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1.
Pharmacogenomics J ; 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33168928

RESUMO

The emergence of genomic data in biobanks and health systems offers new ways to derive medically important phenotypes, including acute phenotypes occurring during inpatient clinical care. Here we study the genetic underpinnings of the rapid response to phenylephrine, an α1-adrenergic receptor agonist commonly used to treat hypotension during anesthesia and surgery. We quantified this response by extracting blood pressure (BP) measurements 5 min before and after the administration of phenylephrine. Based on this derived phenotype, we show that systematic differences exist between self-reported ancestry groups: European-Americans (EA; n = 1387) have a significantly higher systolic response to phenylephrine than African-Americans (AA; n = 1217) and Hispanic/Latinos (HA; n = 1713) (31.3% increase, p value < 6e-08 and 22.9% increase, p value < 5e-05 respectively), after adjusting for genetic ancestry, demographics, and relevant clinical covariates. We performed a genome-wide association study to investigate genetic factors underlying individual differences in this derived phenotype. We discovered genome-wide significant association signals in loci and genes previously associated with BP measured in ambulatory settings, and a general enrichment of association in these genes. Finally, we discovered two low frequency variants, present at ~1% in EAs and AAs, respectively, where patients carrying one copy of these variants show no phenylephrine response. This work demonstrates our ability to derive a quantitative phenotype suited for comparative statistics and genome-wide association studies from dense clinical and physiological measures captured for managing patients during surgery. We identify genetic variants underlying non response to phenylephrine, with implications for preemptive pharmacogenomic screening to improve safety during surgery.

2.
Am J Hum Genet ; 107(5): 932-941, 2020 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-33108757

RESUMO

Harmonization of variant pathogenicity classification across laboratories is important for advancing clinical genomics. The two CLIA-accredited Electronic Medical Record and Genomics Network sequencing centers and the six CLIA-accredited laboratories and one research laboratory performing genome or exome sequencing in the Clinical Sequencing Evidence-Generating Research Consortium collaborated to explore current sources of discordance in classification. Eight laboratories each submitted 20 classified variants in the ACMG secondary finding v.2.0 genes. After removing duplicates, each of the 158 variants was annotated and independently classified by two additional laboratories using the ACMG-AMP guidelines. Overall concordance across three laboratories was assessed and discordant variants were reviewed via teleconference and email. The submitted variant set included 28 P/LP variants, 96 VUS, and 34 LB/B variants, mostly in cancer (40%) and cardiac (27%) risk genes. Eighty-six (54%) variants reached complete five-category (i.e., P, LP, VUS, LB, B) concordance, and 17 (11%) had a discordance that could affect clinical recommendations (P/LP versus VUS/LB/B). 21% and 63% of variants submitted as P and LP, respectively, were discordant with VUS. Of the 54 originally discordant variants that underwent further review, 32 reached agreement, for a post-review concordance rate of 84% (118/140 variants). This project provides an updated estimate of variant concordance, identifies considerations for LP classified variants, and highlights ongoing sources of discordance. Continued and increased sharing of variant classifications and evidence across laboratories, and the ongoing work of ClinGen to provide general as well as gene- and disease-specific guidance, will lead to continued increases in concordance.

4.
J Child Neurol ; : 883073820953001, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32928027

RESUMO

OBJECTIVE: To describe a founder mutation effect and the clinical phenotype of homozygous FRRS1L c.737_739delGAG (p.Gly246del) variant in 15 children of Puerto Rican (Boricua) ancestry presenting with early infantile epileptic encephalopathy (EIEE-37) with prominent movement disorder. BACKGROUND: EIEE-37 is caused by biallelic loss of function variants in the FRRS1L gene, which is critical for AMPA-receptor function, resulting in intractable epilepsy and dyskinesia. METHODS: A retrospective, multicenter chart review of patients sharing the same homozygous FRRS1L (p.Gly246del) pathogenic variant identified by clinical genetic testing. Clinical information was collected regarding neurodevelopmental outcomes, neuroimaging, electrographic features and clinical response to antiseizure medications. RESULTS: Fifteen patients from 12 different families of Puerto Rican ancestry were homozygous for the FRRS1L (p.Gly246del) pathogenic variant, with ages ranging from 1 to 25 years. The onset of seizures was from 6 to 24 months. All had hypotonia, severe global developmental delay, and most had hyperkinetic involuntary movements. Developmental regression during the first year of life was common (86%). Electroencephalogram showed hypsarrhythmia in 66% (10/15), with many older children evolving into Lennox-Gastaut syndrome. Six patients demonstrated progressive volume loss and/or cerebellar atrophy on brain magnetic resonance imaging (MRI). CONCLUSIONS: We describe the largest cohort to date of patients with epileptic encephalopathy. We estimate that 0.76% of unaffected individuals of Puerto Rican ancestry carry this pathogenic variant due to a founder effect. Children homozygous for the FRRS1L (p.Gly246del) Boricua variant exhibit a very homogenous phenotype of early developmental regression and epilepsy, starting with infantile spasms and evolving into Lennox-Gastaut syndrome with hyperkinetic movement disorder.

5.
Circ Genom Precis Med ; 13(4): e002680, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32602732

RESUMO

BACKGROUND: We examined how expanding electrocardiographic trait genome-wide association studies to include ancestrally diverse populations, prioritize more precise phenotypic measures, and evaluate evidence for shared genetic effects enabled the detection and characterization of loci. METHODS: We decomposed 10 seconds, 12-lead electrocardiograms from 34 668 multi-ethnic participants (15% Black; 30% Hispanic/Latino) into 6 contiguous, physiologically distinct (P wave, PR segment, QRS interval, ST segment, T wave, and TP segment) and 2 composite, conventional (PR interval and QT interval) interval scale traits and conducted multivariable-adjusted, trait-specific univariate genome-wide association studies using 1000-G imputed single-nucleotide polymorphisms. Evidence of shared genetic effects was evaluated by aggregating meta-analyzed univariate results across the 6 continuous electrocardiographic traits using the combined phenotype adaptive sum of powered scores test. RESULTS: We identified 6 novels (CD36, PITX2, EMB, ZNF592, YPEL2, and BC043580) and 87 known loci (adaptive sum of powered score test P<5×10-9). Lead single-nucleotide polymorphism rs3211938 at CD36 was common in Blacks (minor allele frequency=10%), near monomorphic in European Americans, and had effects on the QT interval and TP segment that ranked among the largest reported to date for common variants. The other 5 novel loci were observed when evaluating the contiguous but not the composite electrocardiographic traits. Combined phenotype testing did not identify novel electrocardiographic loci unapparent using traditional univariate approaches, although this approach did assist with the characterization of known loci. CONCLUSIONS: Despite including one-third as many participants as published electrocardiographic trait genome-wide association studies, our study identified 6 novel loci, emphasizing the importance of ancestral diversity and phenotype resolution in this era of ever-growing genome-wide association studies.

6.
Nature ; 582(7811): 234-239, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32499652

RESUMO

On average, Peruvian individuals are among the shortest in the world1. Here we show that Native American ancestry is associated with reduced height in an ethnically diverse group of Peruvian individuals, and identify a population-specific, missense variant in the FBN1 gene (E1297G) that is significantly associated with lower height. Each copy of the minor allele (frequency of 4.7%) reduces height by 2.2 cm (4.4 cm in homozygous individuals). To our knowledge, this is the largest effect size known for a common height-associated variant. FBN1 encodes the extracellular matrix protein fibrillin 1, which is a major structural component of microfibrils. We observed less densely packed fibrillin-1-rich microfibrils with irregular edges in the skin of individuals who were homozygous for G1297 compared with individuals who were homozygous for E1297. Moreover, we show that the E1297G locus is under positive selection in non-African populations, and that the E1297 variant shows subtle evidence of positive selection specifically within the Peruvian population. This variant is also significantly more frequent in coastal Peruvian populations than in populations from the Andes or the Amazon, which suggests that short stature might be the result of adaptation to factors that are associated with the coastal environment in Peru.


Assuntos
Estatura/genética , Fibrilina-1/genética , Mutação de Sentido Incorreto , Seleção Genética , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Hereditariedade , Humanos , Índios Sul-Americanos/genética , Masculino , Microfibrilas/química , Microfibrilas/genética , Peru
9.
J Hepatol ; 72(6): 1070-1081, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32145261

RESUMO

BACKGROUND & AIMS: The Ile138Met variant (rs738409) in the PNPLA3 gene has the largest effect on non-alcoholic fatty liver disease (NAFLD), increasing the risk of progression to severe forms of liver disease. It remains unknown if the variant plays a role in age of NAFLD onset. We aimed to determine if rs738409 impacts on the age of NAFLD diagnosis. METHODS: We applied a novel natural language processing (NLP) algorithm to a longitudinal electronic health records (EHR) dataset of >27,000 individuals with genetic data from a multi-ethnic biobank, defining NAFLD cases (n = 1,703) and confirming controls (n = 8,119). We conducted i) a survival analysis to determine if age at diagnosis differed by rs738409 genotype, ii) a receiver operating characteristics analysis to assess the utility of the rs738409 genotype in discriminating NAFLD cases from controls, and iii) a phenome-wide association study (PheWAS) between rs738409 and 10,095 EHR-derived disease diagnoses. RESULTS: The PNPLA3 G risk allele was associated with: i) earlier age of NAFLD diagnosis, with the strongest effect in Hispanics (hazard ratio 1.33; 95% CI 1.15-1.53; p <0.0001) among whom a NAFLD diagnosis was 15% more likely in risk allele carriers vs. non-carriers; ii) increased NAFLD risk (odds ratio 1.61; 95% CI 1.349-1.73; p <0.0001), with the strongest effect among Hispanics (odds ratio 1.43; 95% CI 1.28-1.59; p <0.0001); iii) additional liver diseases in a PheWAS (p <4.95 × 10-6) where the risk variant also associated with earlier age of diagnosis. CONCLUSION: Given the role of the rs738409 in NAFLD diagnosis age, our results suggest that stratifying risk within populations known to have an enhanced risk of liver disease, such as Hispanic carriers of the rs738409 variant, would be effective in earlier identification of those who would benefit most from early NAFLD prevention and treatment strategies. LAY SUMMARY: Despite clear associations between the PNPLA3 rs738409 variant and elevated risk of progression from non-alcoholic fatty liver disease (NAFLD) to more severe forms of liver disease, it remains unknown if PNPLA3 rs738409 plays a role in the age of NAFLD onset. Herein, we found that this risk variant is associated with an earlier age of NAFLD and other liver disease diagnoses; an observation most pronounced in Hispanic Americans. We conclude that PNPLA3 rs738409 could be used to better understand liver disease risk within vulnerable populations and identify patients that may benefit from early prevention strategies.

10.
Nature ; 577(7789): 179-189, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31915397

RESUMO

A primary goal of human genetics is to identify DNA sequence variants that influence biomedical traits, particularly those related to the onset and progression of human disease. Over the past 25 years, progress in realizing this objective has been transformed by advances in technology, foundational genomic resources and analytical tools, and by access to vast amounts of genotype and phenotype data. Genetic discoveries have substantially improved our understanding of the mechanisms responsible for many rare and common diseases and driven development of novel preventative and therapeutic strategies. Medical innovation will increasingly focus on delivering care tailored to individual patterns of genetic predisposition.


Assuntos
Variação Genética , Animais , Testes Genéticos , Genômica , Genótipo , Humanos , Fenótipo , Doenças Raras/genética
11.
JAMA ; 322(22): 2191-2202, 2019 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-31821430

RESUMO

Importance: Hereditary transthyretin (TTR) amyloid cardiomyopathy (hATTR-CM) due to the TTR V122I variant is an autosomal-dominant disorder that causes heart failure in elderly individuals of African ancestry. The clinical associations of carrying the variant, its effect in other African ancestry populations including Hispanic/Latino individuals, and the rates of achieving a clinical diagnosis in carriers are unknown. Objective: To assess the association between the TTR V122I variant and heart failure and identify rates of hATTR-CM diagnosis among carriers with heart failure. Design, Setting, and Participants: Cross-sectional analysis of carriers and noncarriers of TTR V122I of African ancestry aged 50 years or older enrolled in the Penn Medicine Biobank between 2008 and 2017 using electronic health record data from 1996 to 2017. Case-control study in participants of African and Hispanic/Latino ancestry with and without heart failure in the Mount Sinai BioMe Biobank enrolled between 2007 and 2015 using electronic health record data from 2007 to 2018. Exposures: TTR V122I carrier status. Main Outcomes and Measures: The primary outcome was prevalent heart failure. The rate of diagnosis with hATTR-CM among TTR V122I carriers with heart failure was measured. Results: The cross-sectional cohort included 3724 individuals of African ancestry with a median age of 64 years (interquartile range, 57-71); 1755 (47%) were male, 2896 (78%) had a diagnosis of hypertension, and 753 (20%) had a history of myocardial infarction or coronary revascularization. There were 116 TTR V122I carriers (3.1%); 1121 participants (30%) had heart failure. The case-control study consisted of 2307 individuals of African ancestry and 3663 Hispanic/Latino individuals; the median age was 73 years (interquartile range, 68-80), 2271 (38%) were male, 4709 (79%) had a diagnosis of hypertension, and 1008 (17%) had a history of myocardial infarction or coronary revascularization. There were 1376 cases of heart failure. TTR V122I was associated with higher rates of heart failure (cross-sectional cohort: n = 51/116 TTR V122I carriers [44%], n = 1070/3608 noncarriers [30%], adjusted odds ratio, 1.7 [95% CI, 1.2-2.4], P = .006; case-control study: n = 36/1376 heart failure cases [2.6%], n = 82/4594 controls [1.8%], adjusted odds ratio, 1.8 [95% CI, 1.2-2.7], P = .008). Ten of 92 TTR V122I carriers with heart failure (11%) were diagnosed as having hATTR-CM; the median time from onset of symptoms to clinical diagnosis was 3 years. Conclusions and Relevance: Among individuals of African or Hispanic/Latino ancestry enrolled in 2 academic medical center-based biobanks, the TTR V122I genetic variant was significantly associated with heart failure.


Assuntos
Afro-Americanos/genética , Neuropatias Amiloides Familiares/genética , Insuficiência Cardíaca/genética , Hispano-Americanos/genética , Pré-Albumina/genética , Centros Médicos Acadêmicos , Idoso , Neuropatias Amiloides Familiares/complicações , Neuropatias Amiloides Familiares/etnologia , Bancos de Espécimes Biológicos , Estudos de Casos e Controles , Estudos Transversais , Feminino , Variação Genética , Insuficiência Cardíaca/etnologia , Humanos , Masculino , Pessoa de Meia-Idade
14.
BMC Med Genomics ; 12(Suppl 6): 108, 2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31345219

RESUMO

BACKGROUND: Genetic loss-of-function variants (LoFs) associated with disease traits are increasingly recognized as critical evidence for the selection of therapeutic targets. We integrated the analysis of genetic and clinical data from 10,511 individuals in the Mount Sinai BioMe Biobank to identify genes with loss-of-function variants (LoFs) significantly associated with cardiovascular disease (CVD) traits, and used RNA-sequence data of seven metabolic and vascular tissues isolated from 600 CVD patients in the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) study for validation. We also carried out in vitro functional studies of several candidate genes, and in vivo studies of one gene. RESULTS: We identified LoFs in 433 genes significantly associated with at least one of 10 major CVD traits. Next, we used RNA-sequence data from the STARNET study to validate 115 of the 433 LoF harboring-genes in that their expression levels were concordantly associated with corresponding CVD traits. Together with the documented hepatic lipid-lowering gene, APOC3, the expression levels of six additional liver LoF-genes were positively associated with levels of plasma lipids in STARNET. Candidate LoF-genes were subjected to gene silencing in HepG2 cells with marked overall effects on cellular LDLR, levels of triglycerides and on secreted APOB100 and PCSK9. In addition, we identified novel LoFs in DGAT2 associated with lower plasma cholesterol and glucose levels in BioMe that were also confirmed in STARNET, and showed a selective DGAT2-inhibitor in C57BL/6 mice not only significantly lowered fasting glucose levels but also affected body weight. CONCLUSION: In sum, by integrating genetic and electronic medical record data, and leveraging one of the world's largest human RNA-sequence datasets (STARNET), we identified known and novel CVD-trait related genes that may serve as targets for CVD therapeutics and as such merit further investigation.

15.
Front Genet ; 10: 511, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31249589

RESUMO

Uterine fibroids affect up to 77% of women by menopause and account for up to $34 billion in healthcare costs each year. Although fibroid risk is heritable, genetic risk for fibroids is not well understood. We conducted a two-stage case-control meta-analysis of genetic variants in European and African ancestry women with and without fibroids classified by a previously published algorithm requiring pelvic imaging or confirmed diagnosis. Women from seven electronic Medical Records and Genomics (eMERGE) network sites (3,704 imaging-confirmed cases and 5,591 imaging-confirmed controls) and women of African and European ancestry from UK Biobank (UKB, 5,772 cases and 61,457 controls) were included in the discovery genome-wide association study (GWAS) meta-analysis. Variants showing evidence of association in Stage I GWAS (P < 1 × 10-5) were targeted in an independent replication sample of African and European ancestry individuals from the UKB (Stage II) (12,358 cases and 138,477 controls). Logistic regression models were fit with genetic markers imputed to a 1000 Genomes reference and adjusted for principal components for each race- and site-specific dataset, followed by fixed-effects meta-analysis. Final analysis with 21,804 cases and 205,525 controls identified 326 genome-wide significant variants in 11 loci, with three novel loci at chromosome 1q24 (sentinel-SNP rs14361789; P = 4.7 × 10-8), chromosome 16q12.1 (sentinel-SNP rs4785384; P = 1.5 × 10-9) and chromosome 20q13.1 (sentinel-SNP rs6094982; P = 2.6 × 10-8). Our statistically significant findings further support previously reported loci including SNPs near WT1, TNRC6B, SYNE1, BET1L, and CDC42/WNT4. We report evidence of ancestry-specific findings for sentinel-SNP rs10917151 in the CDC42/WNT4 locus (P = 1.76 × 10-24). Ancestry-specific effect-estimates for rs10917151 were in opposite directions (P-Het-between-groups = 0.04) for predominantly African (OR = 0.84) and predominantly European women (OR = 1.16). Genetically-predicted gene expression of several genes including LUZP1 in vagina (P = 4.6 × 10-8), OBFC1 in esophageal mucosa (P = 8.7 × 10-8), NUDT13 in multiple tissues including subcutaneous adipose tissue (P = 3.3 × 10-6), and HEATR3 in skeletal muscle tissue (P = 5.8 × 10-6) were associated with fibroids. The finding for HEATR3 was supported by SNP-based summary Mendelian randomization analysis. Our study suggests that fibroid risk variants act through regulatory mechanisms affecting gene expression and are comprised of alleles that are both ancestry-specific and shared across continental ancestries.

16.
Am J Clin Nutr ; 110(1): 16-23, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31161206

RESUMO

BACKGROUND: African Americans (AAs) and Hispanic/Latinos (HLs) have higher risk of obesity than European Americans, possibly due to differences in environment and lifestyle, but also reflecting differences in genetic background. OBJECTIVE: To gain insight into factors contributing to BMI (in kg/m2) and obesity risk (BMI ≥ 30) among ancestry groups, we investigate the role of self-reported ancestry, proportion of genetic African ancestry, and country of birth in 6368 self-identified AA and 7569 HL participants of the New York-based BioMe Biobank. METHODS: AAs and HLs are admixed populations that trace their genetic ancestry to the Americas, Africa, and Europe. The proportion of African ancestry (PAA), quantified using ADMIXTURE, was higher among self-reported AA (median: 87%; IQR: 79-92%) than among HL (26%; 15-41%) participants. Approximately 18% of AA and 59% of HL participants were non-US-born. RESULTS: Because of significant differences between sexes (PPAA*sex interaction = 4.8 × 10-22), we considered women and men separately. Among women, country of birth and genetic ancestry contributed independently to BMI. US-born women had a BMI 1.99 higher than those born abroad (P = 7.7 × 10-25). Every 10% increase in PAA was associated with a BMI 0.29 higher (P = 7.1 × 10-10). After accounting for PAA and country of birth, the contribution of self-reported ancestry was small (P = 0.046). The contribution of PAA to higher BMI was significantly more pronounced among US-born (0.35/10%PAA, P = 0.003) than among non-US-born (0.26/10%PAA, P = 0.01) women (PPAA*sex interaction = 0.004). In contrast, among men, only US-born status influenced BMI. US-born men had a BMI 1.33 higher than non-US-born men, whereas PAA and self-reported ancestry were not associated with BMI. Associations with obesity risk were similar to those observed for BMI. CONCLUSIONS: Being US-born is associated with a substantially higher BMI and risk of obesity in both men and women. Genetic ancestry, but not self-reported ancestry, is associated with obesity susceptibility, but only among US-born women in this New York-based population.


Assuntos
Afro-Americanos/genética , Grupos de Populações Continentais/genética , Predisposição Genética para Doença , Hispano-Americanos/genética , Obesidade/genética , Grupo com Ancestrais do Continente Africano/genética , Fatores Etários , Idoso , Índice de Massa Corporal , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Técnicas de Genotipagem , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Características de Residência , Fatores Sexuais , Estados Unidos/etnologia
17.
Am J Hum Genet ; 104(6): 1088-1096, 2019 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-31104772

RESUMO

Conceptual frameworks are useful in research because they can highlight priority research domains, inform decisions about interventions, identify outcomes and factors to measure, and display how factors might relate to each other to generate and test hypotheses. Discovery, translational, and implementation research are all critical to the overall mission of genomic medicine and prevention, but they have yet to be organized into a unified conceptual framework. To fill this gap, our diverse team collaborated to develop the Genomic Medicine Integrative Research (GMIR) Framework, a simple but comprehensive tool to aid the genomics community in developing research questions, strategies, and measures and in integrating genomic medicine and prevention into clinical practice. Here we present the GMIR Framework and its development, along with examples of its use for research development, demonstrating how we applied it to select and harmonize measures for use across diverse genomic medicine implementation projects. Researchers can utilize the GMIR Framework for their own research, collaborative investigations, and clinical implementation efforts; clinicians can use it to establish and evaluate programs; and all stakeholders can use it to help allocate resources and make sure that the full complexity of etiology is included in research and program design, development, and evaluation.


Assuntos
Pesquisa Biomédica , Prestação Integrada de Cuidados de Saúde , Genética Médica , Genômica/métodos , Medicina de Precisão/métodos , Doenças Raras/genética , Projetos de Pesquisa , Humanos , Modelos Teóricos
18.
Annu Rev Genomics Hum Genet ; 20: 181-200, 2019 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-30978304

RESUMO

The past decade has seen a technological revolution in human genetics that has empowered population-level investigations into genetic associations with phenotypes. Although these discoveries rely on genetic variation across individuals, association studies have overwhelmingly been performed in populations of European descent. In this review, we describe limitations faced by single-population studies and provide an overview of strategies to improve global representation in existing data sets and future human genomics research via diversity-focused, multiethnic studies. We highlight the successes of individual studies and meta-analysis consortia that have provided unique knowledge. Additionally, we outline the approach taken by the Population Architecture Using Genomics and Epidemiology (PAGE) study to develop best practices for performing genetic epidemiology in multiethnic contexts. Finally, we discuss how limiting investigations to single populations impairs findings in the clinical domain for both rare-variant identification and genetic risk prediction.


Assuntos
Grupos de Populações Continentais/genética , Grupos Étnicos/genética , Variação Genética , Genética Humana/tendências , Metagenômica/tendências , Epidemiologia Molecular/tendências , Viés , Bases de Dados Factuais , Genoma Humano , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Fenótipo
19.
Cell ; 177(1): 58-69, 2019 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-30901549

RESUMO

Personalized medicine has largely been enabled by the integration of genomic and other data with electronic health records (EHRs) in the United States and elsewhere. Increased EHR adoption across various clinical settings and the establishment of EHR-linked population-based biobanks provide unprecedented opportunities for the types of translational and implementation research that drive personalized medicine. We review advances in the digitization of health information and the proliferation of genomic research in health systems and provide insights into emerging paths for the widespread implementation of personalized medicine.


Assuntos
Registros Eletrônicos de Saúde/tendências , Medicina de Precisão/métodos , Medicina de Precisão/tendências , Testes Genéticos , Genoma Humano/genética , Genômica/métodos , Genômica/tendências , Humanos , Estados Unidos
20.
Nat Commun ; 10(1): 880, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30787307

RESUMO

Asthma is a complex disease with striking disparities across racial and ethnic groups. Despite its relatively high burden, representation of individuals of African ancestry in asthma genome-wide association studies (GWAS) has been inadequate, and true associations in these underrepresented minority groups have been inconclusive. We report the results of a genome-wide meta-analysis from the Consortium on Asthma among African Ancestry Populations (CAAPA; 7009 asthma cases, 7645 controls). We find strong evidence for association at four previously reported asthma loci whose discovery was driven largely by non-African populations, including the chromosome 17q12-q21 locus and the chr12q13 region, a novel (and not previously replicated) asthma locus recently identified by the Trans-National Asthma Genetic Consortium (TAGC). An additional seven loci reported by TAGC show marginal evidence for association in CAAPA. We also identify two novel loci (8p23 and 8q24) that may be specific to asthma risk in African ancestry populations.


Assuntos
Afro-Americanos/genética , Asma/genética , Predisposição Genética para Doença/genética , Asma/epidemiologia , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 8/genética , Loci Gênicos , Estudo de Associação Genômica Ampla , Hispano-Americanos/genética , Humanos , Polimorfismo de Nucleotídeo Único/genética , Estados Unidos/epidemiologia
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