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1.
Nat Commun ; 12(1): 5078, 2021 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-34426578

RESUMO

Genome-wide association studies (GWAS) have identified loci for kidney disease, but the causal variants, genes, and pathways remain unknown. Here we identify two kidney disease genes Dipeptidase 1 (DPEP1) and Charged Multivesicular Body Protein 1 A (CHMP1A) via the triangulation of kidney function GWAS, human kidney expression, and methylation quantitative trait loci. Using single-cell chromatin accessibility and genome editing, we fine map the region that controls the expression of both genes. Mouse genetic models demonstrate the causal roles of both genes in kidney disease. Cellular studies indicate that both Dpep1 and Chmp1a are important regulators of a single pathway, ferroptosis and lead to kidney disease development via altering cellular iron trafficking.


Assuntos
Dipeptidases/genética , Ferroptose/genética , Loci Gênicos , Predisposição Genética para Doença , Nefropatias/genética , Proteínas de Transporte Vesicular/genética , Animais , Nitrogênio da Ureia Sanguínea , Cromatina/metabolismo , Cisplatino , Metilação de DNA/genética , Dipeptidases/deficiência , Dipeptidases/metabolismo , Ácido Fólico , Edição de Genes , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Haploinsuficiência/genética , Humanos , Ferro/metabolismo , Rim/patologia , Nefropatias/induzido quimicamente , Camundongos , Necroptose/genética , Especificidade de Órgãos , Mapeamento Físico do Cromossomo , Piroptose/genética , Locos de Características Quantitativas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Transporte Vesicular/deficiência , Proteínas de Transporte Vesicular/metabolismo
2.
Nat Genet ; 53(9): 1322-1333, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34385711

RESUMO

The functional interpretation of genome-wide association studies (GWAS) is challenging due to the cell-type-dependent influences of genetic variants. Here, we generated comprehensive maps of expression quantitative trait loci (eQTLs) for 659 microdissected human kidney samples and identified cell-type-eQTLs by mapping interactions between cell type abundances and genotypes. By partitioning heritability using stratified linkage disequilibrium score regression to integrate GWAS with single-cell RNA sequencing and single-nucleus assay for transposase-accessible chromatin with high-throughput sequencing data, we prioritized proximal tubules for kidney function and endothelial cells and distal tubule segments for blood pressure pathogenesis. Bayesian colocalization analysis nominated more than 200 genes for kidney function and hypertension. Our study clarifies the mechanism of commonly used antihypertensive and renal-protective drugs and identifies drug repurposing opportunities for kidney disease.


Assuntos
Hipertensão/genética , Túbulos Renais Distais/patologia , Túbulos Renais Proximais/patologia , Locos de Características Quantitativas/genética , Insuficiência Renal Crônica/genética , Sequência de Bases , Mapeamento Cromossômico , Células Endoteliais/patologia , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Polimorfismo de Nucleotídeo Único/genética , Característica Quantitativa Herdável , Insuficiência Renal Crônica/patologia , Análise de Sequência de RNA , Análise de Célula Única
3.
Hum Genet ; 140(10): 1433-1440, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34302236

RESUMO

Uterine fibroids disproportionately impact Black women. Evidence suggests Black women have earlier onset and higher cumulative risk. This risk disparity may be due an imbalance of risk alleles in one parental geographic ancestry subgroup relative to others. We investigated ancestry proportions for the 1000 Genomes phase 3 populations clustered into six geographic groups for association with fibroid traits in Black women (n = 583 cases, 797 controls) and White women (n = 1195 cases, 1164 controls). Global ancestry proportions were estimated using ADMIXTURE. Dichotomous (fibroids status and multiple fibroid status) and continuous outcomes (volume and largest dimension) were modeled for association with ancestry proportions using logistic and linear regression adjusting for age. Effect estimates are reported per 10% increase in genetically inferred ancestry proportion. Among Black women, West African (WAFR) ancestry was associated with fibroid risk, East African ancestry was associated with risk of multiple fibroids, Northern European (NEUR) ancestry was protective for multiple fibroids, Southern European ancestry was protective for fibroids and multiple fibroids, and South Asian (SAS) ancestry was positively associated with volume and largest dimension. In White women, NEUR ancestry was protective for fibroids, SAS ancestry was associated with fibroid risk, and WAFR ancestry was positively associated with volume and largest dimension. These results suggest that a proportion of fibroid risk and fibroid trait racial disparities are due to genetic differences between geographic groups. Further investigation at the local ancestry and single variant levels may yield novel insights into disease architecture and genetic mechanisms underlying ethnic disparities in fibroid risk.


Assuntos
Afro-Americanos/genética , Grupos Étnicos/genética , Grupo com Ancestrais do Continente Europeu/genética , Variação Genética , Geografia , Leiomioma/genética , Neoplasias Uterinas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Fatores Raciais , Fatores de Risco
5.
J Clin Endocrinol Metab ; 106(7): 2124-2132, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-33895829

RESUMO

CONTEXT: A genetic predisposition to lower thyrotropin (TSH) levels is associated with increased atrial fibrillation (AF) risk through undefined mechanisms. OBJECTIVE: Defining the genetic mediating mechanisms could lead to improved targeted therapies to mitigate AF risk. METHODS: We used 2-sample mendelian randomization (MR) to test associations between TSH-associated single-nucleotide variations and 16 candidate mediators. We then performed multivariable mendelian randomization (MVMR) to test for a significant attenuation of the genetic association between TSH and AF, after adjusting for each mediator significantly associated with TSH. RESULTS: Four candidate mediators (free thyroxine, systolic blood pressure, heart rate, and height) were significantly inversely associated with genetically predicted TSH after adjusting for multiple testing. In MVMR analyses, adjusting for height significantly decreased the magnitude of the association between TSH and AF from -0.12 (SE 0.02) occurrences of AF per SD change in height to -0.06 (0.02) (P = .005). Adjusting for the other candidate mediators did not significantly attenuate the association. CONCLUSION: The genetic association between TSH and increased AF risk is mediated, in part, by taller stature. Thus, some genetic mechanisms underlying TSH variability may contribute to AF risk through mechanisms determining height occurring early in life that differ from those driven by thyroid hormone-level elevations in later life.


Assuntos
Fibrilação Atrial/genética , Estatura/genética , Predisposição Genética para Doença/genética , Tireotropina/sangue , Pressão Sanguínea/genética , Estudo de Associação Genômica Ampla , Fatores de Risco de Doenças Cardíacas , Humanos , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Testes de Função Tireóidea , Glândula Tireoide/metabolismo
9.
J Hypertens ; 39(4): 633-642, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33534346

RESUMO

OBJECTIVES: Ethnic disparities in hypertension prevalence are well documented, though the influence of genetic ancestry is unclear. The aim of this study was to evaluate associations of geographic genetic ancestry with hypertension and underlying blood pressure traits. METHODS: We tested genetically inferred ancestry proportions from five 1000 Genomes reference populations (GBR, PEL, YRI, CHB, and LWK) for association with four continuous blood pressure (BP) traits (SBP, DBP, PP, MAP) and the dichotomous outcomes hypertension and apparent treatment-resistant hypertension in 220 495 European American, 59 927 African American, and 21 273 Hispanic American individuals from the Million Veteran Program. Ethnicity stratified results were meta-analyzed to report effect estimates per 10% difference for a given ancestry proportion in all samples. RESULTS: Percentage GBR was negatively associated with BP (P = 2.13 × 10-19, 7.92 × 10-8, 4.41 × 10-11, and 3.57 × 10-13 for SBP, DBP, PP, and MAP, respectively; coefficient range -0.10 to -0.21 mmHg per 10% increase in ancestry proportion) and was protective against hypertension [P = 2.59 × 10-5, odds ratio (OR) = 0.98] relative to other ancestries. YRI percentage was positively associated with BP (P = 1.63 × 10-23, 1.94 × 10-26, 0.012, and 3.26 × 10-29 for SBP, DBP, PP, and MAP, respectively; coefficient range 0.06-0.32 mmHg per 10% increase in ancestry proportion) and was positively associated with hypertension risk (P = 3.10 × 10-11, OR = 1.04) and apparent treatment-resistant hypertension risk (P = 1.86 × 10-4, OR = 1.04) compared with other ancestries. Percentage PEL was inversely associated with DBP (P = 2.84 × 10-5, beta = -0.11 mmHg per 10% increase in ancestry proportion). CONCLUSION: These results demonstrate that risk for BP traits varies significantly by genetic ancestry. Our findings provide insight into the geographic origin of genetic factors underlying hypertension risk and establish that a portion of BP trait ethnic disparities are because of genetic differences between ancestries.


Assuntos
Hipertensão , Afro-Americanos , Pressão Sanguínea/genética , Grupo com Ancestrais do Continente Europeu , Hispano-Americanos , Humanos , Hipertensão/epidemiologia , Hipertensão/genética
10.
Clin Nutr ; 40(5): 3305-3313, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33190990

RESUMO

BACKGROUND & AIMS: In contrast to many observational studies, large-scale randomized trials do not support the protective role of vitamin D for the prevention of colorectal neoplasia. However, in previous studies, individuals with blunted parathyroid hormone (PTH) response to vitamin D insufficiency/deficiency (BPRVID), were not differentiated from those with high PTH response to vitamin D insufficiency/deficiency (HPRVID). Individuals with BPRVID are responsive to magnesium treatment, particularly treatment of magnesium plus vitamin D while those with HPRVID are responsive to vitamin D treatment. We prospectively compared these two distinct groups (i.e. BPRVID and HPRVID) for risk of incident adenoma, metachronous adenoma, and incident colorectal cancer (CRC) METHODS: Three nested case-control studies in the Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) Screening Trial. RESULTS: We found optimal 25(OH)D levels were associated with a significantly reduced risk of CRC, primarily among women. The associations between 25(OH)D and CRC risk significantly differed by PTH levels, particularly among women. Compared to individuals with optimal levels for both 25(OH)D and PTH, all others were at an elevated risk of incident CRC, primarily in women. We found those with BPRVID had 2.56-fold significantly increased risk of CRC compared to 1.65-fold non-significantly increased risk for those with HPRVID. Among women, we observed those with BPRVID had 4.79-6.25-fold significantly increased risks of incident CRC and adenoma whereas those with HPRVID had 3.65-fold significantly increased risk of CRC. CONCLUSIONS: Individuals with BPRVID are at higher risks of incident adenoma and CRC compared to those with HPRVID, particularly among women.

11.
Nat Genet ; 52(12): 1314-1332, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33230300

RESUMO

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10-8), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.


Assuntos
Pressão Sanguínea/genética , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Hipertensão/genética , Fator de Transcrição GATA5/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Mutação/genética , Fosfolipase C beta/genética , Polimorfismo de Nucleotídeo Único/genética
12.
Sci Rep ; 10(1): 7561, 2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32372017

RESUMO

Left ventricular (LV) mass is a prognostic biomarker for incident heart disease and all-cause mortality. Large-scale genome-wide association studies have identified few SNPs associated with LV mass. We hypothesized that a polygenic discovery approach using LV mass measurements made in a clinical population would identify risk factors and diseases associated with adverse LV remodeling. We developed a polygenic single nucleotide polymorphism-based predictor of LV mass in 7,601 individuals with LV mass measurements made during routine clinical care. We tested for associations between this predictor and 894 clinical diagnoses measured in 58,838 unrelated genotyped individuals. There were 29 clinical phenotypes associated with the LV mass genetic predictor at FDR q < 0.05. Genetically predicted higher LV mass was associated with modifiable cardiac risk factors, diagnoses related to organ dysfunction and conditions associated with abnormal cardiac structure including heart failure and atrial fibrillation. Secondary analyses using polygenic predictors confirmed a significant association between higher LV mass and body mass index and, in men, associations with coronary atherosclerosis and systolic blood pressure. In summary, these analyses show that LV mass-associated genetic variability associates with diagnoses of cardiac diseases and with modifiable risk factors which contribute to these diseases.


Assuntos
Predisposição Genética para Doença , Cardiopatias/epidemiologia , Cardiopatias/etiologia , Ventrículos do Coração/patologia , Herança Multifatorial , Remodelação Ventricular , Ecocardiografia , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Cardiopatias/diagnóstico , Cardiopatias/mortalidade , Ventrículos do Coração/anatomia & histologia , Ventrículos do Coração/diagnóstico por imagem , Humanos , Masculino , Razão de Chances , Tamanho do Órgão , Fenótipo , Polimorfismo de Nucleotídeo Único , Medição de Risco , Fatores de Risco , Remodelação Ventricular/genética
13.
Am J Hypertens ; 32(12): 1146-1153, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31545351

RESUMO

BACKGROUND: Only a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described. METHODS: We conducted a case-control genome-wide association study of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg) or 4 or more medication classes regardless of BP control (nEA = 931, nAA = 228). Both a normotensive control group and a treatment-responsive control group were considered in separate analyses. Normotensive controls were untreated (nEA = 14,210, nAA = 2,480) and had systolic BP/diastolic BP < 140/90 mm Hg. Treatment-responsive controls (nEA = 5,266, nAA = 1,817) had BP at goal (<140/90 mm Hg), while treated with one antihypertensive medication class. Individual cohorts used logistic regression with adjustment for age, sex, study site, and principal components for ancestry to examine the association of single-nucleotide polymorphisms with case-control status. Inverse variance-weighted fixed-effects meta-analyses were carried out using METAL. RESULTS: The known hypertension locus, CASZ1, was a top finding among EAs (P = 1.1 × 10-8) and in the race-combined analysis (P = 1.5 × 10-9) using the normotensive control group (rs12046278, odds ratio = 0.71 (95% confidence interval: 0.6-0.8)). Single-nucleotide polymorphisms in this locus were robustly replicated in the Million Veterans Program (MVP) study in consideration of a treatment-responsive control group. There were no statistically significant findings for the discovery analyses including treatment-responsive controls. CONCLUSION: This genomic discovery effort for aTRH identified CASZ1 as an aTRH risk locus.


Assuntos
Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/genética , Proteínas de Ligação a DNA/genética , Resistência a Medicamentos/genética , Hipertensão/tratamento farmacológico , Hipertensão/genética , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição/genética , Afro-Americanos/genética , Idoso , Anti-Hipertensivos/efeitos adversos , Pressão Sanguínea/efeitos dos fármacos , Estudos de Casos e Controles , DNA (Citosina-5-)-Metiltransferases/genética , Proteínas Associadas à Distrofina/genética , Europa (Continente)/epidemiologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Hipertensão/etnologia , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Cadeias Pesadas de Miosina/genética , Miosina Tipo V/genética , Neuropeptídeos/genética , Farmacogenética , Medição de Risco , Fatores de Risco , Estados Unidos/epidemiologia
14.
Nat Commun ; 10(1): 3842, 2019 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-31451708

RESUMO

Chronic kidney disease (CKD), defined by low estimated glomerular filtration rate (eGFR), contributes to global morbidity and mortality. Here we conduct a transethnic Genome-Wide Association Study of eGFR in 280,722 participants of the Million Veteran Program (MVP), with replication in 765,289 participants from the Chronic Kidney Disease Genetics (CKDGen) Consortium. We identify 82 previously unreported variants, confirm 54 loci, and report interesting findings including association of the sickle cell allele of betaglobin among non-Hispanic blacks. Our transcriptome-wide association study of kidney function in healthy kidney tissue identifies 36 previously unreported and nine known genes, and maps gene expression to renal cell types. In a Phenome-Wide Association Study in 192,868 MVP participants using a weighted genetic score we detect associations with CKD stages and complications and kidney stones. This investigation reinterprets the genetic architecture of kidney function to identify the gene, tissue, and anatomical context of renal homeostasis and the clinical consequences of dysregulation.


Assuntos
Mapeamento Cromossômico/métodos , Taxa de Filtração Glomerular/genética , Rim/fisiopatologia , Insuficiência Renal Crônica/genética , Transcriptoma/genética , Adulto , Idoso , Animais , Linhagem Celular , Estudos de Coortes , Biologia Computacional , Feminino , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Rim/citologia , Rim/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , RNA-Seq , Insuficiência Renal Crônica/fisiopatologia , Estados Unidos , United States Department of Veterans Affairs , Veteranos
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.
Sci Rep ; 9(1): 6077, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30988330

RESUMO

Benign prostatic hyperplasia (BPH) results in a significant public health burden due to the morbidity caused by the disease and many of the available remedies. As much as 70% of men over 70 will develop BPH. Few studies have been conducted to discover the genetic determinants of BPH risk. Understanding the biological basis for this condition may provide necessary insight for development of novel pharmaceutical therapies or risk prediction. We have evaluated SNP-based heritability of BPH in two cohorts and conducted a genome-wide association study (GWAS) of BPH risk using 2,656 cases and 7,763 controls identified from the Electronic Medical Records and Genomics (eMERGE) network. SNP-based heritability estimates suggest that roughly 60% of the phenotypic variation in BPH is accounted for by genetic factors. We used logistic regression to model BPH risk as a function of principal components of ancestry, age, and imputed genotype data, with meta-analysis performed using METAL. The top result was on chromosome 22 in SYN3 at rs2710383 (p-value = 4.6 × 10-7; Odds Ratio = 0.69, 95% confidence interval = 0.55-0.83). Other suggestive signals were near genes GLGC, UNCA13, SORCS1 and between BTBD3 and SPTLC3. We also evaluated genetically-predicted gene expression in prostate tissue. The most significant result was with increasing predicted expression of ETV4 (chr17; p-value = 0.0015). Overexpression of this gene has been associated with poor prognosis in prostate cancer. In conclusion, although there were no genome-wide significant variants identified for BPH susceptibility, we present evidence supporting the heritability of this phenotype, have identified suggestive signals, and evaluated the association between BPH and genetically-predicted gene expression in prostate.


Assuntos
Predisposição Genética para Doença , Padrões de Herança , Hiperplasia Prostática/genética , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Estudos de Casos e Controles , Registros Eletrônicos de Saúde/estatística & dados numéricos , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Próstata/patologia , Hiperplasia Prostática/epidemiologia , Hiperplasia Prostática/patologia
17.
Nat Genet ; 51(1): 51-62, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30578418

RESUMO

In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.


Assuntos
Pressão Sanguínea/genética , Grupos Étnicos/genética , Adolescente , Animais , Feminino , Expressão Gênica/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Túbulos Renais/fisiologia , Masculino , Camundongos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Transcriptoma/genética , Regulação para Cima/genética
18.
Eur J Hum Genet ; 27(2): 269-277, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30262922

RESUMO

High blood pressure (BP) is a major risk factor for cardiovascular disease (CVD) and is more prevalent in African Americans as compared to other US groups. Although large, population-based genome-wide association studies (GWAS) have identified over 300 common polymorphisms modulating inter-individual BP variation, largely in European ancestry subjects, most of them do not localize to regions previously identified through family-based linkage studies. This discrepancy has remained unexplained despite the statistical power differences between current GWAS and prior linkage studies. To address this issue, we performed genome-wide linkage analysis of BP traits in African-American families from the Family Blood Pressure Program (FBPP) and genotyped on the Illumina Human Exome BeadChip v1.1. We identified a genomic region on chromosome 1q31 with LOD score 3.8 for pulse pressure (PP), a region we previously implicated in DBP studies of European ancestry families. Although no reported GWAS variants map to this region, combined linkage and association analysis of PP identified 81 rare and low frequency exonic variants accounting for the linkage evidence. Replication analysis in eight independent African ancestry cohorts (N = 16,968) supports this specific association with PP (P = 0.0509). Additional association and network analyses identified multiple potential candidate genes in this region expressed in multiple tissues and with a strong biological support for a role in BP. In conclusion, multiple genes and rare variants on 1q31 contribute to PP variation. Beyond producing new insights into PP, we demonstrate how family-based linkage and association studies can implicate specific rare and low frequency variants for complex traits.


Assuntos
Cromossomos Humanos Par 1/genética , Hipertensão/genética , Polimorfismo de Nucleotídeo Único , Afro-Americanos/genética , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Hipertensão/etnologia , Desequilíbrio de Ligação
20.
Nat Genet ; 50(10): 1412-1425, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30224653

RESUMO

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.


Assuntos
Pressão Sanguínea/genética , Locos de Características Quantitativas , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Células Cultivadas , Feminino , Loci Gênicos , Predisposição Genética para Doença , Testes Genéticos/métodos , Genética Populacional/métodos , Estudo de Associação Genômica Ampla , Células Endoteliais da Veia Umbilical Humana , Humanos , Hipertensão/genética , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco
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