Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 297
Filtrar
1.
PLoS Genet ; 17(4): e1009464, 2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33901188

RESUMO

As a type of relatively new methodology, the transcriptome-wide association study (TWAS) has gained interest due to capacity for gene-level association testing. However, the development of TWAS has outpaced statistical evaluation of TWAS gene prioritization performance. Current TWAS methods vary in underlying biological assumptions about tissue specificity of transcriptional regulatory mechanisms. In a previous study from our group, this may have affected whether TWAS methods better identified associations in single tissues versus multiple tissues. We therefore designed simulation analyses to examine how the interplay between particular TWAS methods and tissue specificity of gene expression affects power and type I error rates for gene prioritization. We found that cross-tissue identification of expression quantitative trait loci (eQTLs) improved TWAS power. Single-tissue TWAS (i.e., PrediXcan) had robust power to identify genes expressed in single tissues, but, often found significant associations in the wrong tissues as well (therefore had high false positive rates). Cross-tissue TWAS (i.e., UTMOST) had overall equal or greater power and controlled type I error rates for genes expressed in multiple tissues. Based on these simulation results, we applied a tissue specificity-aware TWAS (TSA-TWAS) analytic framework to look for gene-based associations with pre-treatment laboratory values from AIDS Clinical Trial Group (ACTG) studies. We replicated several proof-of-concept transcriptionally regulated gene-trait associations, including UGT1A1 (encoding bilirubin uridine diphosphate glucuronosyltransferase enzyme) and total bilirubin levels (p = 3.59×10-12), and CETP (cholesteryl ester transfer protein) with high-density lipoprotein cholesterol (p = 4.49×10-12). We also identified several novel genes associated with metabolic and virologic traits, as well as pleiotropic genes that linked plasma viral load, absolute basophil count, and/or triglyceride levels. By highlighting the advantages of different TWAS methods, our simulation study promotes a tissue specificity-aware TWAS analytic framework that revealed novel aspects of HIV-related traits.

2.
Nat Commun ; 12(1): 1515, 2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33750777

RESUMO

Ribosome-profiling has uncovered pervasive translation in non-canonical open reading frames, however the biological significance of this phenomenon remains unclear. Using genetic variation from 71,702 human genomes, we assess patterns of selection in translated upstream open reading frames (uORFs) in 5'UTRs. We show that uORF variants introducing new stop codons, or strengthening existing stop codons, are under strong negative selection comparable to protein-coding missense variants. Using these variants, we map and validate gene-disease associations in two independent biobanks containing exome sequencing from 10,900 and 32,268 individuals, respectively, and elucidate their impact on protein expression in human cells. Our results suggest translation disrupting mechanisms relating uORF variation to reduced protein expression, and demonstrate that translation at uORFs is genetically constrained in 50% of human genes.


Assuntos
Doença/genética , Fases de Leitura Aberta , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Regiões 5' não Traduzidas , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Estudos de Associação Genética , Genoma Humano , Humanos , Fenótipo , Fosfotransferases (Aceptor do Grupo Fosfato)/genética , Fosfotransferases (Aceptor do Grupo Fosfato)/metabolismo , Biossíntese de Proteínas , Processamento de Proteína Pós-Traducional , Proteínas/genética , Receptor EphB2
3.
Alzheimers Res Ther ; 13(1): 34, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33541420

RESUMO

BACKGROUND: Identification of genetic risk factors that are shared between Alzheimer's disease (AD) and other traits, i.e., pleiotropy, can help improve our understanding of the etiology of AD and potentially detect new therapeutic targets. Previous epidemiological correlations observed between cardiometabolic traits and AD led us to assess the pleiotropy between these traits. METHODS: We performed a set of bivariate genome-wide association studies coupled with colocalization analysis to identify loci that are shared between AD and eleven cardiometabolic traits. For each of these loci, we performed colocalization with Genotype-Tissue Expression (GTEx) project expression quantitative trait loci (eQTL) to identify candidate causal genes. RESULTS: We identified three previously unreported pleiotropic trait associations at known AD loci as well as four novel pleiotropic loci. One associated locus was tagged by a low-frequency coding variant in the gene DOCK4 and is potentially implicated in its alternative splicing. Colocalization with GTEx eQTL data identified additional candidate genes for the loci we detected, including ACE, the target of the hypertensive drug class of ACE inhibitors. We found that the allele associated with decreased ACE expression in brain tissue was also associated with increased risk of AD, providing human genetic evidence of a potential increase in AD risk from use of an established anti-hypertensive therapeutic. CONCLUSION: Our results support a complex genetic relationship between AD and these cardiometabolic traits, and the candidate causal genes identified suggest that blood pressure and immune response play a role in the pleiotropy between these traits.

4.
Nat Med ; 27(1): 66-72, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33432171

RESUMO

The clinical impact of rare loss-of-function variants has yet to be determined for most genes. Integration of DNA sequencing data with electronic health records (EHRs) could enhance our understanding of the contribution of rare genetic variation to human disease1. By leveraging 10,900 whole-exome sequences linked to EHR data in the Penn Medicine Biobank, we addressed the association of the cumulative effects of rare predicted loss-of-function variants for each individual gene on human disease on an exome-wide scale, as assessed using a set of diverse EHR phenotypes. After discovering 97 genes with exome-by-phenome-wide significant phenotype associations (P < 10-6), we replicated 26 of these in the Penn Medicine Biobank, as well as in three other medical biobanks and the population-based UK Biobank. Of these 26 genes, five had associations that have been previously reported and represented positive controls, whereas 21 had phenotype associations not previously reported, among which were genes implicated in glaucoma, aortic ectasia, diabetes mellitus, muscular dystrophy and hearing loss. These findings show the value of aggregating rare predicted loss-of-function variants into 'gene burdens' for identifying new gene-disease associations using EHR phenotypes in a medical biobank. We suggest that application of this approach to even larger numbers of individuals will provide the statistical power required to uncover unexplored relationships between rare genetic variation and disease phenotypes.


Assuntos
Registros Eletrônicos de Saúde , Exoma , Genótipo , Fenótipo , Idoso , Biologia Computacional , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Sequenciamento Completo do Exoma
5.
BMC Med Genomics ; 14(1): 11, 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33407432

RESUMO

BACKGROUND: Elevated triglycerides (TG) are associated with, and may be causal for, cardiovascular disease (CVD), and co-morbidities such as type II diabetes and metabolic syndrome. Pathogenic variants in APOA5 and APOC3 as well as risk SNVs in other genes [APOE (rs429358, rs7412), APOA1/C3/A4/A5 gene cluster (rs964184), INSR (rs7248104), CETP (rs7205804), GCKR (rs1260326)] have been shown to affect TG levels. Knowledge of genetic causes for elevated TG may lead to early intervention and targeted treatment for CVD. We previously identified linkage and association of a rare, highly conserved missense variant in SLC25A40, rs762174003, with hypertriglyceridemia (HTG) in a single large family, and replicated this association with rare, highly conserved missense variants in a European American and African American sample. METHODS: Here, we analyzed a longitudinal mixed-ancestry cohort (European, African and Asian ancestry, N = 8966) from the Electronic Medical Record and Genomics (eMERGE) Network. We tested associations between median TG and the genes of interest, using linear regression, adjusting for sex, median age, median BMI, and the first two principal components of ancestry. RESULTS: We replicated the association between TG and APOC3, APOA5, and risk variation at APOE, APOA1/C3/A4/A5 gene cluster, and GCKR. We failed to replicate the association between rare, highly conserved variation at SLC25A40 and TG, as well as for risk variation at INSR and CETP. CONCLUSIONS: Analysis using data from electronic health records presents challenges that need to be overcome. Although large amounts of genotype data is becoming increasingly accessible, usable phenotype data can be challenging to obtain. We were able to replicate known, strong associations, but were unable to replicate moderate associations due to the limited sample size and missing drug information.

6.
Nat Commun ; 12(1): 168, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33420026

RESUMO

Increasingly, clinical phenotypes with matched genetic data from bio-bank linked electronic health records (EHRs) have been used for pleiotropy analyses. Thus far, pleiotropy analysis using individual-level EHR data has been limited to data from one site. However, it is desirable to integrate EHR data from multiple sites to improve the detection power and generalizability of the results. Due to privacy concerns, individual-level patients' data are not easily shared across institutions. As a result, we introduce Sum-Share, a method designed to efficiently integrate EHR and genetic data from multiple sites to perform pleiotropy analysis. Sum-Share requires only summary-level data and one round of communication from each site, yet it produces identical test statistics compared with that of pooled individual-level data. Consequently, Sum-Share can achieve lossless integration of multiple datasets. Using real EHR data from eMERGE, Sum-Share is able to identify 1734 potential pleiotropic SNPs for five cardiovascular diseases.


Assuntos
Registros Eletrônicos de Saúde/estatística & dados numéricos , Pleiotropia Genética , Comunicação , Bases de Dados Factuais , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Modelos Biológicos , Fenótipo , Polimorfismo de Nucleotídeo Único , Privacidade
8.
PLoS Med ; 17(10): e1003288, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33031386

RESUMO

BACKGROUND: Observational studies have identified height as a strong risk factor for atrial fibrillation, but this finding may be limited by residual confounding. We aimed to examine genetic variation in height within the Mendelian randomization (MR) framework to determine whether height has a causal effect on risk of atrial fibrillation. METHODS AND FINDINGS: In summary-level analyses, MR was performed using summary statistics from genome-wide association studies of height (GIANT/UK Biobank; 693,529 individuals) and atrial fibrillation (AFGen; 65,446 cases and 522,744 controls), finding that each 1-SD increase in genetically predicted height increased the odds of atrial fibrillation (odds ratio [OR] 1.34; 95% CI 1.29 to 1.40; p = 5 × 10-42). This result remained consistent in sensitivity analyses with MR methods that make different assumptions about the presence of pleiotropy, and when accounting for the effects of traditional cardiovascular risk factors on atrial fibrillation. Individual-level phenome-wide association studies of height and a height genetic risk score were performed among 6,567 European-ancestry participants of the Penn Medicine Biobank (median age at enrollment 63 years, interquartile range 55-72; 38% female; recruitment 2008-2015), confirming prior observational associations between height and atrial fibrillation. Individual-level MR confirmed that each 1-SD increase in height increased the odds of atrial fibrillation, including adjustment for clinical and echocardiographic confounders (OR 1.89; 95% CI 1.50 to 2.40; p = 0.007). The main limitations of this study include potential bias from pleiotropic effects of genetic variants, and lack of generalizability of individual-level findings to non-European populations. CONCLUSIONS: In this study, we observed evidence that height is likely a positive causal risk factor for atrial fibrillation. Further study is needed to determine whether risk prediction tools including height or anthropometric risk factors can be used to improve screening and primary prevention of atrial fibrillation, and whether biological pathways involved in height may offer new targets for treatment of atrial fibrillation.

9.
Genes (Basel) ; 11(9)2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32932966

RESUMO

This study aims to determine whether genetic variants that influence CYP3A4 expression are associated with platelet reactivity in clopidogrel-treated patients undergoing elective percutaneous coronary intervention (PCI), and to evaluate the influence of statin/fibrate co-medication on these associations. A study cohort was used containing 1124 consecutive elective PCI patients in whom CYP3A4*22 and PPAR-α (G209A and A208G) SNPs were genotyped and the VerifyNow P2Y12 platelet reactivity test was performed. Minor allele frequencies were 0.4% for CYP3A4*22/*22, 6.8% for PPAR-α G209A AA, and 7.0% for PPAR-α A208G GG. CYP3A4*22 was not associated with platelet reactivity. The PPAR-α genetic variants were significantly associated with platelet reactivity (G209A AA: -24.6 PRU [-44.7, -4.6], p = 0.016; A208G GG: -24.6 PRU [-44.3, -4.8], p = 0.015). Validation of these PPAR-α results in two external cohorts, containing 716 and 882 patients, respectively, showed the same direction of effect, although not statistically significant. Subsequently, meta-analysis of all three cohorts showed statistical significance of both variants in statin/fibrate users (p = 0.04 for PPAR-a G209A and p = 0.03 for A208G), with no difference in statin/fibrate non-users. In conclusion, PPAR-α G209A and A208G were associated with lower platelet reactivity in patients undergoing elective PCI who were treated with clopidogrel and statin/fibrate co-medication. Further research is necessary to confirm these findings.

10.
Biol Psychiatry ; 2020 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-32919613

RESUMO

BACKGROUND: Prediction of disease risk is a key component of precision medicine. Common traits such as psychiatric disorders have a complex polygenic architecture, making the identification of a single risk predictor difficult. Polygenic risk scores (PRSs) denoting the sum of an individual's genetic liability for a disorder are a promising biomarker for psychiatric disorders, but they require evaluation in a clinical setting. METHODS: We developed PRSs for 6 psychiatric disorders (schizophrenia, bipolar disorder, major depressive disorder, cross disorder, attention-deficit/hyperactivity disorder, and anorexia nervosa) and 17 nonpsychiatric traits in more than 10,000 individuals from the Penn Medicine Biobank with accompanying electronic health records. We performed phenome-wide association analyses to test their association across disease categories. RESULTS: Four of the 6 psychiatric PRSs were associated with their primary phenotypes (odds ratios from 1.2 to 1.6). Cross-trait associations were identified both within the psychiatric domain and across trait domains. PRSs for coronary artery disease and years of education were significantly associated with psychiatric disorders, largely driven by an association with tobacco use disorder. CONCLUSIONS: We demonstrated that the genetic architecture of electronic health record-derived psychiatric diagnoses is similar to ascertained research cohorts from large consortia. Psychiatric PRSs are moderately associated with psychiatric diagnoses but are not yet clinically predictive in naïve patients. Cross-trait associations for these PRSs suggest a broader effect of genetic liability beyond traditional diagnostic boundaries. As identification of genetic markers increases, including PRSs alongside other clinical risk factors may enhance prediction of psychiatric disorders and associated conditions in clinical registries.

11.
Clin Infect Dis ; 2020 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-32829410

RESUMO

BACKGROUND: Unwanted weight gain affects some people living with HIV who are prescribed integrase strand transfer inhibitors (INSTI). Mechanisms and risk factors are incompletely understood. METHODS: We utilized two cohorts to study pharmacogenetics of weight gain following switch from efavirenz- to INSTI-based regimens. In an observational cohort, we studied weight gain at 48 weeks following switch from efavirenz- to INSTI-based regimens among patients who had been virologically suppressed for at least 2 years at a clinic in the United States. Associations were characterized with CYP2B6 and UGT1A1 genotypes that affect efavirenz and INSTI metabolism, respectively. In a clinical trials cohort, we studied weight gain at 48 weeks among treatment-naïve participants who were randomized to receive efavirenz-containing regimens in AIDS Clinical Trials Group studies A5095, A5142 and A5202 and did not receive INSTIs. RESULTS: In the observational cohort (N=61), CYP2B6 slow metabolizers had greater weight gain after switch (p=0.01). This was seen following switch to elvitegravir or raltegravir, but not dolutegravir. UGT1A1 genotype was not associated with weight gain. In the clinical trials cohort (N=462), CYP2B6 slow metabolizers had lesser weight gain at week 48 among participants receiving efavirenz with tenofovir disoproxil fumarate (p=0.001) but not those receiving efavirenz with abacavir (p=0.65). Findings were consistent when stratified by race/ethnicity and by sex. CONCLUSIONS: Among patients who switched from efavirenz- to INSTI-based therapy, CYP2B6 genotype was associated with weight gain, possibly reflecting withdrawal of the inhibitory effect of higher efavirenz concentrations on weight gain. The difference by concomitant nucleoside analogue is unexplained.

12.
BioData Min ; 13: 3, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32419848

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic has had a significant impact on population health and wellbeing. Biomedical informatics is central to COVID-19 research efforts and for the delivery of healthcare for COVID-19 patients. Critical to this effort is the participation of informaticians who typically work on other basic science or clinical problems. The goal of this editorial is to highlight some examples of COVID-19 research areas that could benefit from informatics expertise. Each research idea summarizes the COVID-19 application area, followed by an informatics methodology, approach, or technology that could make a contribution. It is our hope that this piece will motivate and make it easy for some informaticians to adopt COVID-19 research projects.

14.
Clin Pharmacol Ther ; 108(5): 1067-1077, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32472697

RESUMO

Antiplatelet response to clopidogrel shows wide variation, and poor response is correlated with adverse clinical outcomes. CYP2C19 loss-of-function alleles play an important role in this response, but account for only a small proportion of variability in response to clopidogrel. An aim of the International Clopidogrel Pharmacogenomics Consortium (ICPC) is to identify other genetic determinants of clopidogrel pharmacodynamics and clinical response. A genomewide association study (GWAS) was performed using DNA from 2,750 European ancestry individuals, using adenosine diphosphate-induced platelet reactivity and major cardiovascular and cerebrovascular events as outcome parameters. GWAS for platelet reactivity revealed a strong signal for CYP2C19*2 (P value = 1.67e-33). After correction for CYP2C19*2 no other single-nucleotide polymorphism reached genomewide significance. GWAS for a combined clinical end point of cardiovascular death, myocardial infarction, or stroke (5.0% event rate), or a combined end point of cardiovascular death or myocardial infarction (4.7% event rate) showed no significant results, although in coronary artery disease, percutaneous coronary intervention, and acute coronary syndrome subgroups, mutations in SCOS5P1, CDC42BPA, and CTRAC1 showed genomewide significance (lowest P values: 1.07e-09, 4.53e-08, and 2.60e-10, respectively). CYP2C19*2 is the strongest genetic determinant of on-clopidogrel platelet reactivity. We identified three novel associations in clinical outcome subgroups, suggestive for each of these outcomes.

15.
Nat Rev Genet ; 21(8): 493-502, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32235907

RESUMO

Accurate prediction of disease risk based on the genetic make-up of an individual is essential for effective prevention and personalized treatment. Nevertheless, to date, individual genetic variants from genome-wide association studies have achieved only moderate prediction of disease risk. The aggregation of genetic variants under a polygenic model shows promising improvements in prediction accuracies. Increasingly, electronic health records (EHRs) are being linked to patient genetic data in biobanks, which provides new opportunities for developing and applying polygenic risk scores in the clinic, to systematically examine and evaluate patient susceptibilities to disease. However, the heterogeneous nature of EHR data brings forth many practical challenges along every step of designing and implementing risk prediction strategies. In this Review, we present the unique considerations for using genotype and phenotype data from biobank-linked EHRs for polygenic risk prediction.


Assuntos
Registros Eletrônicos de Saúde , Estudos de Associação Genética , Predisposição Genética para Doença , Herança Multifatorial , Algoritmos , Biologia Computacional/métodos , Estudo de Associação Genômica Ampla , Genômica/métodos , Genótipo , Humanos , Fenótipo , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Risco
16.
J Clin Endocrinol Metab ; 105(6)2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31917831

RESUMO

CONTEXT: As many as 75% of patients with polycystic ovary syndrome (PCOS) are estimated to be unidentified in clinical practice. OBJECTIVE: Utilizing polygenic risk prediction, we aim to identify the phenome-wide comorbidity patterns characteristic of PCOS to improve accurate diagnosis and preventive treatment. DESIGN, PATIENTS, AND METHODS: Leveraging the electronic health records (EHRs) of 124 852 individuals, we developed a PCOS risk prediction algorithm by combining polygenic risk scores (PRS) with PCOS component phenotypes into a polygenic and phenotypic risk score (PPRS). We evaluated its predictive capability across different ancestries and perform a PRS-based phenome-wide association study (PheWAS) to assess the phenomic expression of the heightened risk of PCOS. RESULTS: The integrated polygenic prediction improved the average performance (pseudo-R2) for PCOS detection by 0.228 (61.5-fold), 0.224 (58.8-fold), 0.211 (57.0-fold) over the null model across European, African, and multi-ancestry participants respectively. The subsequent PRS-powered PheWAS identified a high level of shared biology between PCOS and a range of metabolic and endocrine outcomes, especially with obesity and diabetes: "morbid obesity", "type 2 diabetes", "hypercholesterolemia", "disorders of lipid metabolism", "hypertension", and "sleep apnea" reaching phenome-wide significance. CONCLUSIONS: Our study has expanded the methodological utility of PRS in patient stratification and risk prediction, especially in a multifactorial condition like PCOS, across different genetic origins. By utilizing the individual genome-phenome data available from the EHR, our approach also demonstrates that polygenic prediction by PRS can provide valuable opportunities to discover the pleiotropic phenomic network associated with PCOS pathogenesis.

17.
Pac Symp Biocomput ; 25: 743-747, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31797645

RESUMO

Translational bioinformatics (TBI) is focused on the integration of biomedical data science and informatics. This combination is extremely powerful for scientific discovery as well as translation into clinical practice. Several topics where TBI research is at the leading edge are 1) the use of large-scale biobanks linked to electronic health records, 2) pharmacogenomics, and 3) artificial intelligence and machine learning. This perspective discusses these three topics and points to the important elements for driving precision medicine into the future.

18.
Eur Heart J Cardiovasc Pharmacother ; 6(4): 203-210, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31504375

RESUMO

AIMS: Clopidogrel is prescribed for the prevention of atherothrombotic events. While investigations have identified genetic determinants of inter-individual variability in on-treatment platelet inhibition (e.g. CYP2C19*2), evidence that these variants have clinical utility to predict major adverse cardiovascular events (CVEs) remains controversial. METHODS AND RESULTS: We assessed the impact of 31 candidate gene polymorphisms on adenosine diphosphate (ADP)-stimulated platelet reactivity in 3391 clopidogrel-treated coronary artery disease patients of the International Clopidogrel Pharmacogenomics Consortium (ICPC). The influence of these polymorphisms on CVEs was tested in 2134 ICPC patients (N = 129 events) in whom clinical event data were available. Several variants were associated with on-treatment ADP-stimulated platelet reactivity (CYP2C19*2, P = 8.8 × 10-54; CES1 G143E, P = 1.3 × 10-16; CYP2C19*17, P = 9.5 × 10-10; CYP2B6 1294 + 53 C > T, P = 3.0 × 10-4; CYP2B6 516 G > T, P = 1.0 × 10-3; CYP2C9*2, P = 1.2 × 10-3; and CYP2C9*3, P = 1.5 × 10-3). While no individual variant was associated with CVEs, generation of a pharmacogenomic polygenic response score (PgxRS) revealed that patients who carried a greater number of alleles that associated with increased on-treatment platelet reactivity were more likely to experience CVEs (ß = 0.17, SE 0.06, P = 0.01) and cardiovascular-related death (ß = 0.43, SE 0.16, P = 0.007). Patients who carried eight or more risk alleles were significantly more likely to experience CVEs [odds ratio (OR) = 1.78, 95% confidence interval (CI) 1.14-2.76, P = 0.01] and cardiovascular death (OR = 4.39, 95% CI 1.35-14.27, P = 0.01) compared to patients who carried six or fewer of these alleles. CONCLUSION: Several polymorphisms impact clopidogrel response and PgxRS is a predictor of cardiovascular outcomes. Additional investigations that identify novel determinants of clopidogrel response and validating polygenic models may facilitate future precision medicine strategies.


Assuntos
Clopidogrel/uso terapêutico , Doença da Artéria Coronariana/terapia , Técnicas de Apoio para a Decisão , Intervenção Coronária Percutânea , Variantes Farmacogenômicos , Inibidores da Agregação de Plaquetas/uso terapêutico , Agregação Plaquetária/efeitos dos fármacos , Polimorfismo de Nucleotídeo Único , Idoso , Isquemia Encefálica/mortalidade , Isquemia Encefálica/prevenção & controle , Clopidogrel/efeitos adversos , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/mortalidade , Trombose Coronária/mortalidade , Trombose Coronária/prevenção & controle , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/prevenção & controle , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/instrumentação , Intervenção Coronária Percutânea/mortalidade , Agregação Plaquetária/genética , Inibidores da Agregação de Plaquetas/efeitos adversos , Valor Preditivo dos Testes , Medição de Risco , Fatores de Risco , Stents , Acidente Vascular Cerebral/mortalidade , Acidente Vascular Cerebral/prevenção & controle , Resultado do Tratamento
19.
Genet Med ; 22(1): 102-111, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31383942

RESUMO

PURPOSE: "Genome-first" approaches, in which genetic sequencing is agnostically linked to associated phenotypes, can enhance our understanding of rare variants' contributions to disease. Loss-of-function variants in LMNA cause a range of rare diseases, including cardiomyopathy. METHODS: We leveraged exome sequencing from 11,451 unselected individuals in the Penn Medicine Biobank to associate rare variants in LMNA with diverse electronic health record (EHR)-derived phenotypes. We used Rare Exome Variant Ensemble Learner (REVEL) to annotate rare missense variants, clustered predicted deleterious and loss-of-function variants into a "gene burden" (N = 72 individuals), and performed a phenome-wide association study (PheWAS). Major findings were replicated in DiscovEHR. RESULTS: The LMNA gene burden was significantly associated with primary cardiomyopathy (p = 1.78E-11) and cardiac conduction disorders (p = 5.27E-07). Most patients had not been clinically diagnosed with LMNA cardiomyopathy. We also noted an association with chronic kidney disease (p = 1.13E-06). Regression analyses on echocardiography and serum labs revealed that LMNA variant carriers had dilated cardiomyopathy and primary renal disease. CONCLUSION: Pathogenic LMNA variants are an underdiagnosed cause of cardiomyopathy. We also find that LMNA loss of function may be a primary cause of renal disease. Finally, we show the value of aggregating rare, annotated variants into a gene burden and using PheWAS to identify novel ontologies for pleiotropic human genes.


Assuntos
Doença do Sistema de Condução Cardíaco/genética , Cardiomiopatias/genética , Lamina Tipo A/genética , Mutação com Perda de Função , Insuficiência Renal Crônica/genética , Sequenciamento Completo do Exoma/métodos , Idoso , Comorbidade , Biologia Computacional/métodos , Registros Eletrônicos de Saúde , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Fenótipo
20.
Int J Cardiol ; 298: 107-113, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31447229

RESUMO

BACKGROUND: Cardiovascular disease is the leading cause of death in the United States. Consequently, individuals who are genetically predisposed for high risk of cardiovascular disease would benefit most from prevention and early intervention approaches. Among common health risk factors affecting adult populations, we evaluated 23 cardiovascular disease-related traits, including BMI, glucose levels and lipid profiling to determine their associations with low-frequency recurrent copy number variations (CNV) (population frequency < 5%). RESULTS: We examined 10,619 unrelated subjects of European ancestry from the Electronic Medical Records and Genomics (eMERGE) Network who were genotyped with 657,366 markers genome-wide on the Illumina Infinium Quad 660 array. We performed CNV calling based on array marker intensity and evaluated data quality, ancestry stratification, and relatedness to ensure unbiased association discovery. Using a segment-based scoring approach, we assessed the association of all CNVs with each trait. In this large genome-wide analysis of low-frequency CNVs, we observed 11 novel genome-wide significant associations of low-frequency CNVs with major cardiovascular disease traits. CONCLUSION: In one of the largest genome-wide studies for low-frequency recurrent CNVs, we identified 11 loci associated with cardiovascular disease and related traits at the genome-wide significance level that may serve as biomarkers for prevention and early intervention studies in subjects who are at elevated risk. Our study further supports the role of low-frequency recurrent CNVs in the pathogenesis of common complex disease traits.


Assuntos
Índice de Massa Corporal , Doenças Cardiovasculares/genética , Variações do Número de Cópias de DNA/genética , Estudo de Associação Genômica Ampla/métodos , Genômica/métodos , Fenótipo , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/fisiopatologia , Eletrocardiografia/métodos , Registros Eletrônicos de Saúde , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...