Interrogating Type 2 Diabetes Genome-Wide Association Data Using a Biological Pathway-Based Approach

OBJECTIVE-Recent genome-wide association Studies have resulted in a dramatic increase in our knowledge of the genetic loci involved in type 2 diabetes. In a complementary approach to these single-marker studies, we attempted to identify biological pathways associated with type 2 diabetes. This approach could allow its to identify additional risk loci. RESEARCH DESIGN AND METHODS-We used individual level genotype data generated from the Wellcome Trust Case Control Consortium (WTCCC) type 2 diabetes study, consisting of 393,143 autosomal SNPs, genotyped across 1,924 case subjects and 2,938 control subjects. We sought additional evidence from summary level data available from the Diabetes Genetics Initiative (DGI) and the Finland-United States Investigation of NIDDM Genetics (FUSION) studies. Statistical analysis of pathways was performed using a modification of the Gene Set Enrichment Algorithm (GSEA). A total of 439 pathways were analyzed from the Kyoto Encyclopedia of Genes and Genomes, Gene Ontology, and BioCarta databases. RESULTS-After correcting for the number of pathways tested, we found no strong evidence for any pathway showing association with type 2 diabetes (top P-adj = 0.31). The candidate WNT-signaling pathway ranked top (nominal P = 0.0007, excluding TCF7L2; P = 0.002), containing a number of promising single gene associations. These include CCND2 (rs11833537; P = 0.003), SMAD3 (rs7178347; P = 0.0006), and PRICKLE1 (rs1796390; P = 0.001), all expressed in the pancreas. CONCLUSIONS-Common variants involved in type 2 diabetes risk are likely to occur in or near genes in multiple pathways. Pathway-based approaches to genome-wide association data may be more Successful for some complex traits than others, depending on the nature of the underlying disease physiology. Diabetes 58:1463-1467, 200

Type 2 Diabetes Risk Alleles Are Associated With Reduced Size at Birth

OBJECTIVE: Low birth weight is associated with an increased risk of type 2 diabetes. The mechanisms underlying this association are unknown and may represent intrauterine programming or two phenotypes of one genotype. The fetal insulin hypothesis proposes that common genetic variants that reduce insulin secretion or action may predispose to type 2 diabetes and also reduce birth weight, since insulin is a key fetal growth factor. We tested whether common genetic variants that predispose to type 2 diabetes also reduce birth weight. RESEARCH DESIGN AND METHODS: We genotyped single-nucleotide polymorphisms (SNPs) at five recently identified type 2 diabetes loci (CDKAL1, CDKN2A/B, HHEX-IDE, IGF2BP2, and SLC30A8) in 7,986 mothers and 19,200 offspring from four studies of white Europeans. We tested the association between maternal or fetal genotype at each locus and birth weight of the offspring. RESULTS: We found that type 2 diabetes risk alleles at the CDKAL1 and HHEX-IDE loci were associated with reduced birth weight when inherited by the fetus (21 g [95% CI 11-31], P = 2 x 10(-5), and 14 g [4-23], P = 0.004, lower birth weight per risk allele, respectively). The 4% of offspring carrying four risk alleles at these two loci were 80 g (95% CI 39-120) lighter at birth than the 8% carrying none (P(trend) = 5 x 10(-7)). There were no associations between birth weight and fetal genotypes at the three other loci or maternal genotypes at any locus. CONCLUSIONS: Our results are in keeping with the fetal insulin hypothesis and provide robust evidence that common disease-associated variants can alter size at birth directly through the fetal genotype

Genomic analysis of male puberty timing highlights shared genetic basis with hair colour and lifespan.

The timing of puberty is highly variable and is associated with long-term health outcomes. To date, understanding of the genetic control of puberty timing is based largely on studies in women. Here, we report a multi-trait genome-wide association study for male puberty timing with an effective sample size of 205,354 men. We find moderately strong genomic correlation in puberty timing between sexes (rg = 0.68) and identify 76 independent signals for male puberty timing. Implicated mechanisms include an unexpected link between puberty timing and natural hair colour, possibly reflecting common effects of pituitary hormones on puberty and pigmentation. Earlier male puberty timing is genetically correlated with several adverse health outcomes and Mendelian randomization analyses show a genetic association between male puberty timing and shorter lifespan. These findings highlight the relationships between puberty timing and health outcomes, and demonstrate the value of genetic studies of puberty timing in both sexes

Confronting standard models of proto-planetary disks with new mid-infrared sizes from the Keck Interferometer

This is the author accepted manuscript. The final version is available from American Astronomical Society/IOP Publishing via the DOI in this record.The published version is in ORE at http://hdl.handle.net/10871/30943We present near and mid–infrared interferometric observations made with the Keck Interferometer Nuller and near–contemporaneous spectro–photometry from the IRTF of 11 well known young stellar objects, several observed for the first time in these spectral and spatial resolution regimes. With AU–level spatial resolution, we first establish characteristic sizes of the infrared emission using a simple geometrical model consisting of a hot inner rim and mid–infrared disk emission. We find a high degree of correlation between the stellar luminosity and the mid–infrared disk sizes after using near–infrared data to remove the contribution from the inner rim. We then use a semi–analytical physical model to also find that the very widely used “star + inner dust rim+ flared disk” class of models strongly fails to reproduce the SED and spatially–resolved mid–infrared data simultaneously; specifically a more compact source of mid–infrared emission is required than results from the standard flared disk model. We explore the viability of a modification to the model whereby a second dust rim containing smaller dust grains is added, and find that the two–rim model leads to significantly improved fits in most cases. This complexity is largely missed when carrying out SED modelling alone, although detailed silicate feature fitting by McClure et al. (2013) recently came to a similar conclusion. As has been suggested recently by Menu et al. (2015), the difficulty in predicting mid–infrared sizes from the SED alone might hint at “transition disk”–like gaps in the inner AU; however, the relatively high correlation found in our mid–infrared disk size vs. stellar luminosity relation favors layered disk morphologies and points to missing disk model ingredients instead.The authors wish to acknowledge fruitful discussions with Nuria Calvet and Melissa McClure. Part of this work was performed while X. C. was a Visiting Graduate Student Research Fellow at the Infrared Processing and Analysis Center (IPAC), California Institute of Technology. The Keck Interferometer was funded by the National Aeronautics and Space Administration as part of its Exoplanet Exploration Program. Data presented herein were obtained at the W.M. Keck Observatory, which is operated as a scientific partnership among the California Institute of Technology, the University of California and the National Aeronautics and Space Administration. The Observatory was made possible by the generous financial support of the W.M. Keck Foundation. The authors wish to recognize and acknowledge the very significant cultural role and reverence that the summit of Mauna Kea has always had within the indigenous Hawaiian community. We are most fortunate to have the opportunity to conduct observations from this mountain. Data presented in this paper were obtained at the Infrared Telescope Facility, which is operated by the University of Hawaii under contract NNH14CK55B with the National Aeronautics and Space Administration. We gratefully acknowledge support and participation in the IRTF/BASS observing runs by Daryl Kim, The Aerospace Corporation. This work has made use of services produced by the NASA Exoplanet Science Institute at the California Institute of Technology. M. S. was supported by NASA ADAP grant NNX09AC73G. R. W. R. was supported by the IR&D program of The Aerospace Corporatio

Two-dimensional Quantum-Corrected Eternal Black Hole

The one-loop quantum corrections to geometry and thermodynamics of black hole are studied for the two-dimensional RST model. We chose boundary conditions corresponding to the eternal black hole being in the thermal equilibrium with the Hawking radiation. The equations of motion are exactly integrated. The one of the solutions obtained is the constant curvature space-time with dilaton being a constant function. Such a solution is absent in the classical theory. On the other hand, we derive the quantum-corrected metric (\ref{solution}) written in the Schwarzschild like form which is a deformation of the classical black hole solution \cite{5d}. The space-time singularity occurs to be milder than in classics and the solution admits two asymptotically flat black hole space-times lying at "different sides" of the singularity. The thermodynamics of the classical black hole and its quantum counterpart is formulated. The thermodynamical quantities (energy, temperature, entropy) are calculated and occur to be the same for both the classical and quantum-corrected black holes. So, no quantum corrections to thermodynamics are observed. The possible relevance of the results obtained to the four-dimensional case is discussed.Comment: Latex, 28 pges; minor corrections in text and abstract made and new references adde

Seismology of the Sun : Inference of Thermal, Dynamic and Magnetic Field Structures of the Interior

Recent overwhelming evidences show that the sun strongly influences the Earth's climate and environment. Moreover existence of life on this Earth mainly depends upon the sun's energy. Hence, understanding of physics of the sun, especially the thermal, dynamic and magnetic field structures of its interior, is very important. Recently, from the ground and space based observations, it is discovered that sun oscillates near 5 min periodicity in millions of modes. This discovery heralded a new era in solar physics and a separate branch called helioseismology or seismology of the sun has started. Before the advent of helioseismology, sun's thermal structure of the interior was understood from the evolutionary solution of stellar structure equations that mimicked the present age, mass and radius of the sun. Whereas solution of MHD equations yielded internal dynamics and magnetic field structure of the sun's interior. In this presentation, I review the thermal, dynamic and magnetic field structures of the sun's interior as inferred by the helioseismology.Comment: To be published in the proceedings of the meeting "3rd International Conference on Current Developments in Atomic, Molecular, Optical and Nano Physics with Applications", December 14-16, 2011, New Delhi, Indi

Loss of GPR75 protects against non-alcoholic fatty liver disease and body fat accumulation

Open Access via the Elsevier Agreement L.K.H. designed the experiments with input from F.M., G.S.H.Y., and J.J.R.; F.M. and J.I. created the CRISPR-Cas9-deleted Gpr75 mouse line with input from A.M.; A.L.-P., C.M., B.Y.H.L., G.K.C.D., N.S., P.B.M.d.M., R.C., K.K., E.J.G., J.R.B.P., F.G., J.R.S., and J.J.R. performed experiments and/or data analysis; D.T. provided reagents and intellectual contributions; and L.K.H. and A.L.-P. wrote the manuscript with input from all other authors.Peer reviewe

A Conformally Invariant Holographic Two-Point Function on the Berger Sphere

We apply our previous work on Green's functions for the four-dimensional quaternionic Taub-NUT manifold to obtain a scalar two-point function on the homogeneously squashed three-sphere (otherwise known as the Berger sphere), which lies at its conformal infinity. Using basic notions from conformal geometry and the theory of boundary value problems, in particular the Dirichlet-to-Robin operator, we establish that our two-point correlation function is conformally invariant and corresponds to a boundary operator of conformal dimension one. It is plausible that the methods we use could have more general applications in an AdS/CFT context.Comment: 1+49 pages, no figures. v2: Several typos correcte

An action for the exact string black hole

A local action is constructed describing the exact string black hole discovered by Dijkgraaf, Verlinde and Verlinde in 1992. It turns out to be a special 2D Maxwell-dilaton gravity theory, linear in curvature and field strength. Two constants of motion exist: mass M>1, determined by the level k, and U(1)-charge Q>0, determined by the value of the dilaton at the origin. ADM mass, Hawking temperature T_H \propto \sqrt{1-1/M} and Bekenstein-Hawking entropy are derived and studied in detail. Winding/momentum mode duality implies the existence of a similar action, arising from a branch ambiguity, which describes the exact string naked singularity. In the strong coupling limit the solution dual to AdS_2 is found to be the 5D Schwarzschild black hole. Some applications to black hole thermodynamics and 2D string theory are discussed and generalizations - supersymmetric extension, coupling to matter and critical collapse, quantization - are pointed out.Comment: 41 pages, 2 eps figures, dedicated to Wolfgang Kummer on occasion of his Emeritierung; v2: added ref; v3: extended discussion in sections 3.2, 3.3 and at the end of 5.3 by adding 2 pages of clarifying text; updated refs; corrected typo

Associations of vomiting and antiemetic use in pregnancy with levels of circulating GDF15 early in the second trimester: A nested case-control study [version 1; referees: 2 approved]

Background: Although nausea and vomiting are very common in pregnancy, their pathogenesis is poorly understood. We tested the hypothesis that circulating growth and differentiation factor 15 (GDF15) concentrations in early pregnancy, whose gene is implicated in hyperemesis gravidarum, are associated with nausea and vomiting. Methods: Blood samples for the measurement of GDF15 and human chorionic gonadotrophin (hCG) concentrations were obtained early in the second trimester (median 15.1 (interquartile range 14.4-15.7) weeks) of pregnancy from 791 women from the Cambridge Baby Growth Study, a prospective pregnancy and birth cohort. During each trimester participants completed a questionnaire which included questions about nausea, vomiting and antiemetic use. Associations with pre-pregnancy body mass indexes (BMI) were validated in 231 pregnant NIPTeR Study participants. Results: Circulating GDF15 concentrations were higher in women reporting vomiting in the second trimester than in women reporting no pregnancy nausea or vomiting: 11,581 (10,977-12,219) (n=175) vs. 10,593 (10,066-11,147) (n=193) pg/mL, p=0.02). In women who took antiemetic drugs during pregnancy (n=11) the GDF15 levels were also raised 13,157 (10,558-16,394) pg/mL (p =0.04). Serum GFD15 concentrations were strongly positively correlated with hCG levels but were inversely correlated with maternal BMIs, a finding replicated in the NIPTeR Study. Conclusions: Week 15 serum GDF15 concentrations are positively associated with second trimester vomiting and maternal antiemetic use in pregnancy. Given GDF15’s site of action in the chemoreceptor trigger zone of the brainstem and its genetic associations with hyperemesis gravidarum, these data support the concept that GDF15 may be playing a pathogenic role in pregnancy-associated vomiting