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1.
Am J Respir Crit Care Med ; 209(12): 1477-1485, 2024 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-38470220

RESUMEN

Rationale: Chronic thromboembolic pulmonary hypertension involves the formation and nonresolution of thrombus, dysregulated inflammation, angiogenesis, and the development of a small-vessel vasculopathy. Objectives: We aimed to establish the genetic basis of chronic thromboembolic pulmonary hypertension to gain insight into its pathophysiological contributors. Methods: We conducted a genome-wide association study on 1,907 European cases and 10,363 European control subjects. We coanalyzed our results with existing results from genome-wide association studies on deep vein thrombosis, pulmonary embolism, and idiopathic pulmonary arterial hypertension. Measurements and Main Results: Our primary association study revealed genetic associations at the ABO, FGG, F11, MYH7B, and HLA-DRA loci. Through our coanalysis, we demonstrate further associations with chronic thromboembolic pulmonary hypertension at the F2, TSPAN15, SLC44A2, and F5 loci but find no statistically significant associations shared with idiopathic pulmonary arterial hypertension. Conclusions: Chronic thromboembolic pulmonary hypertension is a partially heritable polygenic disease, with related though distinct genetic associations with pulmonary embolism and deep vein thrombosis.


Asunto(s)
Estudio de Asociación del Genoma Completo , Hipertensión Pulmonar , Embolia Pulmonar , Humanos , Embolia Pulmonar/genética , Embolia Pulmonar/complicaciones , Hipertensión Pulmonar/genética , Masculino , Femenino , Persona de Mediana Edad , Enfermedad Crónica , Genómica , Predisposición Genética a la Enfermedad , Adulto , Estudios de Casos y Controles , Anciano , Trombosis de la Vena/genética
2.
BMC Bioinformatics ; 23(1): 310, 2022 Jul 30.
Artículo en Inglés | MEDLINE | ID: mdl-35907789

RESUMEN

BACKGROUND: Genome-wide association studies (GWAS) are limited in power to detect associations that exceed the stringent genome-wide significance threshold. This limitation can be alleviated by leveraging relevant auxiliary data, such as functional genomic data. Frameworks utilising the conditional false discovery rate have been developed for this purpose, and have been shown to increase power for GWAS discovery whilst controlling the false discovery rate. However, the methods are currently only applicable for continuous auxiliary data and cannot be used to leverage auxiliary data with a binary representation, such as whether SNPs are synonymous or non-synonymous, or whether they reside in regions of the genome with specific activity states. RESULTS: We describe an extension to the cFDR framework for binary auxiliary data, called "Binary cFDR". We demonstrate FDR control of our method using detailed simulations, and show that Binary cFDR performs better than a comparator method in terms of sensitivity and FDR control. We introduce an all-encompassing user-oriented CRAN R package ( https://annahutch.github.io/fcfdr/ ; https://cran.r-project.org/web/packages/fcfdr/index.html ) and demonstrate its utility in an application to type 1 diabetes, where we identify additional genetic associations. CONCLUSIONS: Our all-encompassing R package, fcfdr, serves as a comprehensive toolkit to unite GWAS and functional genomic data in order to increase statistical power to detect genetic associations.


Asunto(s)
Diabetes Mellitus Tipo 1 , Estudio de Asociación del Genoma Completo , Diabetes Mellitus Tipo 1/genética , Genoma , Estudio de Asociación del Genoma Completo/métodos , Genómica/métodos , Humanos , Polimorfismo de Nucleótido Simple
3.
Eur Respir J ; 59(3)2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-34588193

RESUMEN

BACKGROUND: Inflammation and dysregulated immunity are important in the development of pulmonary arterial hypertension (PAH). Compelling preclinical data supports the therapeutic blockade of interleukin-6 (IL-6) signalling. METHODS: We conducted a phase 2 open-label study of intravenous tocilizumab (8 mg·kg-1) over 6 months in patients with group 1 PAH. Co-primary end-points were safety, defined by incidence and severity of adverse events, and change in pulmonary vascular resistance. Separately, a mendelian randomisation study was undertaken on 11 744 individuals with European ancestry including 2085 patients with idiopathic/heritable disease for the IL-6 receptor (IL6R) variant (rs7529229), known to associate with circulating IL-6R levels. RESULTS: We recruited 29 patients (male/female 10/19; mean±sd age 54.9±11.4 years). Of these, 19 had heritable/idiopathic PAH and 10 had connective tissue disease-associated PAH. Six were withdrawn prior to drug administration; 23 patients received at least one dose of tocilizumab. Tocilizumab was discontinued in four patients owing to serious adverse events. There were no deaths. Despite evidence of target engagement in plasma IL-6 and C-reactive protein levels, both intention-to-treat and modified intention-to-treat analyses demonstrated no change in pulmonary vascular resistance. Inflammatory markers did not predict treatment response. Mendelian randomisation did not support an effect of the lead IL6R variant on risk of PAH (OR 0.99, p=0.88). CONCLUSION: Adverse events were consistent with the known safety profile of tocilizumab. Tocilizumab did not show any consistent treatment effect.


Asunto(s)
Investigación Biomédica , Hipertensión Arterial Pulmonar , Adulto , Anciano , Hipertensión Pulmonar Primaria Familiar , Femenino , Humanos , Interleucina-6 , Masculino , Persona de Mediana Edad , Resultado del Tratamiento
4.
Am J Respir Crit Care Med ; 201(5): 575-585, 2020 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-31661308

RESUMEN

Rationale: Recently, rare heterozygous mutations in GDF2 were identified in patients with pulmonary arterial hypertension (PAH). GDF2 encodes the circulating BMP (bone morphogenetic protein) type 9, which is a ligand for the BMP2 receptor.Objectives: Here we determined the functional impact of GDF2 mutations and characterized plasma BMP9 and BMP10 levels in patients with idiopathic PAH.Methods: Missense BMP9 mutant proteins were expressed in vitro and the impact on BMP9 protein processing and secretion, endothelial signaling, and functional activity was assessed. Plasma BMP9 and BMP10 levels and activity were assayed in patients with PAH with GDF2 variants and in control subjects. Levels were also measured in a larger cohort of control subjects (n = 120) and patients with idiopathic PAH (n = 260).Measurements and Main Results: We identified a novel rare variation at the GDF2 and BMP10 loci, including copy number variation. In vitro, BMP9 missense proteins demonstrated impaired cellular processing and secretion. Patients with PAH who carried these mutations exhibited reduced plasma levels of BMP9 and reduced BMP activity. Unexpectedly, plasma BMP10 levels were also markedly reduced in these individuals. Although overall BMP9 and BMP10 levels did not differ between patients with PAH and control subjects, BMP10 levels were lower in PAH females. A subset of patients with PAH had markedly reduced plasma levels of BMP9 and BMP10 in the absence of GDF2 mutations.Conclusions: Our findings demonstrate that GDF2 mutations result in BMP9 loss of function and are likely causal. These mutations lead to reduced circulating levels of both BMP9 and BMP10. These findings support therapeutic strategies to enhance BMP9 or BMP10 signaling in PAH.


Asunto(s)
Proteínas Morfogenéticas Óseas/genética , Factor 2 de Diferenciación de Crecimiento/genética , Hipertensión Arterial Pulmonar/genética , Adulto , Proteínas Morfogenéticas Óseas/metabolismo , Estudios de Casos y Controles , Variaciones en el Número de Copia de ADN , Femenino , Factor 2 de Diferenciación de Crecimiento/metabolismo , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Mutación Missense , Transporte de Proteínas , Hipertensión Arterial Pulmonar/metabolismo , Factores Sexuales
5.
Biom J ; 63(5): 1096-1130, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33682201

RESUMEN

High-dimensional hypothesis testing is ubiquitous in the biomedical sciences, and informative covariates may be employed to improve power. The conditional false discovery rate (cFDR) is a widely used approach suited to the setting where the covariate is a set of p-values for the equivalent hypotheses for a second trait. Although related to the Benjamini-Hochberg procedure, it does not permit any easy control of type-1 error rate and existing methods are over-conservative. We propose a new method for type-1 error rate control based on identifying mappings from the unit square to the unit interval defined by the estimated cFDR and splitting observations so that each map is independent of the observations it is used to test. We also propose an adjustment to the existing cFDR estimator which further improves power. We show by simulation that the new method more than doubles potential improvement in power over unconditional analyses compared to existing methods. We demonstrate our method on transcriptome-wide association studies and show that the method can be used in an iterative way, enabling the use of multiple covariates successively. Our methods substantially improve the power and applicability of cFDR analysis.


Asunto(s)
Proyectos de Investigación , Simulación por Computador , Fenotipo
6.
BMC Genet ; 19(1): 89, 2018 10 03.
Artículo en Inglés | MEDLINE | ID: mdl-30285617

RESUMEN

BACKGROUND: High dimensional case control studies are ubiquitous in the biological sciences, particularly genomics. To maximise power while constraining cost and to minimise type-1 error rates, researchers typically seek to replicate findings in a second experiment on independent cohorts before proceeding with further analyses. This can be an expensive procedure, particularly when control samples are difficult to recruit or ascertain; for example in inter-disease comparisons, or studies on degenerative diseases. RESULTS: This paper presents a method in which control (or case) samples from the discovery cohort are re-used in a replication study. The theoretical implications of this method are discussed and simulated genome-wide association study (GWAS) tests are used to compare performance against the standard approach in a range of circumstances. Using similar methods, a procedure is proposed for 'partial replication' using a new independent cohort consisting of only controls. This methods can be used to provide some validation of findings when a full replication procedure is not possible. The new method has differing sensitivity to confounding in study cohorts compared to the standard procedure, which must be considered in its application. Type-1 error rates in these scenarios are analytically and empirically derived, and an online tool for comparing power and error rates is provided. CONCLUSIONS: In several common study designs, a shared-control method allows a substantial improvement in power while retaining type-1 error rate control. Although careful consideration must be made of all necessary assumptions, this method can enable more efficient use of data in GWAS and other applications.


Asunto(s)
Estudio de Asociación del Genoma Completo/métodos , Modelos Estadísticos , Estudios de Casos y Controles , Simulación por Computador , Humanos , Modelos Genéticos , Polimorfismo de Nucleótido Simple
7.
PLoS Genet ; 11(2): e1004926, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25658688

RESUMEN

Genome-wide association studies (GWAS) have been successful in identifying single nucleotide polymorphisms (SNPs) associated with many traits and diseases. However, at existing sample sizes, these variants explain only part of the estimated heritability. Leverage of GWAS results from related phenotypes may improve detection without the need for larger datasets. The Bayesian conditional false discovery rate (cFDR) constitutes an upper bound on the expected false discovery rate (FDR) across a set of SNPs whose p values for two diseases are both less than two disease-specific thresholds. Calculation of the cFDR requires only summary statistics and have several advantages over traditional GWAS analysis. However, existing methods require distinct control samples between studies. Here, we extend the technique to allow for some or all controls to be shared, increasing applicability. Several different SNP sets can be defined with the same cFDR value, and we show that the expected FDR across the union of these sets may exceed expected FDR in any single set. We describe a procedure to establish an upper bound for the expected FDR among the union of such sets of SNPs. We apply our technique to pairwise analysis of p values from ten autoimmune diseases with variable sharing of controls, enabling discovery of 59 SNP-disease associations which do not reach GWAS significance after genomic control in individual datasets. Most of the SNPs we highlight have previously been confirmed using replication studies or larger GWAS, a useful validation of our technique; we report eight SNP-disease associations across five diseases not previously declared. Our technique extends and strengthens the previous algorithm, and establishes robust limits on the expected FDR. This approach can improve SNP detection in GWAS, and give insight into shared aetiology between phenotypically related conditions.


Asunto(s)
Enfermedades Autoinmunes/genética , Diabetes Mellitus Tipo 1/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Cirrosis Hepática Biliar/genética , Enfermedades Autoinmunes/patología , Teorema de Bayes , Diabetes Mellitus Tipo 1/patología , Genoma Humano , Genotipo , Humanos , Cirrosis Hepática Biliar/patología , Fenotipo , Polimorfismo de Nucleótido Simple
8.
J Psychiatr Res ; 174: 289-296, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38678686

RESUMEN

Hallucinations are a common feature of psychosis, yet access to effective psychological treatment is limited. The Managing Unusual Sensory Experiences for First-Episode-Psychosis (MUSE-FEP) trial aimed to establish the feasibility and acceptability of a brief, hallucination-specific, digitally provided treatment, delivered by a non-specialist workforce for people with psychosis. MUSE uses psychoeducation about the causal mechanisms of hallucinations and tailored interventions to help a person understand and manage their experiences. We undertook a two-site, single-blind (rater) Randomised Controlled Trial and recruited 82 participants who were allocated 1:1 to MUSE and treatment as usual (TAU) (n = 40) or TAU alone (n = 42). Participants completed assessments before and after treatment (2 months), and at follow up (3-4 months). Information on recruitment rates, adherence, and completion of outcome assessments was collected. Analyses focussed on feasibility outcomes and initial estimates of intervention effects to inform a future trial. The trial is registered with the ISRCTN registry 16793301. Criteria for the feasibility of trial methodology and intervention delivery were met. The trial exceeded the recruitment target, had high retention rates (87.8%) at end of treatment, and at follow up (86.6%), with good acceptability of treatment. There were 3 serious adverse events in the therapy group, and 5 in the TAU group. Improvements were evident in both groups at the end of treatment and follow up, with a particular benefit in perceived recovery in the MUSE group. We showed it was feasible to increase access to psychological intervention but a definitive trial requires further changes to the trial design or treatment.


Asunto(s)
Alucinaciones , Trastornos Psicóticos , Humanos , Alucinaciones/etiología , Alucinaciones/terapia , Trastornos Psicóticos/terapia , Femenino , Masculino , Adulto , Método Simple Ciego , Adulto Joven , Estudios de Factibilidad , Psicoterapia Breve/métodos , Adolescente , Persona de Mediana Edad , Estudios de Seguimiento , Evaluación de Resultado en la Atención de Salud
9.
Nat Commun ; 10(1): 5120, 2019 11 12.
Artículo en Inglés | MEDLINE | ID: mdl-31719529

RESUMEN

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Stratification by ANCA reveals that EGPA comprises two genetically and clinically distinct syndromes. MPO+ ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an HLA-DQ association with MPO+ ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Four candidate genes are targets of therapies in development, supporting their exploration in EGPA.


Asunto(s)
Anticuerpos Anticitoplasma de Neutrófilos/metabolismo , Sitios Genéticos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Granulomatosis con Poliangitis/genética , Granulomatosis con Poliangitis/inmunología , Eosinófilos/patología , Estudios de Asociación Genética , Humanos , Análisis de la Aleatorización Mendeliana
10.
Nat Genet ; 49(2): 310-316, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-28024155

RESUMEN

Many common diseases show wide phenotypic variation. We present a statistical method for determining whether phenotypically defined subgroups of disease cases represent different genetic architectures, in which disease-associated variants have different effect sizes in two subgroups. Our method models the genome-wide distributions of genetic association statistics with mixture Gaussians. We apply a global test without requiring explicit identification of disease-associated variants, thus maximizing power in comparison to standard variant-by-variant subgroup analysis. Where evidence for genetic subgrouping is found, we present methods for post hoc identification of the contributing genetic variants. We demonstrate the method on a range of simulated and test data sets, for which expected results are already known. We investigate subgroups of individuals with type 1 diabetes (T1D) defined by autoantibody positivity, establishing evidence for differential genetic architecture with positivity for thyroid-peroxidase-specific antibody, driven generally by variants in known T1D-associated genomic regions.


Asunto(s)
Diabetes Mellitus Tipo 1/genética , Variación Genética/genética , Heterogeneidad Genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo/métodos , Genómica/métodos , Humanos , Modelos Genéticos , Fenotipo
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