Cosmology with Hypervelocity Stars

In the standard cosmological model, the merger remnant of the Milky Way and Andromeda (Milkomeda) will be the only galaxy remaining within our event horizon once the Universe has aged by another factor of ten, ~10^{11} years after the Big Bang. After that time, the only extragalactic sources of light in the observable cosmic volume will be hypervelocity stars being ejected continuously from Milkomeda. Spectroscopic detection of the velocity-distance relation or the evolution in the Doppler shifts of these stars will allow a precise measurement of the vacuum mass density as well as the local matter distribution. Already in the near future, the next generation of large telescopes will allow photometric detection of individual stars out to the edge of the Local Group, and may target the ~10^{5+-1} hypervelocity stars that originated in it as cosmological tracers.Comment: 4 pages, 2 figures, accepted for publication in the Journal of Cosmology and Astroparticle Physics (JCAP, 2011

Genome-wide association study identifies two susceptibility loci for osteosarcoma

Osteosarcoma is the most common primary bone malignancy of adolescents and young adults. To better understand the genetic etiology of osteosarcoma, we performed a multistage genome-wide association study consisting of 941 individuals with osteosarcoma (cases) and 3,291 cancer-free adult controls of European ancestry. Two loci achieved genome-wide significance: a locus in the GRM4 gene at 6p21.3 (encoding glutamate receptor metabotropic 4; rs1906953; P = 8.1 × 10⁻⁹) and a locus in the gene desert at 2p25.2 (rs7591996 and rs10208273; P = 1.0 × 10⁻⁸ and 2.9 × 10⁻⁷, respectively). These two loci warrant further exploration to uncover the biological mechanisms underlying susceptibility to osteosarcoma

Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes

Lymphoma risk is elevated for relatives with common non-Hodgkin lymphoma (NHL) subtypes, suggesting shared genetic susceptibility across subtypes. To evaluate the extent of mutual heritability among NHL subtypes and discover novel loci shared among subtypes, we analyzed data from eight genome-wide association studies within the InterLymph Consortium, including 10,629 cases and 9505 controls. We utilized Association analysis based on SubSETs (ASSET) to discover loci for subsets of NHL subtypes and evaluated shared heritability across the genome using Genome-wide Complex Trait Analysis (GCTA) and polygenic risk scores. We discovered 17 genome-wide significant loci (P < 5 × 10−8) for subsets of NHL subtypes, including a novel locus at 10q23.33 (HHEX) (P = 3.27 × 10−9). Most subset associations were driven primarily by only one subtype. Genome-wide genetic correlations between pairs of subtypes varied broadly from 0.20 to 0.86, suggesting substantial heterogeneity in the extent of shared heritability among subtypes. Polygenic risk score analyses of established loci for different lymphoid malignancies identified strong associations with some NHL subtypes (P < 5 × 10−8), but weak or null associations with others. Although our analyses suggest partially shared heritability and biological pathways, they reveal substantial heterogeneity among NHL subtypes with each having its own distinct germline genetic architecture

Detectable clonal mosaicism and its relationship to aging and cancer

In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases

Genome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (Pinteraction = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications

Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome

To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events42Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases

Molecular epidemiology: linking molecular scale insights to population impacts

In a broad sense, molecular epidemiology is the axis that unites insights at the molecular level and understanding of disease at the population level. It is also a partnership between epidemiologists and laboratory scientists in which investigations are conducted using the principles of both disciplines. A key trait of molecular epidemiology is to evaluate and establish the relationship between a biomarker and important exogenous and endogenous exposures, susceptibility, or disease, providing understanding that can be used in future research and public health and clinical practice. When potential solutions or interventions are identified, molecular epidemiology is also useful in developing and conducting clinical and intervention trials. It can then contribute to the translation of biomedical research into practical public health and clinical applications by addressing the medical and population implications of molecular phenomena in terms of reducing risk of disease. This chapter summarizes the contributions and research endeavours of molecular epidemiology and how they link with public health initiatives and clinical practice

Future perspectives on molecular epidemiology

Molecular epidemiology is poised to make ever-greater contributions to understanding the genetic and environmental causes of human disease. Both agnostic and hypothesis-driven approaches to both categories of risk factors could lead to leaps in our understanding. Investment in new methods and approaches will be needed, however. Strong links between population scientists, bench scientists, bioinformaticians and engineers must also be fo rged if progress is to be made

Application of OMICS technologies in occupational and environmental health research; current status and projections.

OMICS technologies are relatively new biomarker discovery tools that can be applied to study large sets of biological molecules. Their application in human observational studies (HOS) has become feasible in recent years due to a spectacular increase in the sensitivity, resolution and throughput of OMICS-based assays. Although, the number of OMICS techniques is ever expanding, the five most developed OMICS technologies are genotyping, transcriptomics, epigenomics, proteomics and metabolomics. These techniques have been applied in HOS to various extents. However, their application in occupational environmental health (OEH) research has been limited. Here, we will discuss the opportunities these new techniques provide for OEH research. In addition we will address difficulties and limitations to the interpretation of the data that is generated by OMICS technologies. To illustrate the current status of the application of OMICS in OEH research, we will provide examples of studies that used OMICS technologies to investigate human health effects of two well-known toxicants, benzene and arsenic

Human benzene metabolism following occupational and environmental exposures.

We previously reported evidence that humans metabolize benzene via two enzymes, including a hitherto unrecognized high-affinity enzyme that was responsible for an estimated 73% of total urinary metabolites [sum of phenol (PH), hydroquinone (HQ), catechol (CA), E,E-muconic acid (MA), and S-phenylmercapturic acid (SPMA)] in nonsmoking females exposed to benzene at sub-saturating (ppb) air concentrations. Here, we used the same Michaelis-Menten-like kinetic models to individually analyze urinary levels of PH, HQ, CA and MA from 263 nonsmoking Chinese women (179 benzene-exposed workers and 84 control workers) with estimated benzene air concentrations ranging from less than 0.001-299 ppm. One model depicted benzene metabolism as a single enzymatic process (1-enzyme model) and the other as two enzymatic processes which competed for access to benzene (2-enzyme model). We evaluated model fits based upon the difference in values of Akaike's Information Criterion (DeltaAIC), and we gauged the weights of evidence favoring the two models based upon the associated Akaike weights and Evidence Ratios. For each metabolite, the 2-enzyme model provided a better fit than the 1-enzyme model with DeltaAIC values decreasing in the order 9.511 for MA, 7.379 for PH, 1.417 for CA, and 0.193 for HQ. The corresponding weights of evidence favoring the 2-enzyme model (Evidence Ratios) were: 116.2:1 for MA, 40.0:1 for PH, 2.0:1 for CA and 1.1:1 for HQ. These results indicate that our earlier findings from models of total metabolites were driven largely by MA, representing the ring-opening pathway, and by PH, representing the ring-hydroxylation pathway. The predicted percentage of benzene metabolized by the putative high-affinity enzyme at an air concentration of 0.001 ppm was 88% based upon urinary MA and was 80% based upon urinary PH. As benzene concentrations increased, the respective percentages of benzene metabolized to MA and PH by the high-affinity enzyme decreased successively to 66 and 77% at 0.1 ppm, 20 and 58% at 1 ppm, and 2.7 and 17% at 10 ppm. This indicates that the putative high-affinity enzyme was active primarily below 1 ppm and favored the ring-opening pathway