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A Transcriptome-Wide Association Study Identifies Candidate Susceptibility Genes for Pancreatic Cancer Risk.
Liu D, Zhou D, Sun Y, Zhu J, Ghoneim D, Wu C, Yao Q, Gamazon ER, Cox NJ, Wu L
(2020) Cancer Res 80: 4346-4354
MeSH Terms: Age Factors, Case-Control Studies, European Continental Ancestry Group, Female, Gene Expression Regulation, Neoplastic, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Models, Genetic, Pancreatic Neoplasms, Polymorphism, Single Nucleotide
Show Abstract · Added September 15, 2020
Pancreatic cancer is among the most well-characterized cancer types, yet a large proportion of the heritability of pancreatic cancer risk remains unclear. Here, we performed a large transcriptome-wide association study to systematically investigate associations between genetically predicted gene expression in normal pancreas tissue and pancreatic cancer risk. Using data from 305 subjects of mostly European descent in the Genotype-Tissue Expression Project, we built comprehensive genetic models to predict normal pancreas tissue gene expression, modifying the UTMOST (unified test for molecular signatures). These prediction models were applied to the genetic data of 8,275 pancreatic cancer cases and 6,723 controls of European ancestry. Thirteen genes showed an association of genetically predicted expression with pancreatic cancer risk at an FDR ≤ 0.05, including seven previously reported genes (, and ) and six novel genes not yet reported for pancreatic cancer risk [6q27: OR (95% confidence interval (CI), 1.54 (1.25-1.89); 13q12.13: OR (95% CI), 0.78 (0.70-0.88); 14q24.3: OR (95% CI), 1.35 (1.17-1.56); 17q12: OR (95% CI), 6.49 (2.96-14.27); 17q21.1: OR (95% CI), 1.94 (1.45-2.58); and 20p13: OR (95% CI): 1.41 (1.20-1.66)]. The associations for 10 of these genes (, and ) remained statistically significant even after adjusting for risk SNPs identified in previous genome-wide association study. Collectively, this analysis identified novel candidate susceptibility genes for pancreatic cancer that warrant further investigation. SIGNIFICANCE: A transcriptome-wide association analysis identified seven previously reported and six novel candidate susceptibility genes for pancreatic cancer risk.
©2020 American Association for Cancer Research.
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12 MeSH Terms
Antimüllerian hormone and F2-isoprostanes in the Coronary Artery Risk Development in Young Adults (CARDIA) Study.
Kim C, Slaughter JC, Terry JG, Jacobs DR, Parikh N, Appiah D, Leader B, Moravek MB, Wellons MF
(2020) Fertil Steril 114: 646-652
MeSH Terms: Adult, African Americans, Age Factors, Anti-Mullerian Hormone, Biomarkers, Cross-Sectional Studies, European Continental Ancestry Group, F2-Isoprostanes, Female, Humans, Ovarian Reserve, Oxidative Stress, United States
Show Abstract · Added July 20, 2020
OBJECTIVE - To examine whether F2-isoprostanes, a marker of systematic oxidative stress, are associated with antimüllerian hormone (AMH), an indicator of ovarian reserve, in a population-based cohort of women of black and white ethnicities.
DESIGN - Cross-sectional analysis.
SETTING - Not applicable.
PATIENTS - The CARDIA Women's Study, a population-based cohort. Black (n = 398) and white (n = 432) late reproductive-aged women (mean age 40 ± 3.6 years) without histories of gynecologic surgery.
MAIN OUTCOME MEASURES - Log-transformed serum AMH concentrations.
RESULTS - Linear regression models evaluated whether plasma F2-isoprostanes were associated with log-transformed AMH after adjustment for age, race, smoking, body mass index, and oral contraceptive pill use. Higher levels of F2-isoprostanes were associated with lower AMH levels (β -0.048 per standard deviation, 95% confidence interval -0.087, -0.01). The observed associations were stronger at younger ages (P=.04 for interaction between levels of age and F2-isoprostanes). Indicators of other steps in the oxidative stress pathway (superoxide dismutase, paraoxonase activity, oxidized low-density lipoprotein cholesterol, and carotenoids) were not associated with AMH, although lower phospholipase A2 activity (β 0.036 per standard deviation, 95% confidence interval 0.001, 0.071) was associated with lower AMH across all ages.
CONCLUSION - In a population-based cohort, higher levels of F2-isoprostanes were associated with lower ovarian reserve, particularly at younger ages.
Copyright © 2020 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.
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Health disparities among tennessee pediatric renal tumor patients.
Neuzil K, Apple A, Sybenga A, Chen H, Zhao S, Whiteside M, Correa H, Phelps HM, Lovvorn HN
(2020) J Pediatr Surg 55: 1081-1087
MeSH Terms: Adolescent, African Americans, Carcinoma, Renal Cell, Child, Child, Preschool, Cohort Studies, European Continental Ancestry Group, Female, Healthcare Disparities, Humans, Infant, Kidney Neoplasms, Male, Neoplasm Staging, Registries, Retrospective Studies, Sarcoma, Tennessee, Wilms Tumor
Show Abstract · Added November 30, 2020
BACKGROUND/PURPOSE - Wilms tumor (WT) poses a cancer health disparity to black children globally, which has not been evaluated thoroughly for other pediatric renal cancers. We aimed to characterize health disparities among Tennessee children treated for any renal cancer.
METHODS - The Tennessee Cancer Registry (TCR) was queried for patients ≤18 years having any renal cancer (n = 160). To clarify treatment and outcomes, we performed a retrospective cohort study of pediatric renal cancer patients in our institutional cancer registry (ICR; n = 121). Diagnoses in both registries included WT, Sarcoma/Other, and Renal Cell Carcinoma. Wilcoxon/Pearson, Kaplan-Meier, and logistic regression were completed.
RESULTS - In both registries, WT comprised the most common renal cancer and youngest median age. Sarcoma was intermediate in frequency and age, and RCC was least common, having the oldest age (p < 0.001). In the TCR, black patients comprised 26% of all patients, presented more commonly with distant disease than white patients (37% v. 16%; p = 0.021), and showed worse overall survival (73% v. 89%; p = 0.018), while the ICR showed similar survival between race groups (92% v. 93%, p = 0.868). Sarcoma and metastases were independent predictors of death in both registries (p ≤ 0.002).
CONCLUSIONS - Black children in Tennessee presented with more advanced disease and experienced worse survival when combining all renal cancer types, particularly RCC and Sarcoma. When treated at a comprehensive pediatric cancer center, these survival disparities appear diminished.
TYPE OF STUDY - Prognostic study.
LEVEL OF EVIDENCE - Level II (retrospective cohort).
Copyright © 2020 Elsevier Inc. All rights reserved.
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AGA Technical Review on Gastric Intestinal Metaplasia-Epidemiology and Risk Factors.
Altayar O, Davitkov P, Shah SC, Gawron AJ, Morgan DR, Turner K, Mustafa RA
(2020) Gastroenterology 158: 732-744.e16
MeSH Terms: Ethnic Groups, European Continental Ancestry Group, Gastric Mucosa, Helicobacter Infections, Helicobacter pylori, Humans, Metaplasia, Precancerous Conditions, Risk Factors, Stomach Neoplasms, United States
Added March 3, 2020
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Genome-Wide Association Study of Apparent Treatment-Resistant Hypertension in the CHARGE Consortium: The CHARGE Pharmacogenetics Working Group.
Irvin MR, Sitlani CM, Floyd JS, Psaty BM, Bis JC, Wiggins KL, Whitsel EA, Sturmer T, Stewart J, Raffield L, Sun F, Liu CT, Xu H, Cupples AL, Tanner RM, Rossing P, Smith A, Zilhão NR, Launer LJ, Noordam R, Rotter JI, Yao J, Li X, Guo X, Limdi N, Sundaresan A, Lange L, Correa A, Stott DJ, Ford I, Jukema JW, Gudnason V, Mook-Kanamori DO, Trompet S, Palmas W, Warren HR, Hellwege JN, Giri A, O'donnell C, Hung AM, Edwards TL, Ahluwalia TS, Arnett DK, Avery CL
(2019) Am J Hypertens 32: 1146-1153
MeSH Terms: African Americans, Aged, Antihypertensive Agents, Blood Pressure, Case-Control Studies, DNA (Cytosine-5-)-Methyltransferases, DNA-Binding Proteins, Drug Resistance, Dystrophin-Associated Proteins, Europe, European Continental Ancestry Group, Female, Genetic Loci, Genome-Wide Association Study, Humans, Hypertension, Male, Middle Aged, Myosin Heavy Chains, Myosin Type V, Neuropeptides, Pharmacogenetics, Pharmacogenomic Variants, Polymorphism, Single Nucleotide, Risk Assessment, Risk Factors, Transcription Factors, United States
Show Abstract · Added March 3, 2020
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.
© American Journal of Hypertension, Ltd 2019. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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28 MeSH Terms
Mitochondrial DNA Haplogroups and Delirium During Sepsis.
Samuels DC, Hulgan T, Fessel JP, Billings FT, Thompson JL, Chandrasekhar R, Girard TD
(2019) Crit Care Med 47: 1065-1071
MeSH Terms: Adult, African Americans, Critical Illness, DNA, Mitochondrial, European Continental Ancestry Group, Female, Haplotypes, Humans, Male, Middle Aged, Polymerase Chain Reaction, Retrospective Studies, Sepsis-Associated Encephalopathy, Sequence Analysis, DNA
Show Abstract · Added December 11, 2019
OBJECTIVES - Studies suggest that mitochondrial dysfunction underlies some forms of sepsis-induced organ failure. We sought to test the hypothesis that variations in mitochondrial DNA haplogroup affect susceptibility to sepsis-associated delirium, a common manifestation of acute brain dysfunction during sepsis.
DESIGN - Retrospective cohort study.
SETTING - Medical and surgical ICUs at a large tertiary care center.
PATIENTS - Caucasian and African American adults with sepsis.
MEASUREMENTS AND MAIN RESULTS - We determined each patient's mitochondrial DNA haplogroup using single-nucleotide polymorphisms genotyping data in a DNA databank and extracted outcomes from linked electronic medical records. We then used zero-inflated negative binomial regression to analyze age-adjusted associations between mitochondrial DNA haplogroups and duration of delirium, identified using the Confusion Assessment Method for the ICU. Eight-hundred ten patients accounted for 958 sepsis admissions, with 802 (84%) by Caucasians and 156 (16%) by African Americans. In total, 795 patient admissions (83%) involved one or more days of delirium. The 7% of Caucasians belonging to mitochondrial DNA haplogroup clade IWX experienced more delirium than the 49% in haplogroup H, the most common Caucasian haplogroup (age-adjusted rate ratio for delirium 1.36; 95% CI, 1.13-1.64; p = 0.001). Alternatively, among African Americans the 24% in haplogroup L2 experienced less delirium than those in haplogroup L3, the most common African haplogroup (adjusted rate ratio for delirium 0.60; 95% CI, 0.38-0.94; p = 0.03).
CONCLUSIONS - Variations in mitochondrial DNA are associated with development of and protection from delirium in Caucasians and African Americans during sepsis. Future studies are now required to determine whether mitochondrial DNA and mitochondrial dysfunction contribute to the pathogenesis of delirium during sepsis so that targeted treatments can be developed.
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A catalog of genetic loci associated with kidney function from analyses of a million individuals.
Wuttke M, Li Y, Li M, Sieber KB, Feitosa MF, Gorski M, Tin A, Wang L, Chu AY, Hoppmann A, Kirsten H, Giri A, Chai JF, Sveinbjornsson G, Tayo BO, Nutile T, Fuchsberger C, Marten J, Cocca M, Ghasemi S, Xu Y, Horn K, Noce D, van der Most PJ, Sedaghat S, Yu Z, Akiyama M, Afaq S, Ahluwalia TS, Almgren P, Amin N, Ärnlöv J, Bakker SJL, Bansal N, Baptista D, Bergmann S, Biggs ML, Biino G, Boehnke M, Boerwinkle E, Boissel M, Bottinger EP, Boutin TS, Brenner H, Brumat M, Burkhardt R, Butterworth AS, Campana E, Campbell A, Campbell H, Canouil M, Carroll RJ, Catamo E, Chambers JC, Chee ML, Chee ML, Chen X, Cheng CY, Cheng Y, Christensen K, Cifkova R, Ciullo M, Concas MP, Cook JP, Coresh J, Corre T, Sala CF, Cusi D, Danesh J, Daw EW, de Borst MH, De Grandi A, de Mutsert R, de Vries APJ, Degenhardt F, Delgado G, Demirkan A, Di Angelantonio E, Dittrich K, Divers J, Dorajoo R, Eckardt KU, Ehret G, Elliott P, Endlich K, Evans MK, Felix JF, Foo VHX, Franco OH, Franke A, Freedman BI, Freitag-Wolf S, Friedlander Y, Froguel P, Gansevoort RT, Gao H, Gasparini P, Gaziano JM, Giedraitis V, Gieger C, Girotto G, Giulianini F, Gögele M, Gordon SD, Gudbjartsson DF, Gudnason V, Haller T, Hamet P, Harris TB, Hartman CA, Hayward C, Hellwege JN, Heng CK, Hicks AA, Hofer E, Huang W, Hutri-Kähönen N, Hwang SJ, Ikram MA, Indridason OS, Ingelsson E, Ising M, Jaddoe VWV, Jakobsdottir J, Jonas JB, Joshi PK, Josyula NS, Jung B, Kähönen M, Kamatani Y, Kammerer CM, Kanai M, Kastarinen M, Kerr SM, Khor CC, Kiess W, Kleber ME, Koenig W, Kooner JS, Körner A, Kovacs P, Kraja AT, Krajcoviechova A, Kramer H, Krämer BK, Kronenberg F, Kubo M, Kühnel B, Kuokkanen M, Kuusisto J, La Bianca M, Laakso M, Lange LA, Langefeld CD, Lee JJ, Lehne B, Lehtimäki T, Lieb W, Lifelines Cohort Study, Lim SC, Lind L, Lindgren CM, Liu J, Liu J, Loeffler M, Loos RJF, Lucae S, Lukas MA, Lyytikäinen LP, Mägi R, Magnusson PKE, Mahajan A, Martin NG, Martins J, März W, Mascalzoni D, Matsuda K, Meisinger C, Meitinger T, Melander O, Metspalu A, Mikaelsdottir EK, Milaneschi Y, Miliku K, Mishra PP, V. A. Million Veteran Program, Mohlke KL, Mononen N, Montgomery GW, Mook-Kanamori DO, Mychaleckyj JC, Nadkarni GN, Nalls MA, Nauck M, Nikus K, Ning B, Nolte IM, Noordam R, O'Connell J, O'Donoghue ML, Olafsson I, Oldehinkel AJ, Orho-Melander M, Ouwehand WH, Padmanabhan S, Palmer ND, Palsson R, Penninx BWJH, Perls T, Perola M, Pirastu M, Pirastu N, Pistis G, Podgornaia AI, Polasek O, Ponte B, Porteous DJ, Poulain T, Pramstaller PP, Preuss MH, Prins BP, Province MA, Rabelink TJ, Raffield LM, Raitakari OT, Reilly DF, Rettig R, Rheinberger M, Rice KM, Ridker PM, Rivadeneira F, Rizzi F, Roberts DJ, Robino A, Rossing P, Rudan I, Rueedi R, Ruggiero D, Ryan KA, Saba Y, Sabanayagam C, Salomaa V, Salvi E, Saum KU, Schmidt H, Schmidt R, Schöttker B, Schulz CA, Schupf N, Shaffer CM, Shi Y, Smith AV, Smith BH, Soranzo N, Spracklen CN, Strauch K, Stringham HM, Stumvoll M, Svensson PO, Szymczak S, Tai ES, Tajuddin SM, Tan NYQ, Taylor KD, Teren A, Tham YC, Thiery J, Thio CHL, Thomsen H, Thorleifsson G, Toniolo D, Tönjes A, Tremblay J, Tzoulaki I, Uitterlinden AG, Vaccargiu S, van Dam RM, van der Harst P, van Duijn CM, Velez Edward DR, Verweij N, Vogelezang S, Völker U, Vollenweider P, Waeber G, Waldenberger M, Wallentin L, Wang YX, Wang C, Waterworth DM, Bin Wei W, White H, Whitfield JB, Wild SH, Wilson JF, Wojczynski MK, Wong C, Wong TY, Xu L, Yang Q, Yasuda M, Yerges-Armstrong LM, Zhang W, Zonderman AB, Rotter JI, Bochud M, Psaty BM, Vitart V, Wilson JG, Dehghan A, Parsa A, Chasman DI, Ho K, Morris AP, Devuyst O, Akilesh S, Pendergrass SA, Sim X, Böger CA, Okada Y, Edwards TL, Snieder H, Stefansson K, Hung AM, Heid IM, Scholz M, Teumer A, Köttgen A, Pattaro C
(2019) Nat Genet 51: 957-972
MeSH Terms: Chromosome Mapping, European Continental Ancestry Group, Genetic Association Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Inheritance Patterns, Kidney Function Tests, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Quantitative Trait, Heritable, Renal Insufficiency, Chronic, Uromodulin
Show Abstract · Added March 3, 2020
Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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Association of Thyroid Function Genetic Predictors With Atrial Fibrillation: A Phenome-Wide Association Study and Inverse-Variance Weighted Average Meta-analysis.
Salem JE, Shoemaker MB, Bastarache L, Shaffer CM, Glazer AM, Kroncke B, Wells QS, Shi M, Straub P, Jarvik GP, Larson EB, Velez Edwards DR, Edwards TL, Davis LK, Hakonarson H, Weng C, Fasel D, Knollmann BC, Wang TJ, Denny JC, Ellinor PT, Roden DM, Mosley JD
(2019) JAMA Cardiol 4: 136-143
MeSH Terms: Aged, Analysis of Variance, Atrial Fibrillation, European Continental Ancestry Group, Female, Genome-Wide Association Study, Humans, Hyperthyroidism, Hypothyroidism, Male, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Predictive Value of Tests, Risk Factors, Thyroid Function Tests, Thyroid Gland, Thyrotropin
Show Abstract · Added March 26, 2019
Importance - Thyroid hormone levels are tightly regulated through feedback inhibition by thyrotropin, produced by the pituitary gland. Hyperthyroidism is overwhelmingly due to thyroid disorders and is well recognized to contribute to a wide spectrum of cardiovascular morbidity, particularly the increasingly common arrhythmia atrial fibrillation (AF).
Objective - To determine the association between genetically determined thyrotropin levels and AF.
Design, Setting, and Participants - This phenome-wide association study scanned 1318 phenotypes associated with a polygenic predictor of thyrotropin levels identified by a previously published genome-wide association study that included participants of European ancestry. North American individuals of European ancestry with longitudinal electronic health records were analyzed from May 2008 to November 2016. Analysis began March 2018.
Main Outcomes and Measures - Clinical diagnoses associated with a polygenic predictor of thyrotropin levels.
Exposures - Genetically determined thyrotropin levels.
Results - Of 37 154 individuals, 19 330 (52%) were men. The thyrotropin polygenic predictor was positively associated with hypothyroidism (odds ratio [OR], 1.10; 95% CI, 1.07-1.14; P = 5 × 10-11) and inversely associated with diagnoses related to hyperthyroidism (OR, 0.64; 95% CI, 0.54-0.74; P = 2 × 10-8 for toxic multinodular goiter). Among nonthyroid associations, the top association was AF/flutter (OR, 0.93; 95% CI, 0.9-0.95; P = 9 × 10-7). When the analyses were repeated excluding 9801 individuals with any diagnoses of a thyroid-related disease, the AF association persisted (OR, 0.91; 95% CI, 0.88-0.95; P = 2.9 × 10-6). To replicate this association, we conducted an inverse-variance weighted average meta-analysis using AF single-nucleotide variant weights from a genome-wide association study of 17 931 AF cases and 115 142 controls. As in the discovery analyses, each SD increase in predicted thyrotropin was associated with a decreased risk of AF (OR, 0.86; 95% CI, 0.79-0.93; P = 4.7 × 10-4). In a set of AF cases (n = 745) and controls (n = 1680) older than 55 years, directly measured thyrotropin levels that fell within the normal range were inversely associated with AF risk (OR, 0.91; 95% CI, 0.83-0.99; P = .04).
Conclusions and Relevance - This study suggests a role for genetically determined variation in thyroid function within a physiologically accepted normal range as a risk factor for AF. The clinical decision to treat subclinical thyroid disease should incorporate the risk for AF as antithyroid medications to treat hyperthyroidism may reduce AF risk and thyroid hormone replacement for hypothyroidism may increase AF risk.
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18 MeSH Terms
Functionally oriented analysis of cardiometabolic traits in a trans-ethnic sample.
Petty LE, Highland HM, Gamazon ER, Hu H, Karhade M, Chen HH, de Vries PS, Grove ML, Aguilar D, Bell GI, Huff CD, Hanis CL, Doddapaneni H, Munzy DM, Gibbs RA, Ma J, Parra EJ, Cruz M, Valladares-Salgado A, Arking DE, Barbeira A, Im HK, Morrison AC, Boerwinkle E, Below JE
(2019) Hum Mol Genet 28: 1212-1224
MeSH Terms: Adult, Aged, Blood Pressure, Body Mass Index, Chromosome Mapping, Ethnic Groups, European Continental Ancestry Group, Female, Forecasting, Genetic Association Studies, Genome-Wide Association Study, Humans, Male, Metabolome, Middle Aged, Multifactorial Inheritance, Phenotype, Polymorphism, Single Nucleotide, Transcriptome
Show Abstract · Added February 15, 2019
Interpretation of genetic association results is difficult because signals often lack biological context. To generate hypotheses of the functional genetic etiology of complex cardiometabolic traits, we estimated the genetically determined component of gene expression from common variants using PrediXcan (1) and determined genes with differential predicted expression by trait. PrediXcan imputes tissue-specific expression levels from genetic variation using variant-level effect on gene expression in transcriptome data. To explore the value of imputed genetically regulated gene expression (GReX) models across different ancestral populations, we evaluated imputed expression levels for predictive accuracy genome-wide in RNA sequence data in samples drawn from European-ancestry and African-ancestry populations and identified substantial predictive power using European-derived models in a non-European target population. We then tested the association of GReX on 15 cardiometabolic traits including blood lipid levels, body mass index, height, blood pressure, fasting glucose and insulin, RR interval, fibrinogen level, factor VII level and white blood cell and platelet counts in 15 755 individuals across three ancestry groups, resulting in 20 novel gene-phenotype associations reaching experiment-wide significance across ancestries. In addition, we identified 18 significant novel gene-phenotype associations in our ancestry-specific analyses. Top associations were assessed for additional support via query of S-PrediXcan (2) results derived from publicly available genome-wide association studies summary data. Collectively, these findings illustrate the utility of transcriptome-based imputation models for discovery of cardiometabolic effect genes in a diverse dataset.
© The Author(s) 2019. Published by Oxford University Press.
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19 MeSH Terms
Genetic Data from Nearly 63,000 Women of European Descent Predicts DNA Methylation Biomarkers and Epithelial Ovarian Cancer Risk.
Yang Y, Wu L, Shu X, Lu Y, Shu XO, Cai Q, Beeghly-Fadiel A, Li B, Ye F, Berchuck A, Anton-Culver H, Banerjee S, Benitez J, Bjørge L, Brenton JD, Butzow R, Campbell IG, Chang-Claude J, Chen K, Cook LS, Cramer DW, deFazio A, Dennis J, Doherty JA, Dörk T, Eccles DM, Edwards DV, Fasching PA, Fortner RT, Gayther SA, Giles GG, Glasspool RM, Goode EL, Goodman MT, Gronwald J, Harris HR, Heitz F, Hildebrandt MA, Høgdall E, Høgdall CK, Huntsman DG, Kar SP, Karlan BY, Kelemen LE, Kiemeney LA, Kjaer SK, Koushik A, Lambrechts D, Le ND, Levine DA, Massuger LF, Matsuo K, May T, McNeish IA, Menon U, Modugno F, Monteiro AN, Moorman PG, Moysich KB, Ness RB, Nevanlinna H, Olsson H, Onland-Moret NC, Park SK, Paul J, Pearce CL, Pejovic T, Phelan CM, Pike MC, Ramus SJ, Riboli E, Rodriguez-Antona C, Romieu I, Sandler DP, Schildkraut JM, Setiawan VW, Shan K, Siddiqui N, Sieh W, Stampfer MJ, Sutphen R, Swerdlow AJ, Szafron LM, Teo SH, Tworoger SS, Tyrer JP, Webb PM, Wentzensen N, White E, Willett WC, Wolk A, Woo YL, Wu AH, Yan L, Yannoukakos D, Chenevix-Trench G, Sellers TA, Pharoah PDP, Zheng W, Long J
(2019) Cancer Res 79: 505-517
MeSH Terms: Biomarkers, Tumor, Carcinoma, Ovarian Epithelial, Cohort Studies, DNA Methylation, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Humans, Models, Genetic, Ovarian Neoplasms, Predictive Value of Tests, Risk, Women's Health
Show Abstract · Added March 26, 2019
DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study ( = 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of < 7.94 × 10. Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely , and . We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression. SIGNIFICANCE: Identification of novel DNA methylation markers associated with EOC risk suggests that methylation at multiple CpG may affect EOC risk through regulation of gene expression.
©2018 American Association for Cancer Research.
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13 MeSH Terms