67 research outputs found
Replication and Explorations of High-Order Epistasis Using a Large Advanced Intercross Line Pedigree
Dissection of the genetic architecture of complex traits persists as a major challenge in biology; despite considerable efforts, much remains unclear including the role and importance of genetic interactions. This study provides empirical evidence for a strong and persistent contribution of both second- and third-order epistatic interactions to long-term selection response for body weight in two divergently selected chicken lines. We earlier reported a network of interacting loci with large effects on body weight in an F2 intercross between these high– and low–body weight lines. Here, most pair-wise interactions in the network are replicated in an independent eight-generation advanced intercross line (AIL). The original report showed an important contribution of capacitating epistasis to growth, meaning that the genotype at a hub in the network releases the effects of one or several peripheral loci. After fine-mapping of the loci in the AIL, we show that these interactions were persistent over time. The replication of five of six originally reported epistatic loci, as well as the capacitating epistasis, provides strong empirical evidence that the originally observed epistasis is of biological importance and is a contributor in the genetic architecture of this population. The stability of genetic interaction mechanisms over time indicates a non-transient role of epistasis on phenotypic change. Third-order epistasis was for the first time examined in this study and was shown to make an important contribution to growth, which suggests that the genetic architecture of growth is more complex than can be explained by two-locus interactions only. Our results illustrate the importance of designing studies that facilitate exploration of epistasis in populations for obtaining a comprehensive understanding of the genetics underlying a complex trait
New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.
Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes
Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.
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
A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes
dentification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 x 10(-8)) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.Peer reviewe
The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals
To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure–associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure–related pathways and highlight tissues beyond the classical renal system in blood pressure regulation
Past, Present, and Future X-Ray and Gamma-Ray Missions
X- and -ray astronomy began in the early sixties of the last century with balloons flights, sounding rocket experiment and satellites. Long before space satellite detected X- and -rays emitted by cosmic sources, scientists had known that the Universe should be producing these photons. In this chapter we provided an overview of past and present missions that has made the X- and -ray astronomy an integral part of astronomical research, and prospects of future developments
THE IRON K-ALPHA RESPONSE IN AN X-RAY ILLUMINATED RELATIVISTIC DISK AND A BLACK-HOLE MASS ESTIMATE
A method is proposed for the estimate of the black hole mass in an active galactic nucleus which is based on the response of the intensity, centroid energy and width of the iron Kalpha fluorescence line to variations of the ionizing continuum. The method is illustrated for the case of a geometrically thin and optically thick, X-ray illuminated disc, in Keplerian rotation around a Schwarzschild black hole, using a detailed model of the line emissivity. This method is complementary to the one that makes use of variations in detailed line profiles, and could be applied also to measurements obtained at moderate energy resolution
X-ray obscuration and obscured AGN in the local universe
We discuss the X-ray properties of 49 local (z = sigma(t)(-1) similar or equal to 1.6 x 10(24) cm(-2)) is similar or equal to 50%, and reaches similar or equal to 80% for log (F2-10) 0.6 keV) are common in our sample ( 6 new detections at a confidence level >= 2 sigma). They are explained as due to reflection off the illuminated side of optically thick material. We confirm a correlation between the presence of a similar to 100-pc scale nuclear dust in the WFC2 images and Compton-thin obscuration. We interpret this correlation as due to the large covering fraction of gas associated with the dust lanes. The X-ray spectra of highly obscured AGN invariably present a prominent soft excess emission above the extrapolation of the hard X-ray component. This soft component can account for a very large fraction of the overall X-ray energy budget. As this component is generally unobscured - and therefore likely produced in extended gas structures - it may lead to a severe underestimation of the nuclear obscuration in z similar to 1 absorbed AGN, if standard X-ray colors are used to classify them. As a by-product of our study, we report the discovery of a soft X-ray, luminous (similar or equal to 7 x 10(40) erg s(-1)) halo embedding the interacting galaxy pair Mkn 266
MULTIPLE-PEAKED LINE-PROFILES FROM RELATIVISTIC DISKS AT HIGH INCLINATION ANGLES
The profiles of lines from a flat. relativistic disk around a Schwarzschild black hole are computed with a rigorous treatment of the energy shifts and photon trajectories. It is found that, unless the disk is optically thin, further structures emerge between the two Doppler horns, at high ( greater than or similar to 80-degrees) inclination angles. These structures are due to a geodesics focusing effect on photons emitted from the ''far'' side of the disk. Their shape and relative intensity are a function of the radial dependence and angular distribution of the line emissivity. Since these structures are due to a purely general relativistic effect, they could provide an unambiguous signature of a relativistic disk in Active Galactic Nuclei and in X-ray binaries
THE IRON LINE AND HIGH-ENERGY BUMP AS X-RAY SIGNATURES OF COLD MATTER IN SEYFERT-1 GALAXIES
Ginga observations of several bright Seyfert 1 galaxies have recently revealed the presence in their X-ray spectra of both the iron K fluorescence line and a high energy bump, which together are currently interpreted as due to the reprocessing of the primary radiation by cold matter located near the putative black hole. A number of quantitative model predictions on the reprocessed radiation, when the matter is assumed to be distributed in an accretion disk, are presented in this paper; they were obtained, on the basis of Monte Carlo simulations, for different geometries of the disk surface and of the primary X-ray source. The case of a flat disk and a point source placed above the disk on its symmetry axis is treated in greater detail, taking into account the general relativistic and kinematic effects, which have dramatic consequences on the shape of the K line and edge. These effects are less relevant for the equivalent width (W-alpha) of the line and for the strength of the high energy bump, and were therefore ignored for simplicity in computing these two quantities for other source geometries (an optically thin corona, which turns out to be well approximated by the point source, and an optically thick sphere), and for other configurations of the disk surface (conical and concave). Concerning W-alpha, its maximum value is about 150 eV for a flat, 180 eV for a conical and 230 eV for a concave disk seen face-on. Concerning the strength of the bump, it turns out to be an excellent indicator of strong deviations from the planar configuration, and it is shown that, being practically independent of the iron abundance, it can be used to constrain the abundance when used in conjunction with W-alpha. Several observational implications are discussed, in particular it is noted that the relativistic and kinematic effects on the shape of the edge might lead to a misinterpretation of low resolution measurements in terms of absorption by highly ionized iron
- …