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

A model for the X-ray absorption in Compton-thin AGN

The fraction of AGN with photoelectric absorption in the X-rays ranging from N-H of 10(22) up to about 10(24) cm(-2) (Compton-thin) appears observationally to be anticorrelated to their luminosity L-x. This recently found evidence is used to investigate the location of the absorbing gas. The molecular torus invoked in the unified picture of AGN, while it can be regarded as confirmed on several grounds to explain the Compton-thick objects, do not conform to this new constraint, at least in its physical models as developed so far. In the frame of observationally based evidence that in Compton-thin sources the absorbing gas might be located far away from the X-ray source, it is shown that the gravitational effects of the black hole (BH) on the molecular gas in a disk, within 25 - 450 pc ( depending on the BH mass, from 10(6) to 10(9) M-.), leads naturally to the observed anticorrelation, under the assumption of a statistical correlation between the BH mass and Lx. Its normalization is also reproduced provided that the surface density, Sigma, of this gas is larger than about 150 - 200 M-. pc(-2), and assuming that the bolometric luminosity is one tenth of the Eddington limit. Interestingly, the required values are consistent with the value of the 300 pc molecular disk in our own galaxy, namely 500 M-. pc(-2). In a sample of nearby galaxies from the BIMA SONG survey, it is found that half of the objects have central Sigma larger than 150 M-. pc(-2). Given the simplicity of the proposed model, this finding is very encouraging, waiting for future higher resolution surveys in CO on more distant galaxies

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