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Louise V Wain,
Germaine C Verwoert,
Paul F O'Reilly, Gang Shi,
Toby Johnson,
Andrew D Johnson,
Murielle Bochud,
Kenneth M Rice,
Peter Henneman,
Albert V Smith, [......],
Vilmundur Gudnason,
Christopher Newton-Cheh,
Daniel Levy,
Patricia B Munroe,
Bruce M Psaty,
Mark J Caulfield,
Dabeeru C Rao,
Martin D Tobin,
Paul Elliott,
Cornelia M van Duijn
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ABSTRACT: Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.
Nature Genetics 09/2011; 43(10):1005-11. · 35.53 Impact Factor
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Georg B Ehret,
Patricia B Munroe,
Kenneth M Rice,
Murielle Bochud,
Andrew D Johnson,
Daniel I Chasman,
Albert V Smith,
Martin D Tobin,
Germaine C Verwoert,
Shih-Jen Hwang, [......],
Marjo-Riitta Järvelin,
Bruce M Psaty,
Gonçalo R Abecasis,
Aravinda Chakravarti,
Paul Elliott,
Cornelia M van Duijn,
Christopher Newton-Cheh,
Daniel Levy,
Mark J Caulfield,
Toby Johnson
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ABSTRACT: Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.
Nature 09/2011; 478(7367):103-9. · 36.28 Impact Factor
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ABSTRACT: A recent meta-analysis of genome-wide linkage scans of blood pressure (BP) in the large (N = 13,044) Family Blood Pressure Program (FBPP) identified five quantitative trait loci (QTLs) on chromosomes 6, 8, 20, and 21. We conducted follow-up fine mapping studies in 1,251 African (AA) and 1,254 European American (EA) participants of the Hypertension Genetic Epidemiology Network (HyperGEN).
Ethnic-specific linear mixed effects models were used to test associations of BP with genotyped and imputed single nucleotide polymorphisms (SNPs) contained in the logarithm of odds (LOD) score ≥2 interval under each of the QTL peaks. We used multipoint variance components models to perform linkage analysis conditional on each significant SNP in the QTL region to see if the SNP explained the QTL.
Three intergenic SNPs (rs898164, rs2876587, rs6935795) on chromosome 6p22.3 were significantly associated with pulse pressure (using appropriate Bonferroni correction). Conditioning on the significant SNPs reduced the chromosome 6 QTL linkage evidence by 14-30%. Both AAs and EAs exhibited suggestive associations between BP and intronic SNPs on chromosomes 8q24.12 (genes: OPG in AAs, SAMD12 in EAs), 20q13.12 (genes: SLC13A3 in AAs, SLC12A5 in EAs), and 21q21.1 (genes: C21orf34 in AAs, BC039377 in EAs).
Significant associations with common SNPs explained less than 1/3 of the QTL evidence. Our results cannot refute the hypothesis that rare variants account for most of the statistical evidence for the FBPP linkage peaks. Whole genome resequencing can identify the variants driving the linkage peaks and genome-wide association study (GWAS) hits thereby spurring investigations to deepen our understanding of hypertension pathophysiology.
American Journal of Hypertension 08/2011; 24(11):1227-33. · 3.18 Impact Factor
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ABSTRACT: Recent advances in next-generation sequencing technologies make it affordable to search for rare and functional variants for common complex diseases systematically. We investigated strategies for enriching rare variants in the samples selected for sequencing so as to optimize the power for their discovery. In particular, we investigated the roles of alternative sources of enrichment in families through computer simulations. We showed that linkage information, extreme phenotype, and nonrandom ascertainment, such as multiply affected families, constitute different sources for enriching rare and functional variants in a sequencing study design. Linkage is well known to have limited power for detecting small genetic effects, and hence not considered to be a powerful tool for discovering variants for common complex diseases. However, those families with some degree of family-specific linkage evidence provide an effective sampling strategy to sub-select the most linkage-informative families for sequencing. Compared with selecting subjects with extreme phenotypes, linkage evidence performs better with larger families, while extreme-phenotype method is more efficient with smaller families. Families with multiple affected siblings were found to provide the largest enrichment of rare variants. Finally, we showed that combined strategies, such as selecting linkage-informative families from multiply affected families, provide much higher enrichment of rare functional variants than either strategy alone.
Genetic Epidemiology 05/2011; 35(6):572-9. · 3.44 Impact Factor
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Jeannette Simino, Gang Shi,
Rezart Kume,
Karen Schwander,
Michael A Province,
C Charles Gu,
Sharon Kardia,
Aravinda Chakravarti,
Georg Ehret,
Richard A Olshen, [......],
Low-Tone Ho,
Xiaofeng Zhu,
Cashell Jaquish,
Dina Paltoo,
Richard S Cooper,
Alan Weder,
J David Curb,
Eric Boerwinkle,
Steven C Hunt,
Dabeeru C Rao
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ABSTRACT: A preliminary genome-wide linkage analysis of blood pressure in the Family Blood Pressure Program (FBPP) was reported previously. We harnessed the power and ethnic diversity of the final pooled FBPP dataset to identify novel loci for blood pressure thereby enhancing localization of genes containing less common variants with large effects on blood pressure levels and hypertension.
We performed one overall and 4 race-specific meta-analyses of genome-wide blood pressure linkage scans using data on 4,226 African-American, 2,154 Asian, 4,229 Caucasian, and 2,435 Mexican-American participants (total N = 13,044). Variance components models were fit to measured (raw) blood pressure levels and two types of antihypertensive medication adjusted blood pressure phenotypes within each of 10 subgroups defined by race and network. A modified Fisher's method was used to combine the P values for each linkage marker across the 10 subgroups.
Five quantitative trait loci (QTLs) were detected on chromosomes 6p22.3, 8q23.1, 20q13.12, 21q21.1, and 21q21.3 based on significant linkage evidence (defined by logarithm of odds (lod) score ≥3) in at least one meta-analysis and lod scores ≥1 in at least 2 subgroups defined by network and race. The chromosome 8q23.1 locus was supported by Asian-, Caucasian-, and Mexican-American-specific meta-analyses.
The new QTLs reported justify new candidate gene studies. They may help support results from genome-wide association studies (GWAS) that fall in these QTL regions but fail to achieve the genome-wide significance.
American Journal of Hypertension 03/2011; 24(3):347-54. · 3.18 Impact Factor
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ABSTRACT: We propose a two-stage approach to analyze genome-wide association data in order to identify a set of promising single-nucleotide polymorphisms (SNPs). In stage one, we select a list of top signals from single SNP analyses by controlling false discovery rate. In stage two, we use the least absolute shrinkage and selection operator (LASSO) regression to reduce false positives. The proposed approach was evaluated using simulated quantitative traits based on genome-wide SNP data on 8,861 Caucasian individuals from the Atherosclerosis Risk in Communities (ARIC) Study. Our first stage, targeted at controlling false negatives, yields better power than using Bonferroni-corrected significance level. The LASSO regression reduces the number of significant SNPs in stage two: it reduces false-positive SNPs and it reduces true-positive SNPs also at simulated causal loci due to linkage disequilibrium. Interestingly, the LASSO regression preserves the power from stage one, i.e., the number of causal loci detected from the LASSO regression in stage two is almost the same as in stage one, while reducing false positives further. Real data on systolic blood pressure in the ARIC study was analyzed using our two-stage approach which identified two significant SNPs, one of which was reported to be genome-significant in a meta-analysis containing a much larger sample size. On the other hand, a single SNP association scan did not yield any significant results.
Genetic Epidemiology 02/2011; 35(2):111-8. · 3.44 Impact Factor
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ABSTRACT: The reactivities of model hydrocarbons (n-paraffins, i-paraffins, olefins, naphthenes, and aromatics) typical for fluid catalytic cracking (FCC) gasoline were investigated over a Ni−Mo/modified HZSM-5 + Al2O3 catalyst. Olefins had the highest reactivity and were unidirectionally converted into molecules of the other groups, especially i-paraffins and aromatics. On the basis of the results, a reaction mechanism was proposed for olefin hydroisomerization and aromatization in the presence of excess hydrogen. During the olefin hydroisomerization and aromatization, the initial adsorption sites of the olefins are the acid sites rather than the metal sites of the bifunctional catalyst. The olefin hydroisomerization reaction is in accordance with the hydrogen spillover concept. The function of the metal sites is to dissociate hydrogen molecules into active H ions, and the acid sites are the reaction sites. The olefin aromatization in the presence of hydrogen occurs through diene and cyclo-olefin intermediates by hydrogen transfer/dehydrogenation and cyclization. The results obtained form the fundamental basis for the olefin conversion in the presence of hydrogen and shed a light on the correlation between the reactivity of model compounds and that of real gasoline with complex compositions.
06/2009;
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ABSTRACT: ABSTRACT : We compared family-based single-marker association analysis using Merlin and multi-marker analysis using LASSO (least absolute shrinkage and selection operator) for the low-density lipoprotein phenotype at the first visit for all 200 replicates of the Genetic Analysis Workshop 16 Framingham simulated data sets. Using "answers," we selected single-nucleotide polymorphisms (SNPs) on chromosome 22 for comparison of results between single-marker and multi-marker analyses. For the major causal SNP rs2294207 on chromosome 22, both single-marker and multi-marker analyses provided similar results, indicating the importance of this SNP. For the 12 polygenic SNPs on the same chromosome, both single-marker and multi-marker analyses failed to provide statistically significant associations, indicating that their effects were too weak to be detected by either method. The main difference between the two methods was that for the 14 SNPs near the causal SNPs, p-values from Merlin were the next smallest, whereas LASSO often excluded these non-causal neighboring SNPs entirely from the first 10,000 models.
BMC proceedings 01/2009; 3 Suppl 7:S27.
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ABSTRACT: ABSTRACT : Problems associated with medication use and the consequent effects on genome-wide association analyses were explored using the Genetic Analysis Workshop 16 Problem 3 data. Lipid phenotypes were simulated in the Framingham Heart Study using several measured variables including causal genes (based on a 500 k SNP panel), smoking, dietary intake, and medication usage. We report a sensitivity analysis of how medication use (which artificially alters lipid values) affects association inferences. Associations were performed for LDL-c under seven different correction schemes: 1) ignore medication use entirely (no correction) and adjust for covariates; 2) delete medicated subjects then adjust for covariates; 3) include medication use (Yes/No) as a covariate during covariate adjustments; 4) correct raw values using clinical trials information then adjust for covariates; 5) correct raw values using the actual simulation protocol ("truth") then adjust for covariates; and 6-7) over-corrections (add arbitrary values) then adjust for covariates. Results indicate that failure to properly correct for medication usage can profoundly affect the heritability, and hence the association results. The empirical results yielded one genome-wide significant locus on chromosome 22 (RS2294207), consistent with the simulation protocol. This signal was detected under all schemes that corrected the raw values (clinical trials, simulation protocol, or over corrections), but was not detected under the first three adjustment schemes (ignore medication use, delete medicated individuals, use medication status as covariate). In summary, we confirm that failure to properly account for medication usage can have a profound impact on genetic associations.
BMC proceedings 01/2009; 3 Suppl 7:S52.
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ABSTRACT: ABSTRACT : Longitudinal studies that collect repeated measurements on the same subjects over time have long been considered as being more powerful and providing much better information on individual changes than cross-sectional data. We propose a three-level linear mixed-effects model for testing genetic main effects and gene-age interactions with longitudinal family data. The simulated Genetic Analysis Workshop 16 Problem 3 data sets were used to evaluate the method. Genome-wide association analyses were conducted based on cross-sectional data, i.e., each of the three single-visit data sets separately, and also on the longitudinal data, i.e., using data from all three visits simultaneously. Results from the analysis of coronary artery calcification phenotype showed that the longitudinal association tests were much more powerful than those based on single-visit data only. Gene-age interactions were evaluated under the same framework for detecting genetic effects that are modulated by age.
BMC proceedings 01/2009; 3 Suppl 7:S89.
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ABSTRACT: Genome-wide linkage analysis was performed for systolic and diastolic blood pressures in the Hypertension Genetic Epidemiology Network. We investigated the role of gene-age interactions using a recently developed variance components method that incorporates age variation in genetic effects. Substantially improved linkage evidence, in terms of both the number of linkage peaks and their significance levels, was observed. Twenty-six linkage peaks were identified with maximum logarithm of odds scores ranging between 3.0 and 4.6, 15 of which were cross-validated by the literature. The chromosomal region 1p36 that showed the highest logarithm of odds score in our study was found to be supported by evidence from 3 studies. The new method also led to vastly improved validation across ethnic groups. Ten of the 15 supported linkage peaks were cross-validated between 2 different ethnic groups, and 2 peaks on chromosomal region 1q31 and 16p11 were validated in 3 ethnic groups. In conclusion, this investigation demonstrates that genetic effects on blood pressure vary by age. The improved genetic linkage results presented here should help to identify the specific genetic variants that explain the observed results.
Hypertension 12/2008; 53(1):35-41. · 6.21 Impact Factor
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ABSTRACT: Linkage analysis has been one of the most widely used methods for identifying regions of the human genome which contain genes responsible for human diseases. Evidence suggests that the effects of some of the trait causing genes may vary with the age of an individual, giving rise to temporal trends in genetic effects. Linkage analysis routinely tends to ignore such gene-by-age interactions. While linkage analysis methods have been proposed for analysis of longitudinal family data for exploring temporal trends, there are no models to characterize such trends nor methods for analysis of cross-sectional family data. We extend variance component linkage analysis methodology by modeling the variance components due to the quantitative trait locus (QTL) and that due to the polygenic effect to be age dependent. With this model, we investigate the power of linkage analysis in the presence of temporal trends. We show that modeling true temporal trends in QTL effects can substantially increase the power of linkage analysis even when the average locus-specific heritabilities (when trends are ignored) are quite low, thereby demonstrating that, ignoring the gene-by-age interactions, when present, could jeopardize gene discovery.
Genetic Epidemiology 02/2008; 32(1):61-72. · 3.44 Impact Factor
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ABSTRACT: Time-reversal methods have attracted increasing interest recently. The so-called computational time-reversal approach creates an image of the illuminated scene by computing the back-propagated field and is useful for detecting and estimating targets in the scene. In Shi and Nehorai [ldquoMaximum Likelihood Estimation of Point Scatterers for Computational Time-Reversal Imaging,rdquo Communications in Information and Systems, vol. 5, no. 2, pp. 227-256, 2005], we estimated point scatterers by maximum-likelihood estimate (MLE) using the Born-approximated physical model, as well as the Foldy-Lax model. In this correspondence, we further find an explicit relationship between energy-based basic time-reversal imaging and the MLE approach: the time-reversal imaging function differs by only a scaling factor from the likelihood imaging function using the estimated scattering potential when a single-scatterer model is employed. Furthermore, this scaling factor is a function of the imaging position only. We show that, as a result, time-reversal imaging has a near-far problem that tends to produce a weaker image for areas further away from the imaging arrays, whereas the MLE-based image is more balanced. Experimental results confirm this conclusion.
IEEE Transactions on Signal Processing 10/2007; · 2.63 Impact Factor
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ABSTRACT: In order to further understand the deactivation behavior of a NiMo/HZSM-5 catalyst system used for fluid catalytic cracking (FCC) gasoline hydro-upgrading, fresh and coked catalysts after operation for different times-on-stream (TOS) with FCC gasoline as a feedstock were characterized by X-ray diffraction, Fourier transformed infrared (FTIR) spectroscopy, nitrogen adsorption, and temperature-programmed desorption of ammonia, as well as FTIR analysis of adsorbed pyridine. The results showed that the amount, nature, and location of coke formed in the catalysts depended upon TOS. Coke was preferentially formed on the strong acid sites, especially on the strong Lewis acid sites in the pore channels and/or on the external surface of the catalysts, resting with the size of the reactant molecules in FCC gasoline. Coke formation led to increases in the selectivities to C8, C9, and C9+ aromatics and decreases in the selectivities to benzene and toluene in the aromatics products. Using real FCC gasoline as a feedstock, this work showed that the deactivation behavior of the HZSM-5 zeolite-based catalyst was different from that obtained using model compounds as feedstocks due to the wide size distribution of the hydrocarbon molecules in FCC gasoline and to the complex reaction mechanisms among these components. The results provided some clues for finely tuning the physicochemical properties of the catalyst to further enhance its on-stream stability.
07/2007;
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ABSTRACT: The resolution improvements of time reversal methods through exploiting nonhomogeneous media have attracted much interest recently with broad applications, including underwater acoustics, radar, detection of defects in metals, communications, and destruction of kidney stones. In this paper, we analyze the effect of inhomogeneity generated by multiple scattering among point scatterers under a multistatic sensing setup. We derive the Crameacuter-Rao bounds (CRBs) on parameters of the scatterers and compare the CRBs for multiple scattering using the Foldy-Lax model with the reference case without multiple scattering using the Born approximation. We find that multiple scattering could significantly improve the estimation performance of the system and higher order scattering components actually contain much richer information about the scatterers. For the case where multiple scattering is not possible, e.g., where only a single target scatterer exists in the illuminated scenario, we propose the use of artificial scatterers, which could effectively improve the estimation performance of the target despite a decrease in the degrees of freedom of the estimation problem due to the introduced unknown parameters of the artificial scatterers. Numerical examples demonstrate the advantages of the artificial scatterers
IEEE Transactions on Signal Processing 07/2007; · 2.63 Impact Factor
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ABSTRACT: We develop a semi-deterministic semi-stochastic channel model for the multiple-input multiple-output (MIMO) system under the macrocell environment with local-to-mobile and local-to-base scatterers. We show that employing closely-spaced antennas (e.g., phased array) at the base station is capable of achieving diversity via the local-to-base scatterers, which avoids impractical large aperture requirement for the spatial diversity at the base station. We evaluate the system performance in terms of ergodic capacity, average pairwise error probability (PEP), and signal-to-noise ratio (SNR); derive closed-form expressions for lower and upper bounds on the capacity and PEP; and show that the capacity, multiplexing and diversity gains are limited by the number of multipaths around the base station. The base-station array affects the lower bound on the capacity and the upper bound on the error probability through the same metric; thus, optimal design of the base station array based on this metric will optimize the two different information theoretic measures simultaneously. The fading correlation matrix also appears in the two bounds in the same form. To improve the performance of the macrocell MIMO system, we propose using artificial scatterers and discuss optimal design issues. Numerical examples demonstrate the accuracy of our analytical results and tightness of performance bounds.
IEEE Transactions on Wireless Communications 06/2006; · 2.59 Impact Factor
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ABSTRACT: This article describes the synthesis, characterization and application of a novel aluminosilicate/silicoaluminophosphate composite zeolite ZSM-5/SAPO-11. The composite was synthesized by the in situ overgrowth of SAPO-11 on ZSM-5 and was characterized by means of X-ray diffraction (XRD), scanning electron microscopy (SEM), Fourier transformed infrared (FT-IR) spectrometry, N2 adsorption and infrared spectroscopy of adsorbed pyridine. The results were compared with those of the mechanical mixture composed of individual ZSM-5 and SAPO-11. In the mechanical mixture, the ZSM-5 phase was morphologically separate from the SAPO-11 phase, while the ZSM-5/SAPO-11 composite existed in a form of a core-shell structure, with the ZSM-5 phase as the core and the SAPO-11 phase as the shell. Compared with the mechanical mixture, the composite had more mesopores and moderate acidity distribution, which could accelerate the diffusion of substances and enhance the synergetic effect between Brönsted and Lewis acids. The comparison of the catalytic performances of the mechanical mixture and the composite-based Ni–Mo catalysts for FCC gasoline hydro-upgrading showed that, due to the above advantages of the composite, the corresponding catalyst yielded improved gasoline research octane number, high liquid yield, good desulfurization activity and lower coke amount and thus could be considered as a potential catalyst system for hydro-upgrading FCC gasoline.
Catalysis Today - CATAL TODAY. 01/2006; 114(4):388-396.
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ABSTRACT: We develop a semi-deterministic semi-stochastic channel model for a multiple-input multiple-output (MIMO) system under the macrocell environment with local-to-mobile and local-to-base scatterers, and show that the channel capacity, multiplexing gain and diversity gain are multipath limited in the sense that they are limited by the number of multipaths around the base station. We derive a lower bound on the ergodic capacity and an upper bound on the average pairwise error detection probability. It is shown that the base-station array affects the two different information theoretic measures through the same metric, and the fading correlation matrix also appears in the two bounds with the same form. Numerical examples show the tightness of the two bounds.
Acoustics, Speech, and Signal Processing, 2004. Proceedings. (ICASSP '04). IEEE International Conference on; 06/2004 · 4.63 Impact Factor
