Blood Institutes Framingham Heart Study

Framingham, United States

Blood Institutes Framingham Heart Study

Framingham, United States

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Imboden M.,SwissTPH | Imboden M.,University of Basel | Bouzigon E.,French Institute of Health and Medical Research | Bouzigon E.,Fondation Jean Dausset Center dEtude du Polymorphisme Humain | And 55 more authors.
Journal of Allergy and Clinical Immunology | Year: 2012

Background: Genome-wide association studies have identified determinants of chronic obstructive pulmonary disease, asthma, and lung function level; however, none have addressed decline in lung function. Objective: We conducted the first genome-wide association study on the age-related decrease in FEV 1 and its ratio to forced vital capacity (FVC) stratified a priori by asthma status. Methods: Discovery cohorts included adults of European ancestry (1,441 asthmatic and 2,677 nonasthmatic participants: the Epidemiological Study on the Genetics and Environment of Asthma, the Swiss Cohort Study on Air Pollution and Lung and Heart Disease in Adults, and the European Community Respiratory Health Survey). The associations of FEV 1 and FEV 1/FVC ratio decrease with 2.5 million single nucleotide polymorphisms (SNPs) were estimated. Thirty loci were followed up by in silico replication (1,160 asthmatic and 10,858 nonasthmatic participants: Atherosclerosis Risk in Communities, the Framingham Heart Study, the British 1958 Birth Cohort, and the Dutch Asthma Study). Results: Main signals identified differed between asthmatic and nonasthmatic participants. None of the SNPs reached genome-wide significance. The association between the height-related gene DLEU7 and FEV 1 decrease suggested for nonasthmatic participants in the discovery phase was replicated (discovery, P = 4.8 × 10 -6; replication, P =.03), and additional sensitivity analyses point to a relation to growth. The top ranking signal, TUSC3, which is associated with FEV 1/FVC ratio decrease in asthmatic participants (P = 5.3 × 10 -8), did not replicate. SNPs previously associated with cross-sectional lung function were not prominently associated with decline. Conclusions: Genetic heterogeneity of lung function might be extensive. Our results suggest that genetic determinants of longitudinal and cross-sectional lung function differ and vary by asthma status. © 2012 American Academy of Allergy, Asthma & Immunology.


Goto A.,Diabetes Research Center | Chen B.H.,Blood Institutes Framingham Heart Study | Song Y.,Harvard University | Cauley J.,University of Pittsburgh | And 11 more authors.
Clinical Chemistry | Year: 2014

BACKGROUND: Circulating concentrations of sex hormone- binding globulin (SHBG) have been associated with cardiovascular diseases, type 2 diabetes, metabolic syndrome, and hormone-dependent cancers; however, correlates of SHBG concentrations are not well understood. METHODS: We comprehensively investigated correlates of SHBG concentrations among 13 547 women who participated in the Women's Health Initiative and who had SHBG measurements. We estimated study- and ethnicity-specific associations of age, reproductive history, usage of exogenous estrogen, body mass index (BMI), and lifestyle factors such as physical activity, smoking, alcohol consumption, coffee intake, and dietary factors with SHBG concentrations. These estimates were pooled using random-effects models. We also examined potential nonlinear associations using spline analyses. RESULTS: There was no significant ethnic difference in the age-adjusted mean concentrations of SHBG. Age, exogenous estrogen use, physical activity, and regular coffee intake were positively associated with SHBG concentrations, whereas BMI was inversely associated with SHBG concentrations after adjustment for potential confounding factors. Similar patterns were observed among both ever users and never users of exogenous estrogen. The spline analysis indicated nonlinear relations of regular intake of coffee, age, and BMI with SHBG concentrations. Two or more cups/day of regular coffee consumption and age of 60 years or older were associated with higher SHBG concentrations; the inverse BMI-SHBG relation was especially strong among women whose BMI was below 30. CONCLUSIONS: In this large sample of postmenopausal women, age, exogenous estrogen use, physical activity, regular coffee intake, and BMI were significant correlates of SHBG concentrations, presenting potential targets for interventions. © 2013 American Association for Clinical Chemistry.


Do R.,Massachusetts General Hospital | Do R.,Harvard University | Do R.,Cambridge Broad Institute | Stitziel N.O.,University of Washington | And 102 more authors.
Nature | Year: 2015

Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance. When MI occurs early in life, genetic inheritance is a major component to risk. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families, whereas common variants at more than 45 loci have been associated with MI risk in the population. Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl-1. At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase and apolipoprotein C-III (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk. © 2015 Macmillan Publishers Limited. All rights reserved.


PubMed | Karolinska Institutet, University of Michigan, University of Verona, Stanford University and 40 more.
Type: Journal Article | Journal: Nature | Year: 2015

Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance. When MI occurs early in life, genetic inheritance is a major component to risk. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families, whereas common variants at more than 45 loci have been associated with MI risk in the population. Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (50 years in males and 60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190mgdl(-1). At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase and apolipoprotein C-III (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.


Chen M.-H.,Boston University | Chen M.-H.,Blood Institutes Framingham Heart Study | Huang J.,Blood Institutes Framingham Heart Study | Huang J.,Wellcome Trust Sanger Institute | And 13 more authors.
PLoS ONE | Year: 2012

Imputation has been widely used in genome-wide association studies (GWAS) to infer genotypes of un-genotyped variants based on the linkage disequilibrium in external reference panels such as the HapMap and 1000 Genomes. However, imputation has only rarely been performed based on family relationships to infer genotypes of un-genotyped individuals. Using 8998 Framingham Heart Study (FHS) participants genotyped with Affymetrix 550K SNPs, we imputed genotypes of same set of SNPs for additional 3121 participants, most of whom were never genotyped due to lack of DNA sample. Prior to imputation, 122 pedigrees were too large to be handled by the imputation software Merlin. Therefore, we developed a novel pedigree splitting algorithm that can maximize the number of genotyped relatives for imputing each un-genotyped individual, while keeping new sub-pedigrees under a pre-specified size. In GWAS of four phenotypes available in FHS (Alzheimer disease, circulating levels of fibrinogen, high-density lipoprotein cholesterol, and uric acid), we compared results using genotyped individuals only with results using both genotyped and imputed individuals. We studied the impact of applying different imputation quality filtering thresholds on the association results and did not found a universal threshold that always resulted in a more significant p-value for previously identified loci. However most of these loci had a lower p-value when we only included imputed genotypes with with ≥60% SNP- and ≥50% person-specific imputation certainty. In summary, we developed a novel algorithm for splitting large pedigrees for imputation and found a plausible imputation quality filtering threshold based on FHS. Further examination may be required to generalize this threshold to other studies. © 2012 Chen et al.


Yang Q.,Boston University | Yang Q.,Blood Institutes Framingham Heart Study | Wu H.,Boston University | Wu H.,Wentworth Institute of Technology | And 4 more authors.
Genetic Epidemiology | Year: 2010

Multivariate phenotypes are frequently encountered in genome-wide association studies (GWAS). Such phenotypes contain more information than univariate phenotypes, but how to best exploit the information to increase the chance of detecting genetic variant of pleiotropic effect is not always clear. Moreover, when multivariate phenotypes contain a mixture of quantitative and qualitative measures, limited methods are applicable. In this paper, we first evaluated the approach originally proposed by O'Brien and by Wei and Johnson that combines the univariate test statistics and then we proposed two extensions to that approach. The original and proposed approaches are applicable to a multivariate phenotype containing any type of components including continuous, categorical and survival phenotypes, and applicable to samples consisting of families or unrelated samples. Simulation results suggested that all methods had valid type I error rates. Our extensions had a better power than O'Brien's method with heterogeneous means among univariate test statistics, but were less powerful than O'Brien's with homogeneous means among individual test statistics. All approaches have shown considerable increase in power compared to testing each component of a multivariate phenotype individually in some cases. We apply all the methods to GWAS of serum uric acid levels and gout with 550,000 single nucleotide polymorphisms in the Framingham Heart Study. © 2010 Wiley-Liss, Inc.


Joehanes R.,Blood Institutes Framingham Heart Study | Joehanes R.,U.S. National Institutes of Health | Johnson A.D.,Blood Institutes Framingham Heart Study | Johnson A.D.,U.S. National Institutes of Health | And 9 more authors.
Physiological Genomics | Year: 2012

Despite a growing number of reports of gene expression analysis from blood-derived RNA sources, there have been few systematic comparisons of various RNA sources in transcriptomic analysis or for biomarker discovery in the context of cardiovascular disease (CVD). As a pilot study of the Systems Approach to Biomarker Research (SABRe) in CVD Initiative, this investigation used Affymetrix Exon arrays to characterize gene expression of three blood-derived RNA sources: lymphoblastoid cell lines (LCL), whole blood using PAXgene tubes (PAX), and peripheral blood mononuclear cells (PBMC). Their performance was compared in relation to identifying transcript associations with sex and CVD risk factors, such as age, high-density lipoprotein, and smoking status, and the differential blood cell count. We also identified a set of exons that vary substantially between participants, but consistently in each RNA source. Such exons are thus stable phenotypes of the participant and may potentially become useful fingerprinting biomarkers. In agreement with previous studies, we found that each of the RNA sources is distinct. Unlike PAX and PBMC, LCL gene expression showed little association with the differential blood count. LCL, however, was able to detect two genes related to smoking status. PAX and PBMC identified Y-chromosome probe sets similarly and slightly better than LCL. © 2012 the American Physiological Society.

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