb, including a large part of the coding DNA sequence of PRKN. We could diagnose the affected subjects as compound heterozygous carriers of PRKN. We analyzed whole genome sequencing data of 43,538 participants of the UK-Biobank and 4,941 participants of the AMP-PD datasets. Nine inversions in the UK-Biobank and two in AMP PD were identified and were considered potentially damaging and likely to affect PRKN isoforms. Conclusions: This is the first report describing a large 7Mb inversion involving breakpoints outside of PRKN. This study highlights the importance of using long-read whole genome sequencing for structural variant analysis in unresolved young-onset PD cases.
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BACKGROUND: In the phase 3 STELLAR trial, sotatercept, an investigational first-in-class activin signalling inhibitor, demonstrated beneficial effects on 6-min walk distance and additional efficacy endpoints in pre-treated participants with pulmonary arterial hypertension (PAH). METHODS: This post hoc analysis evaluated data from right heart catheterisation (RHC) and echocardiography (ECHO) obtained from the STELLAR trial. Changes from baseline in RHC and ECHO parameters were assessed at 24â weeks. An analysis of covariance (ANCOVA) model was used to estimate differences in least squares means with treatment and randomisation stratification (mono/double versus triple therapy; World Health Organization functional class II versus III) as fixed factors, and baseline value as covariate. RESULTS: Relative to placebo, treatment with sotatercept led to significant (all p<0.0001 except where noted) improvements from baseline in mean pulmonary artery (PA) pressure (-13.9â mmHg), pulmonary vascular resistance (-254.8 dyn·s·cm-5), mean right atrial pressure (-2.7â mmHg), mixed venous oxygen saturation (3.84%), PA elastance (-0.42â mmHg·mL-1·beat-1), PA compliance (0.58â mL·mmHg-1), cardiac efficiency (0.48â mL·beat-1·mmHg-1), right ventricular (RV) work (-0.85â g·m) and RV power (-32.70â mmHg·L·min-1). ECHO showed improvements in tricuspid annular plane systolic excursion (TAPSE) to systolic pulmonary artery pressure ratio (0.12â mm·mmHg-1), end-systolic and end-diastolic RV areas (-4.39â cm2 and -5.31â cm2, respectively), tricuspid regurgitation and RV fractional area change (2.04% p<0.050). No significant between-group changes from baseline were seen for TAPSE, heart rate, cardiac output, stroke volume or their indices. CONCLUSION: In pre-treated patients with PAH, sotatercept demonstrated substantial improvements in PA pressures, PA compliance, PA-RV coupling and right heart function.
Subject(s)
Heart , Hemodynamics , Humans , Recombinant Fusion Proteins/therapeutic use , Cardiac Catheterization , Familial Primary Pulmonary HypertensionABSTRACT
Age is a major common risk factor underlying neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Previous studies reported that chronological age correlates with differential gene expression across different brain regions. However, prior datasets have not disambiguated whether expression associations with age are due to changes in cell numbers and/or gene expression per cell. In this study, we leveraged single nucleus RNA-sequencing (snRNAseq) to examine changes in cell proportions and transcriptomes in four different brain regions, each from 12 donors aged 20-30 years (young) or 60-85 years (old). We sampled 155,192 nuclei from two cortical regions (entorhinal cortex and middle temporal gyrus) and two subcortical regions (putamen and subventricular zone) relevant to neurodegenerative diseases or the proliferative niche. We found no changes in cellular composition of different brain regions with healthy aging. Surprisingly, we did find that each brain region has a distinct aging signature, with only minor overlap in differentially associated genes across regions. Moreover, each cell type shows distinct age-associated expression changes, including loss of protein synthesis genes in cortical inhibitory neurons, axonogenesis genes in excitatory neurons and oligodendrocyte precursor cells, enhanced gliosis markers in astrocytes and disease-associated markers in microglia, and genes critical for neuron-glia communication. Importantly, we find cell type-specific enrichments of age associations with genes nominated by Alzheimer's disease and Parkinson's disease genome-wide association studies (GWAS), such as apolipoprotein E (APOE), and leucine-rich repeat kinase 2 (LRRK2) in microglia that are independent of overall expression levels across cell types. We present this data as a new resource which highlights, first, region- and cell type-specific transcriptomic changes in healthy aging that may contribute to selective vulnerability and, second, provide context for testing GWAS-nominated disease risk genes in relevant subtypes and developing more targeted therapeutic strategies. The data is readily accessible without requirement for extensive computational support in a public website, https://brainexp-hykyffa56a-uc.a.run.app/.
ABSTRACT
Parkinson's disease has a large heritable component and genome-wide association studies have identified over 90 variants with disease-associated common variants, providing deeper insights into the disease biology. However, there have not been large-scale rare variant analyses for Parkinson's disease. To address this gap, we investigated the rare genetic component of Parkinson's disease at minor allele frequencies <1%, using whole genome and whole exome sequencing data from 7184 Parkinson's disease cases, 6701 proxy cases and 51 650 healthy controls from the Accelerating Medicines Partnership Parkinson's disease (AMP-PD) initiative, the National Institutes of Health, the UK Biobank and Genentech. We performed burden tests meta-analyses on small indels and single nucleotide protein-altering variants, prioritized based on their predicted functional impact. Our work identified several genes reaching exome-wide significance. Two of these genes, GBA1 and LRRK2, have variants that have been previously implicated as risk factors for Parkinson's disease, with some variants in LRRK2 resulting in monogenic forms of the disease. We identify potential novel risk associations for variants in B3GNT3, AUNIP, ADH5, TUBA1B, OR1G1, CAPN10 and TREML1 but were unable to replicate the observed associations across independent datasets. Of these, B3GNT3 and TREML1 could provide new evidence for the role of neuroinflammation in Parkinson's disease. To date, this is the largest analysis of rare genetic variants in Parkinson's disease.
Subject(s)
Parkinson Disease , Humans , Parkinson Disease/genetics , Genetic Predisposition to Disease/genetics , Genome-Wide Association Study/methods , Risk Factors , Gene Frequency , Receptors, ImmunologicABSTRACT
A plasma spheroidization treatment was applied to stock stainless steel 316L powder for additive manufacturing. The normal and treated powders were compared both in the powder state as well as in the resulting laser powder bed fusion (L-PBF) builds. The plasma spheroidization process slightly increased treated powder aspect ratio and sphericity and shifted the size distribution to larger diameters relative to the normal powder. The normal powder was austenitic in nature whereas the plasma spheroidization process introduced a small fraction (â¼3.5 vol %) of ferrite in the treated powder. Ferrite in the powder was not retained in the printed samples and was not shown to negatively affect the build quality. Porosity areal fraction was generally smaller in the treated powder builds. The normal powder builds had a 6% higher yield strength than treated, however the scatter was significantly larger in the 45° and horizontal orientations compared to the treated powder builds.
ABSTRACT
BACKGROUND: Pulmonary arterial hypertension is a progressive disease involving proliferative remodeling of the pulmonary vessels. Despite therapeutic advances, the disease-associated morbidity and mortality remain high. Sotatercept is a fusion protein that traps activins and growth differentiation factors involved in pulmonary arterial hypertension. METHODS: We conducted a multicenter, double-blind, phase 3 trial in which adults with pulmonary arterial hypertension (World Health Organization [WHO] functional class II or III) who were receiving stable background therapy were randomly assigned in a 1:1 ratio to receive subcutaneous sotatercept (starting dose, 0.3 mg per kilogram of body weight; target dose, 0.7 mg per kilogram) or placebo every 3 weeks. The primary end point was the change from baseline at week 24 in the 6-minute walk distance. Nine secondary end points, tested hierarchically in the following order, were multicomponent improvement, change in pulmonary vascular resistance, change in N-terminal pro-B-type natriuretic peptide level, improvement in WHO functional class, time to death or clinical worsening, French risk score, and changes in the Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT) Physical Impacts, Cardiopulmonary Symptoms, and Cognitive/Emotional Impacts domain scores; all were assessed at week 24 except time to death or clinical worsening, which was assessed when the last patient completed the week 24 visit. RESULTS: A total of 163 patients were assigned to receive sotatercept and 160 to receive placebo. The median change from baseline at week 24 in the 6-minute walk distance was 34.4 m (95% confidence interval [CI], 33.0 to 35.5) in the sotatercept group and 1.0 m (95% CI, -0.3 to 3.5) in the placebo group. The Hodges-Lehmann estimate of the difference between the sotatercept and placebo groups in the change from baseline at week 24 in the 6-minute walk distance was 40.8 m (95% CI, 27.5 to 54.1; P<0.001). The first eight secondary end points were significantly improved with sotatercept as compared with placebo, whereas the PAH-SYMPACT Cognitive/Emotional Impacts domain score was not. Adverse events that occurred more frequently with sotatercept than with placebo included epistaxis, dizziness, telangiectasia, increased hemoglobin levels, thrombocytopenia, and increased blood pressure. CONCLUSIONS: In patients with pulmonary arterial hypertension who were receiving stable background therapy, sotatercept resulted in a greater improvement in exercise capacity (as assessed by the 6-minute walk test) than placebo. (Funded by Acceleron Pharma, a subsidiary of MSD; STELLAR ClinicalTrials.gov number, NCT04576988.).
Subject(s)
Pulmonary Arterial Hypertension , Recombinant Fusion Proteins , Adult , Humans , Double-Blind Method , Hypertension, Pulmonary/drug therapy , Pulmonary Arterial Hypertension/diagnosis , Pulmonary Arterial Hypertension/drug therapy , Recombinant Fusion Proteins/administration & dosage , Recombinant Fusion Proteins/adverse effects , Recombinant Fusion Proteins/pharmacology , Recombinant Fusion Proteins/therapeutic use , Treatment Outcome , Vascular Resistance/drug effects , Injections, Subcutaneous , Walk Test , Exercise Tolerance/drug effects , Cardiovascular Agents/administration & dosage , Cardiovascular Agents/adverse effects , Cardiovascular Agents/pharmacology , Cardiovascular Agents/therapeutic use , Respiratory System Agents/administration & dosage , Respiratory System Agents/adverse effects , Respiratory System Agents/pharmacology , Respiratory System Agents/therapeutic useABSTRACT
AIMS: To develop a suite of quality indicators (QIs) for the evaluation of the care and outcomes for adults with pulmonary arterial hypertension (PAH). METHODS AND RESULTS: We followed the European Society of Cardiology (ESC) methodology for the development of QIs. This included (i) the identification of key domains of care for the management of PAH, (ii) the proposal of candidate QIs following systematic review of the literature, and (iii) the selection of a set of QIs using a modified Delphi method. The process was undertaken in parallel with the writing of the 2022 ESC/European Respiratory Society (ERS) guidelines for the diagnosis and treatment of pulmonary hypertension and involved the Task Force chairs, experts in PAH, Heart Failure Association (HFA) members and patient representatives. We identified five domains of care for patients with PAH: structural framework, diagnosis and risk stratification, initial treatment, follow-up, and outcomes. In total, 23 main and one secondary QIs for PAH were selected. CONCLUSION: This document presents the ESC QIs for PAH, describes their development process and offers scientific rationale for their selection. The indicators may be used to quantify and improve adherence to guideline-recommended clinical practice and improve patient outcomes.
Subject(s)
Cardiology , Heart Failure , Hypertension, Pulmonary , Pulmonary Arterial Hypertension , Humans , Adult , Pulmonary Arterial Hypertension/diagnosis , Quality Indicators, Health Care , Heart Failure/complications , Heart Failure/diagnosis , Heart Failure/therapy , Hypertension, Pulmonary/diagnosis , Hypertension, Pulmonary/therapyABSTRACT
The Foundational Data Initiative for Parkinson Disease (FOUNDIN-PD) is an international collaboration producing fundamental resources for Parkinson disease (PD). FOUNDIN-PD generated a multi-layered molecular dataset in a cohort of induced pluripotent stem cell (iPSC) lines differentiated to dopaminergic (DA) neurons, a major affected cell type in PD. The lines were derived from the Parkinson's Progression Markers Initiative study, which included participants with PD carrying monogenic PD variants, variants with intermediate effects, and variants identified by genome-wide association studies and unaffected individuals. We generated genetic, epigenetic, regulatory, transcriptomic, and longitudinal cellular imaging data from iPSC-derived DA neurons to understand molecular relationships between disease-associated genetic variation and proximate molecular events. These data reveal that iPSC-derived DA neurons provide a valuable cellular context and foundational atlas for modeling PD genetic risk. We have integrated these data into a FOUNDIN-PD data browser as a resource for understanding the molecular pathogenesis of PD.
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CAG repeat expansions in exon 1 of the AR gene on the X chromosome cause spinal and bulbar muscular atrophy, a male-specific progressive neuromuscular disorder associated with a variety of extra-neurological symptoms. The disease has a reported male prevalence of approximately 1:30 000 or less, but the AR repeat expansion frequency is unknown. We established a pipeline, which combines the use of the ExpansionHunter tool and visual validation, to detect AR CAG expansion on whole-genome sequencing data, benchmarked it to fragment PCR sizing, and applied it to 74 277 unrelated individuals from four large cohorts. Our pipeline showed sensitivity of 100% [95% confidence interval (CI) 90.8-100%], specificity of 99% (95% CI 94.2-99.7%), and a positive predictive value of 97.4% (95% CI 84.4-99.6%). We found the mutation frequency to be 1:3182 (95% CI 1:2309-1:4386, n = 117 734) X chromosomes-10 times more frequent than the reported disease prevalence. Modelling using the novel mutation frequency led to estimate disease prevalence of 1:6887 males, more than four times more frequent than the reported disease prevalence. This discrepancy is possibly due to underdiagnosis of this neuromuscular condition, reduced penetrance, and/or pleomorphic clinical manifestations.
Subject(s)
Muscular Atrophy, Spinal , Receptors, Androgen , Humans , Male , Receptors, Androgen/genetics , Muscular Atrophy, Spinal/genetics , Muscular Atrophy , Polymerase Chain Reaction , Trinucleotide Repeat Expansion/geneticsABSTRACT
We identified a knowledge gap in the non-pharmacological and non-surgical management of osteoporotic vertebral fractures. MAIN RESULTS: This international consensus process established multidisciplinary biopsychosocial recommendations on pain, nutrition, safe movement, and exercise for individuals with acute and chronic vertebral fractures. SIGNIFICANCE: These recommendations will guide clinical practice and inform interventions for future research. PURPOSE: To establish international consensus on recommendations for the non-pharmacological and non-surgical management of osteoporotic vertebral fractures. METHODS: We adopted a five-step modified Delphi consensus process: (1) literature search and content analysis, (2) creation of the survey, (3) selection of the expert panel, (4) first round of the rating process, and (5) second round of the rating process. The first round included 49 statements and eight open-ended questions; the second round included 30 statements. Panelists were asked to rate their agreement with each of the statements using a 9-point scale, with the option to provide further comments. Consensus for each statement was determined by counting the number of panelists whose rating was outside the 3-point region containing the median. RESULTS: We invited 76 people with degree in medicine, physiotherapy, kinesiology, and experience in the management of osteoporotic vertebral; 31 (41%) and 27 (36%) experts agreed to participate to the first and the second round, respectively. The mean percentage agreement after the first and second rounds was 76.6% ± 16.0% and 90.7% ± 6.5%, respectively. We established consensus on recommendations on pain, early satiety, weight loss, bracing, safe movement, and exercise for individuals with acute and chronic vertebral fractures. CONCLUSION: Our international consensus provides multidisciplinary biopsychosocial recommendations to guide the management of osteoporotic vertebral fractures and inform interventions for future research.
Subject(s)
Osteoporotic Fractures , Spinal Fractures , Humans , Consensus , Osteoporotic Fractures/therapy , Spine , Spinal Fractures/therapy , Pain , Delphi TechniqueABSTRACT
Further understanding of when to initiate therapies in pulmonary arterial hypertension (PAH) is important to improve long-term outcomes. Post hoc analyses of GRIPHON (NCT01106014) and exploratory analyses of TRITON (NCT02558231) suggested benefit of early selexipag initiation on long-term outcomes, despite no additional benefit versus initial double combination on haemodynamic and functional parameters in TRITON. Post hoc analyses investigated the effect of early selexipag initiation on disease progression and survival in a large, pooled PAH cohort. Data from newly diagnosed (≤6â months) PAH patients from GRIPHON and TRITON were pooled. Patients on active therapy with selexipag (pooled selexipag group) were compared with those on control therapy with placebo (pooled control group). Disease progression end-points were defined as per the individual studies. Hazard ratios (HR) and 95% CI for time to first disease progression event up to end of double-blind treatment (selexipag/placebo) +7â days and time to all-cause death up to end of study were estimated using Cox regression models. The pooled dataset comprised 649 patients, with 44% on double background therapy. Selexipag reduced the risk of disease progression by 52% versus control (HR: 0.48; 95% CI: 0.35-0.66). HR for risk of all-cause death was 0.70 (95% CI: 0.46-1.10) for the pooled selexipag versus control group. Sensitivity analyses accounting for the impact of PAH background therapy showed consistent results, confirming the appropriateness of data pooling. These post hoc, pooled analyses build on previous insights, further supporting selexipag use within 6â months of diagnosis, including as part of triple therapy, to delay disease progression.
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OBJECTIVE: Identification of genetic risk factors for Parkinson disease (PD) has to date been primarily limited to the study of single nucleotide variants, which only represent a small fraction of the genetic variation in the human genome. Consequently, causal variants for most PD risk are not known. Here we focused on structural variants (SVs), which represent a major source of genetic variation in the human genome. We aimed to discover SVs associated with PD risk by performing the first large-scale characterization of SVs in PD. METHODS: We leveraged a recently developed computational pipeline to detect and genotype SVs from 7,772 Illumina short-read whole genome sequencing samples. Using this set of SV variants, we performed a genome-wide association study using 2,585 cases and 2,779 controls and identified SVs associated with PD risk. Furthermore, to validate the presence of these variants, we generated a subset of matched whole-genome long-read sequencing data. RESULTS: We genotyped and tested 3,154 common SVs, representing over 412 million nucleotides of previously uncatalogued genetic variation. Using long-read sequencing data, we validated the presence of three novel deletion SVs that are associated with risk of PD from our initial association analysis, including a 2 kb intronic deletion within the gene LRRN4. INTERPRETATION: We identified three SVs associated with genetic risk of PD. This study represents the most comprehensive assessment of the contribution of SVs to the genetic risk of PD to date. ANN NEUROL 2023;93:1012-1022.
Subject(s)
Genome-Wide Association Study , Parkinson Disease , Humans , Parkinson Disease/genetics , Genome, Human , Whole Genome Sequencing , GenotypeABSTRACT
BACKGROUND: In participants with pulmonary arterial hypertension, 24 weeks of sotatercept resulted in a significantly greater reduction from baseline in pulmonary vascular resistance than placebo. This report characterises the longer-term safety and efficacy of sotatercept in the PULSAR open-label extension. We report cumulative safety, and efficacy at months 18-24, for all participants treated with sotatercept. METHODS: PULSAR was a phase 2, randomised, double-blind, placebo-controlled study followed by an open-label extension, which evaluated sotatercept on top of background pulmonary arterial hypertension therapy in adults. Participants originally randomised to placebo were re-randomised 1:1 to sotatercept 0.3 or 0.7â mg·kg-1 (placebo-crossed group); those initially randomised to sotatercept continued the same sotatercept dose (continued-sotatercept group). Safety was evaluated in all participants who received ≥1 dose of sotatercept. The primary efficacy endpoint was change from baseline to months 18-24 in pulmonary vascular resistance. Secondary endpoints included 6-min walk distance and functional class. Two prespecified analyses, placebo-crossed and delayed-start, evaluated efficacy irrespective of dose. RESULTS: Of 106 participants enrolled in the PULSAR study, 97 continued into the extension period. Serious treatment-emergent adverse events were reported in 32 (30.8%) participants; 10 (9.6%) reported treatment-emergent adverse events leading to study discontinuation. Three (2.9%) participants died, none considered related to study drug. The placebo-crossed group demonstrated significant improvement across primary and secondary endpoints and clinical efficacy was maintained in the continued-sotatercept group. CONCLUSION: These results support the longer-term safety and durability of clinical benefit of sotatercept for pulmonary arterial hypertension.