Estimating Effects and Making Predictions from Genome-Wide Marker Data

In genome-wide association studies (GWAS), hundreds of thousands of genetic markers (SNPs) are tested for association with a trait or phenotype. Reported effects tend to be larger in magnitude than the true effects of these markers, the so-called ``winner's curse.'' We argue that the classical definition of unbiasedness is not useful in this context and propose to use a different definition of unbiasedness that is a property of the estimator we advocate. We suggest an integrated approach to the estimation of the SNP effects and to the prediction of trait values, treating SNP effects as random instead of fixed effects. Statistical methods traditionally used in the prediction of trait values in the genetics of livestock, which predates the availability of SNP data, can be applied to analysis of GWAS, giving better estimates of the SNP effects and predictions of phenotypic and genetic values in individuals.Comment: Published in at http://dx.doi.org/10.1214/09-STS306 the Statistical Science (http://www.imstat.org/sts/) by the Institute of Mathematical Statistics (http://www.imstat.org

Genetic architecture of body size in mammals

Much of the heritability for human stature is caused by mutations of small-to-medium effect. This is because detrimental pleiotropy restricts large-effect mutations to very low frequencies

Prediction of individual genetic risk to disease from genome-wide association studies

Empirical studies suggest that the effect sizes of individual causal risk alleles underlying complex genetic diseases are small, with most genotype relative risks in the range of 1.1-2.0. Although the increased risk of disease for a carrier is small for any single locus, knowledge of multiple-risk alleles throughout the genome could allow the identification of individuals that are at high risk. In this study, we investigate the number and effect size of risk loci that underlie complex disease constrained by the disease parameters of prevalence and heritability. Then we quantify the value of prediction of genetic risk to disease using a range of realistic combinations of the number, size, and distribution of risk effects that underlie complex diseases. We propose an approach to assess the genetic risk of a disease in healthy individuals, based on dense genome-wide SNP panels. We test this approach using simulation. When the number of loci contributing to the disease is >50, a large case-control study is needed to identify a set of risk loci for use in predicting the disease risk of healthy people not included in the case-control study. For diseases controlled by 1000 loci of mean relative risk of only 1.04, a case-control study with 10,000 cases and controls can lead to selection of ∼75 loci that explain >50% of the genetic variance. The 5% of people with the highest predicted risk are three to seven times more likely to suffer the disease than the population average, depending on heritability and disease prevalence. Whether an individual with known genetic risk develops the disease depends on known and unknown environmental factors

First normal stress difference and crystallization in a dense sheared granular fluid

The first normal stress difference (${\mathcal N}_1$) and the microstructure in a dense sheared granular fluid of smooth inelastic hard-disks are probed using event-driven simulations. While the anisotropy in the second moment of fluctuation velocity, which is a Burnett-order effect, is known to be the progenitor of normal stress differences in {\it dilute} granular fluids, we show here that the collisional anisotropies are responsible for the normal stress behaviour in the {\it dense} limit. As in the elastic hard-sphere fluids, ${\mathcal N}_1$ remains {\it positive} (if the stress is defined in the {\it compressive} sense) for dilute and moderately dense flows, but becomes {\it negative} above a critical density, depending on the restitution coefficient. This sign-reversal of ${\mathcal N}_1$ occurs due to the {\it microstructural} reorganization of the particles, which can be correlated with a preferred value of the {\it average} collision angle $\theta_{av}=\pi/4 \pm \pi/2$ in the direction opposing the shear. We also report on the shear-induced {\it crystal}-formation, signalling the onset of fluid-solid coexistence in dense granular fluids. Different approaches to take into account the normal stress differences are discussed in the framework of the relaxation-type rheological models.Comment: 21 pages, 13 figure

EXTENDED SUPERCONFORMAL SYMMETRY, FREUDENTHAL TRIPLE SYSTEMS AND GAUGED WZW MODELS

We review the construction of extended ( N=2 and N=4 ) superconformal algebras over triple systems and the gauged WZW models invariant under them. The N=2 superconformal algebras (SCA) realized over Freudenthal triple systems (FTS) admit extension to ``maximal'' N=4 SCA's with SU(2)XSU(2)XU(1) symmetry. A detailed study of the construction and classification of N=2 and N=4 SCA's over Freudenthal triple systems is given. We conclude with a study and classification of gauged WZW models with N=4 superconformal symmetry.Comment: Invited talk presented at the Gursey Memorial Conference I in Istanbul, Turkiye (June 6-10, 1994). To appear in the proceedings of the conference. (21 pages. Latex document.

Scalar and tensorial topological matter coupled to (2+1)-dimensional gravity:A.Classical theory and global charges

We consider the coupling of scalar topological matter to (2+1)-dimensional gravity. The matter fields consist of a 0-form scalar field and a 2-form tensor field. We carry out a canonical analysis of the classical theory, investigating its sectors and solutions. We show that the model admits both BTZ-like black-hole solutions and homogeneous/inhomogeneous FRW cosmological solutions.We also investigate the global charges associated with the model and show that the algebra of charges is the extension of the Kac-Moody algebra for the field-rigid gauge charges, and the Virasoro algebrafor the diffeomorphism charges. Finally, we show that the model can be written as a generalized Chern-Simons theory, opening the perspective for its formulation as a generalized higher gauge theory.Comment: 40 page

Charges, Monopoles and Duality Relations

A charge-monopole theory is derived from simple and self-evident postulates. Charges and monopoles take an analogous theoretical structure. It is proved that charges interact with free waves emitted from monopoles but not with the corresponding velocity fields. Analogous relations hold for monopole equations of motion. The system's equations of motion can be derived from a regular Lagrangian function.Comment: 17 pages + 3 figures

Reducing SS- duality to TT- duality

The infrared limit of $D=4,~~N=4$ Yang-Mills theory with compact gauge group $G$ compactified on a two-torus is governed by an effective superconformal field theory. We conjecture that this is a certain orbifold involving the maximal torus of $G$. Yang-Mills $S$-duality makes predictions for all correlators of this effective conformal field theory. These predictions are shown to be implied by the standard $T$-duality of the conformal field theory. Consequently, Montonen-Olive duality between electric and magnetic states reduces to the standard two-dimensional duality between momentum and winding states.Comment: 13 pages, harvmac, no figures. (Some Comments added. Some references added.

The target space geometry of N=(2,1) string theory

We describe the ${\cal{O}}({\alpha'}^0)$ constraints on the target space geometry of the $N=(2,1)$ heterotic superstring due to the left-moving $N=1$ supersymmetry and $U(1)$ currents. In the fermionic description of the internal sector supersymmetry is realized quantum mechanically, so that both tree-level and one-loop effects contribute to the order ${\cal{O}}({\alpha'}^0)$ constraints. We also discuss the physical interpretation of the resulting target space geometry in terms of configurations of a $2+2$-dimensional object propagating in a $10+2$-dimensional spacetime with a null isometry, which has recently been suggested as a unified description of string and M theory.Comment: 41 pages, 5 figures, standard LaTeX, uses epsf.tex. Some typos corrected, discussion in footnote 1 correcte