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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
Trans-ethnic association study of blood pressure determinants in over 750,000 individuals.
Giri A, Hellwege JN, Keaton JM, Park J, Qiu C, Warren HR, Torstenson ES, Kovesdy CP, Sun YV, Wilson OD, Robinson-Cohen C, Roumie CL, Chung CP, Birdwell KA, Damrauer SM, DuVall SL, Klarin D, Cho K, Wang Y, Evangelou E, Cabrera CP, Wain LV, Shrestha R, Mautz BS, Akwo EA, Sargurupremraj M, Debette S, Boehnke M, Scott LJ, Luan J, Zhao JH, Willems SM, Thériault S, Shah N, Oldmeadow C, Almgren P, Li-Gao R, Verweij N, Boutin TS, Mangino M, Ntalla I, Feofanova E, Surendran P, Cook JP, Karthikeyan S, Lahrouchi N, Liu C, Sepúlveda N, Richardson TG, Kraja A, Amouyel P, Farrall M, Poulter NR, Understanding Society Scientific Group, International Consortium for Blood Pressure, Blood Pressure-International Consortium of Exome Chip Studies, Laakso M, Zeggini E, Sever P, Scott RA, Langenberg C, Wareham NJ, Conen D, Palmer CNA, Attia J, Chasman DI, Ridker PM, Melander O, Mook-Kanamori DO, Harst PV, Cucca F, Schlessinger D, Hayward C, Spector TD, Jarvelin MR, Hennig BJ, Timpson NJ, Wei WQ, Smith JC, Xu Y, Matheny ME, Siew EE, Lindgren C, Herzig KH, Dedoussis G, Denny JC, Psaty BM, Howson JMM, Munroe PB, Newton-Cheh C, Caulfield MJ, Elliott P, Gaziano JM, Concato J, Wilson PWF, Tsao PS, Velez Edwards DR, Susztak K, Million Veteran Program, O'Donnell CJ, Hung AM, Edwards TL
(2019) Nat Genet 51: 51-62
MeSH Terms: Adolescent, Animals, Blood Pressure, Ethnic Groups, Female, Gene Expression, Genome-Wide Association Study, Humans, Kidney Tubules, Male, Mice, Middle Aged, Polymorphism, Single Nucleotide, Transcriptome, Up-Regulation
Show Abstract · Added January 3, 2019
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.
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15 MeSH Terms
Health disparities among adult patients with a phenotypic diagnosis of familial hypercholesterolemia in the CASCADE-FH™ patient registry.
Amrock SM, Duell PB, Knickelbine T, Martin SS, O'Brien EC, Watson KE, Mitri J, Kindt I, Shrader P, Baum SJ, Hemphill LC, Ahmed CD, Andersen RL, Kullo IJ, McCann D, Larry JA, Murray MF, Fishberg R, Guyton JR, Wilemon K, Roe MT, Rader DJ, Ballantyne CM, Underberg JA, Thompson P, Duffy D, Linton MF, Shapiro MD, Moriarty PM, Knowles JW, Ahmad ZS
(2017) Atherosclerosis 267: 19-26
MeSH Terms: Adult, African Americans, Aged, Asian Americans, Cardiovascular Diseases, Cholesterol, HDL, Cholesterol, LDL, Ethnic Groups, Female, Health Status Disparities, Healthcare Disparities, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hyperlipoproteinemia Type II, Male, Middle Aged, Multicenter Studies as Topic, Odds Ratio, Phenotype, Prospective Studies, Registries, Retrospective Studies, Risk Factors, Sex Factors
Show Abstract · Added April 10, 2018
BACKGROUND AND AIMS - Most familial hypercholesterolemia (FH) patients remain undertreated, and it is unclear what role health disparities may play for FH patients in the US. We sought to describe sex and racial/ethnic disparities in a national registry of US FH patients.
METHODS - We analyzed data from 3167 adults enrolled in the CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia (CASCADE-FH) registry. Logistic regression was used to evaluate for disparities in LDL-C goals and statin use, with adjustments for covariates including age, cardiovascular risk factors, and statin intolerance.
RESULTS - In adjusted analyses, women were less likely than men to achieve treated LDL-C of <100 mg/dL (OR 0.68, 95% CI, 0.57-0.82) or ≥50% reduction from pretreatment LDL-C (OR 0.79, 95% CI, 0.65-0.96). Women were less likely than men to receive statin therapy (OR, 0.60, 95% CI, 0.50-0.73) and less likely to receive a high-intensity statin (OR, 0.60, 95% CI, 0.49-0.72). LDL-C goal achievement also varied by race/ethnicity: compared with whites, Asians and blacks were less likely to achieve LDL-C levels <100 mg/dL (Asians, OR, 0.47, 95% CI, 0.24-0.94; blacks, OR, 0.49, 95% CI, 0.32-0.74) or ≥50% reduction from pretreatment LDL-C (Asians, OR 0.56, 95% CI, 0.32-0.98; blacks, OR 0.62, 95% CI, 0.43-0.90).
CONCLUSIONS - In a contemporary US population of FH patients, we identified differences in LDL-C goal attainment and statin usage after stratifying the population by either sex or race/ethnicity. Our findings suggest that health disparities contribute to the undertreatment of US FH patients. Increased efforts are warranted to raise awareness of these disparities.
Copyright © 2017 Elsevier B.V. All rights reserved.
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24 MeSH Terms
Differences in Natriuretic Peptide Levels by Race/Ethnicity (From the Multi-Ethnic Study of Atherosclerosis).
Gupta DK, Daniels LB, Cheng S, deFilippi CR, Criqui MH, Maisel AS, Lima JA, Bahrami H, Greenland P, Cushman M, Tracy R, Siscovick D, Bertoni AG, Cannone V, Burnett JC, Carr JJ, Wang TJ
(2017) Am J Cardiol 120: 1008-1015
MeSH Terms: Aged, Aged, 80 and over, Atherosclerosis, Biomarkers, Continental Population Groups, Ethnic Groups, Female, Follow-Up Studies, Humans, Male, Middle Aged, Morbidity, Natriuretic Peptide, Brain, Peptide Fragments, Prevalence, Prognosis, Prospective Studies, Risk Factors, United States
Show Abstract · Added September 11, 2017
Natriuretic peptides (NP) are cardiac-derived hormones with favorable cardiometabolic actions. Low NP levels are associated with increased risks of hypertension and diabetes mellitus, conditions with variable prevalence by race and ethnicity. Heritable factors underlie a significant proportion of the interindividual variation in NP concentrations, but the specific influences of race and ancestry are unknown. In 5597 individuals (40% white, 24% black, 23% Hispanic, and 13% Chinese) without prevalent cardiovascular disease at baseline in the Multi-Ethnic Study of Atherosclerosis, multivariable linear regression and restricted cubic splines were used to estimate differences in serum N-terminal pro B-type natriuretic peptide (NT-proBNP) levels according to, ethnicity, and ancestry. Ancestry was determined using genetic ancestry informative markers. NT-proBNP concentrations differed significantly by race and ethnicity (black, median 43 pg/ml [interquartile range 17 to 94], Chinese 43 [17 to 90], Hispanic 53 [23 to 107], white 68 [34 to 136]; p = 0.0001). In multivariable models, NT-proBNP was 44% lower (95% confidence interval -48 to -40) in black and 46% lower (-50 to -41) in Chinese, compared with white individuals. Hispanic individuals had intermediate concentrations. Self-identified blacks and Hispanics were the most genetically admixed. Among self-identified black individuals, a 20% increase in genetic European ancestry was associated with 12% higher (1% to 23%) NT-proBNP. Among Hispanic individuals, genetic European and African ancestry were positively and negatively associated with NT-proBNP levels, respectively. In conclusion, NT-proBNP levels differ according to race and ethnicity, with the lowest concentrations in black and Chinese individuals. Racial and ethnic differences in NT-proBNP may have a genetic basis, with European and African ancestry associated with higher and lower NT-proBNP concentrations, respectively.
Copyright © 2017 Elsevier Inc. All rights reserved.
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19 MeSH Terms
Increased expression of deleted in malignant brain tumors (DMBT1) gene in precancerous gastric lesions: Findings from human and animal studies.
Garay J, Piazuelo MB, Lopez-Carrillo L, Leal YA, Majumdar S, Li L, Cruz-Rodriguez N, Serrano-Gomez SJ, Busso CS, Schneider BG, Delgado AG, Bravo LE, Crist AM, Meadows SM, Camargo MC, Wilson KT, Correa P, Zabaleta J
(2017) Oncotarget 8: 47076-47089
MeSH Terms: Animals, Disease Models, Animal, Ethnic Groups, Gastric Mucosa, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genetic Association Studies, Helicobacter Infections, Humans, Mice, Mice, Knockout, Neoplasm Staging, Precancerous Conditions, Receptors, Cell Surface, Stomach Neoplasms
Show Abstract · Added June 29, 2017
Helicobacter pylori infection triggers a cascade of inflammatory stages that may lead to the appearance of non-atrophic gastritis, multifocal atrophic, intestinal metaplasia, dysplasia, and cancer. Deleted in malignant brain tumors 1 (DMBT1) belongs to the group of secreted scavenger receptor cysteine-rich proteins and is considered to be involved in host defense by binding to pathogens. Initial studies showed its deletion and loss of expression in a variety of tumors but the role of this gene in tumor development is not completely understood. Here, we examined the role of DMBT1 in gastric precancerous lesions in Caucasian, African American and Hispanic individuals as well as in the development of gastric pathology in a mouse model of H. pylori infection. We found that in 3 different populations, mucosal DMBT1 expression was significantly increased (2.5 fold) in individuals with dysplasia compared to multifocal atrophic gastritis without intestinal metaplasia; the increase was also observed in individuals with advanced gastritis and positive H. pylori infection. In our animal model, H. pylori infection of Dmbt1-/- mice resulted in significantly higher levels of gastritis, more extensive mucous metaplasia and reduced Il33 expression levels in the gastric mucosa compared to H. pylori-infected wild type mice. Our data in the animal model suggest that in response to H. pylori infection DMBT1 may mediate mucosal protection reducing the risk of developing gastric precancerous lesions. However, the increased expression in human gastric precancerous lesions points to a more complex role of DMBT1 in gastric carcinogenesis.
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Echocardiographic Pulmonary Artery Systolic Pressure in the Coronary Artery Risk Development in Young Adults (CARDIA) Study: Associations With Race and Metabolic Dysregulation.
Brittain EL, Nwabuo C, Xu M, Gupta DK, Hemnes AR, Moreira HT, De Vasconcellos HD, Terry JG, Carr JJ, Lima JA
(2017) J Am Heart Assoc 6:
MeSH Terms: African Americans, Age Factors, Blood Pressure, C-Reactive Protein, Cohort Studies, Coronary Artery Disease, Echocardiography, Echocardiography, Doppler, Ethnic Groups, European Continental Ancestry Group, Female, Humans, Hypertension, Hypertension, Pulmonary, Insulin Resistance, Interleukin-6, Intra-Abdominal Fat, Male, Metabolic Syndrome, Middle Aged, Overweight, Pulmonary Artery, Systole, Tissue Survival, Tomography, X-Ray Computed
Show Abstract · Added September 11, 2017
BACKGROUND - The determinants of pulmonary artery systolic pressure (PASP) are not fully understood. It is unknown whether racial differences in PASP exist or if other population characteristics are associated with pulmonary pressure in humans. We examined echocardiographically estimated PASP in the Coronary Artery Risk Development in Young Adults (CARDIA) study, a middle-aged, biracial community-based cohort.
METHODS AND RESULTS - At the CARDIA year-25 examination, 3469 participants underwent echocardiography, including measurement of tricuspid regurgitant jet velocity to estimate PASP. Clinical features, laboratory values, pulmonary function tests, and measurement of adipose depot volume were analyzed for association with PASP. PASP was estimated in 1311 individuals (61% female, 51% white). Older age, higher blood pressure, and higher body mass index were associated with higher PASP. Black race was associated with higher PASP after adjustment for demographics and left and right ventricular function (β 0.94, 95% CI 0.24-1.64; =0.009), but this association was no longer significant after further adjustment for lung volume (β 0.42, 95% CI -0.68 to 0.96; =0.74). Insulin resistance, inflammation (C-reactive protein and interleukin-6), and visceral adipose volume were independently associated with higher PASP after adjustment for relevant covariates. PASP rose with worsening diastolic function (ratio of early transmitral Doppler velocity to average mitral annular tissue Doppler velocity [E/e'] and left atrial volume index).
CONCLUSIONS - In a large biracial cohort of middle-aged adults, we identified associations among black race, insulin resistance, and diastolic dysfunction with higher echocardiographically estimated PASP. Further studies are needed to examine racial differences in PASP and whether insulin resistance directly contributes to pulmonary vascular disease in humans.
© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.
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25 MeSH Terms
Association analyses of East Asian individuals and trans-ancestry analyses with European individuals reveal new loci associated with cholesterol and triglyceride levels.
Spracklen CN, Chen P, Kim YJ, Wang X, Cai H, Li S, Long J, Wu Y, Wang YX, Takeuchi F, Wu JY, Jung KJ, Hu C, Akiyama K, Zhang Y, Moon S, Johnson TA, Li H, Dorajoo R, He M, Cannon ME, Roman TS, Salfati E, Lin KH, Guo X, Sheu WHH, Absher D, Adair LS, Assimes TL, Aung T, Cai Q, Chang LC, Chen CH, Chien LH, Chuang LM, Chuang SC, Du S, Fan Q, Fann CSJ, Feranil AB, Friedlander Y, Gordon-Larsen P, Gu D, Gui L, Guo Z, Heng CK, Hixson J, Hou X, Hsiung CA, Hu Y, Hwang MY, Hwu CM, Isono M, Juang JJ, Khor CC, Kim YK, Koh WP, Kubo M, Lee IT, Lee SJ, Lee WJ, Liang KW, Lim B, Lim SH, Liu J, Nabika T, Pan WH, Peng H, Quertermous T, Sabanayagam C, Sandow K, Shi J, Sun L, Tan PC, Tan SP, Taylor KD, Teo YY, Toh SA, Tsunoda T, van Dam RM, Wang A, Wang F, Wang J, Wei WB, Xiang YB, Yao J, Yuan JM, Zhang R, Zhao W, Chen YI, Rich SS, Rotter JI, Wang TD, Wu T, Lin X, Han BG, Tanaka T, Cho YS, Katsuya T, Jia W, Jee SH, Chen YT, Kato N, Jonas JB, Cheng CY, Shu XO, He J, Zheng W, Wong TY, Huang W, Kim BJ, Tai ES, Mohlke KL, Sim X
(2017) Hum Mol Genet 26: 1770-1784
MeSH Terms: Adult, Alleles, Asian Continental Ancestry Group, Cholesterol, Ethnic Groups, European Continental Ancestry Group, Female, Gene Frequency, Genetic Association Studies, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Lipids, Lipoproteins, HDL, Lipoproteins, LDL, Male, Middle Aged, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Triglycerides
Show Abstract · Added April 3, 2018
Large-scale meta-analyses of genome-wide association studies (GWAS) have identified >175 loci associated with fasting cholesterol levels, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). With differences in linkage disequilibrium (LD) structure and allele frequencies between ancestry groups, studies in additional large samples may detect new associations. We conducted staged GWAS meta-analyses in up to 69,414 East Asian individuals from 24 studies with participants from Japan, the Philippines, Korea, China, Singapore, and Taiwan. These meta-analyses identified (P < 5 × 10-8) three novel loci associated with HDL-C near CD163-APOBEC1 (P = 7.4 × 10-9), NCOA2 (P = 1.6 × 10-8), and NID2-PTGDR (P = 4.2 × 10-8), and one novel locus associated with TG near WDR11-FGFR2 (P = 2.7 × 10-10). Conditional analyses identified a second signal near CD163-APOBEC1. We then combined results from the East Asian meta-analysis with association results from up to 187,365 European individuals from the Global Lipids Genetics Consortium in a trans-ancestry meta-analysis. This analysis identified (log10Bayes Factor ≥6.1) eight additional novel lipid loci. Among the twelve total loci identified, the index variants at eight loci have demonstrated at least nominal significance with other metabolic traits in prior studies, and two loci exhibited coincident eQTLs (P < 1 × 10-5) in subcutaneous adipose tissue for BPTF and PDGFC. Taken together, these analyses identified multiple novel lipid loci, providing new potential therapeutic targets.
© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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Genome-wide study of resistant hypertension identified from electronic health records.
Dumitrescu L, Ritchie MD, Denny JC, El Rouby NM, McDonough CW, Bradford Y, Ramirez AH, Bielinski SJ, Basford MA, Chai HS, Peissig P, Carrell D, Pathak J, Rasmussen LV, Wang X, Pacheco JA, Kho AN, Hayes MG, Matsumoto M, Smith ME, Li R, Cooper-DeHoff RM, Kullo IJ, Chute CG, Chisholm RL, Jarvik GP, Larson EB, Carey D, McCarty CA, Williams MS, Roden DM, Bottinger E, Johnson JA, de Andrade M, Crawford DC
(2017) PLoS One 12: e0171745
MeSH Terms: Adult, Aged, Algorithms, Antihypertensive Agents, Blood Pressure, Case-Control Studies, Computer Communication Networks, Datasets as Topic, Drug Resistance, Electronic Health Records, Ethnic Groups, Genome-Wide Association Study, Genotype, Humans, Hypertension, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors
Show Abstract · Added May 5, 2017
Resistant hypertension is defined as high blood pressure that remains above treatment goals in spite of the concurrent use of three antihypertensive agents from different classes. Despite the important health consequences of resistant hypertension, few studies of resistant hypertension have been conducted. To perform a genome-wide association study for resistant hypertension, we defined and identified cases of resistant hypertension and hypertensives with treated, controlled hypertension among >47,500 adults residing in the US linked to electronic health records (EHRs) and genotyped as part of the electronic MEdical Records & GEnomics (eMERGE) Network. Electronic selection logic using billing codes, laboratory values, text queries, and medication records was used to identify resistant hypertension cases and controls at each site, and a total of 3,006 cases of resistant hypertension and 876 controlled hypertensives were identified among eMERGE Phase I and II sites. After imputation and quality control, a total of 2,530,150 SNPs were tested for an association among 2,830 multi-ethnic cases of resistant hypertension and 876 controlled hypertensives. No test of association was genome-wide significant in the full dataset or in the dataset limited to European American cases (n = 1,719) and controls (n = 708). The most significant finding was CLNK rs13144136 at p = 1.00x10-6 (odds ratio = 0.68; 95% CI = 0.58-0.80) in the full dataset with similar results in the European American only dataset. We also examined whether SNPs known to influence blood pressure or hypertension also influenced resistant hypertension. None was significant after correction for multiple testing. These data highlight both the difficulties and the potential utility of EHR-linked genomic data to study clinically-relevant traits such as resistant hypertension.
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19 MeSH Terms
Multiethnic genome-wide meta-analysis of ectopic fat depots identifies loci associated with adipocyte development and differentiation.
Chu AY, Deng X, Fisher VA, Drong A, Zhang Y, Feitosa MF, Liu CT, Weeks O, Choh AC, Duan Q, Dyer TD, Eicher JD, Guo X, Heard-Costa NL, Kacprowski T, Kent JW, Lange LA, Liu X, Lohman K, Lu L, Mahajan A, O'Connell JR, Parihar A, Peralta JM, Smith AV, Zhang Y, Homuth G, Kissebah AH, Kullberg J, Laqua R, Launer LJ, Nauck M, Olivier M, Peyser PA, Terry JG, Wojczynski MK, Yao J, Bielak LF, Blangero J, Borecki IB, Bowden DW, Carr JJ, Czerwinski SA, Ding J, Friedrich N, Gudnason V, Harris TB, Ingelsson E, Johnson AD, Kardia SL, Langefeld CD, Lind L, Liu Y, Mitchell BD, Morris AP, Mosley TH, Rotter JI, Shuldiner AR, Towne B, Völzke H, Wallaschofski H, Wilson JG, Allison M, Lindgren CM, Goessling W, Cupples LA, Steinhauser ML, Fox CS
(2017) Nat Genet 49: 125-130
MeSH Terms: Adipocytes, Animals, Body Fat Distribution, Cell Differentiation, Cohort Studies, Ethnic Groups, Female, Genetic Loci, Genetic Markers, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Mice, Mice, Inbred C57BL, Obesity, Phenotype, Polymorphism, Single Nucleotide
Show Abstract · Added September 11, 2017
Variation in body fat distribution contributes to the metabolic sequelae of obesity. The genetic determinants of body fat distribution are poorly understood. The goal of this study was to gain new insights into the underlying genetics of body fat distribution by conducting sample-size-weighted fixed-effects genome-wide association meta-analyses in up to 9,594 women and 8,738 men of European, African, Hispanic and Chinese ancestry, with and without sex stratification, for six traits associated with ectopic fat (hereinafter referred to as ectopic-fat traits). In total, we identified seven new loci associated with ectopic-fat traits (ATXN1, UBE2E2, EBF1, RREB1, GSDMB, GRAMD3 and ENSA; P < 5 × 10; false discovery rate < 1%). Functional analysis of these genes showed that loss of function of either Atxn1 or Ube2e2 in primary mouse adipose progenitor cells impaired adipocyte differentiation, suggesting physiological roles for ATXN1 and UBE2E2 in adipogenesis. Future studies are necessary to further explore the mechanisms by which these genes affect adipocyte biology and how their perturbations contribute to systemic metabolic disease.
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18 MeSH Terms
Are Interactions between cis-Regulatory Variants Evidence for Biological Epistasis or Statistical Artifacts?
Fish AE, Capra JA, Bush WS
(2016) Am J Hum Genet 99: 817-830
MeSH Terms: Artifacts, Binding Sites, Datasets as Topic, Epistasis, Genetic, Ethnic Groups, Gene Expression Regulation, Genetic Variation, Haplotypes, Humans, Linkage Disequilibrium, Models, Genetic, Models, Statistical, Polymorphism, Single Nucleotide, Quantitative Trait Loci, RNA-Binding Proteins, Regulatory Sequences, Nucleic Acid
Show Abstract · Added April 18, 2017
The importance of epistasis-or statistical interactions between genetic variants-to the development of complex disease in humans has been controversial. Genome-wide association studies of statistical interactions influencing human traits have recently become computationally feasible and have identified many putative interactions. However, statistical models used to detect interactions can be confounded, which makes it difficult to be certain that observed statistical interactions are evidence for true molecular epistasis. In this study, we investigate whether there is evidence for epistatic interactions between genetic variants within the cis-regulatory region that influence gene expression after accounting for technical, statistical, and biological confounding factors. We identified 1,119 (FDR = 5%) interactions that appear to regulate gene expression in human lymphoblastoid cell lines, a tightly controlled, largely genetically determined phenotype. Many of these interactions replicated in an independent dataset (90 of 803 tested, Bonferroni threshold). We then performed an exhaustive analysis of both known and novel confounders, including ceiling/floor effects, missing genotype combinations, haplotype effects, single variants tagged through linkage disequilibrium, and population stratification. Every interaction could be explained by at least one of these confounders, and replication in independent datasets did not protect against some confounders. Assuming that the confounding factors provide a more parsimonious explanation for each interaction, we find it unlikely that cis-regulatory interactions contribute strongly to human gene expression, which calls into question the relevance of cis-regulatory interactions for other human phenotypes. We additionally propose several best practices for epistasis testing to protect future studies from confounding.
Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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16 MeSH Terms