Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture

Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10−8). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10−4, Bonferroni corrected), of which six reached P < 5 × 10−8, including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.

Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls

Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with diseaseIRGM for Crohns disease, HLA for Crohns disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetesalthough in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases. © 2010 Macmillan Publishers Limited. All rights reserved.

Genome-wide association study identifies eight loci associated with blood pressure

Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N 71,225 European ancestry, N 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10 24), CYP1A2 (P = 1 × 10 23), FGF5 (P = 1 × 10 21), SH2B3 (P = 3 × 10 18), MTHFR (P = 2 × 10 13), c10orf107 (P = 1 × 10 9), ZNF652 (P = 5 × 10 9) and PLCD3 (P = 1 × 10 8) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.

Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region

Ulcerative colitis is a common form of inflammatory bowel disease with a complex etiology. As part of the Wellcome Trust Case Control Consortium 2, we performed a genome-wide association scan for ulcerative colitis in 2,361 cases and 5,417 controls. Loci showing evidence of association at P 1 × 10 5 were followed up by genotyping in an independent set of 2,321 cases and 4,818 controls. We find genome-wide significant evidence of association at three new loci, each containing at least one biologically relevant candidate gene, on chromosomes 20q13 (HNF4A; P = 3.2 × 10 17), 16q22 (CDH1 and CDH3; P = 2.8 × 10 8) and 7q31 (LAMB1; P = 3.0 × 10 8). Of note, CDH1 has recently been associated with susceptibility to colorectal cancer, an established complication of longstanding ulcerative colitis. The new associations suggest that changes in the integrity of the intestinal epithelial barrier may contribute to the pathogenesis of ulcerative colitis. © 2009 Nature America, Inc. All rights reserved.

Genome-wide association studies and musculoskeletal diseases

Bone and joint diseases are major causes of morbidity and mortality worldwide, and their prevalence is increasing as the average population age increases. Most common musculoskeletal diseases show significant heritability, and few have treatments that prevent disease or can induce true treatment-free, disease-free remission. Furthermore, despite valiant efforts of hypothesis-driven research, our understanding of the etiopathogenesis of these conditions is, with few exceptions, at best moderate. Therefore, there has been a long-standing interest in genetics research in musculoskeletal disease as a hypothesis-free method for investigating disease etiopathogenesis. Important contributions have been made through the identification of monogenic causes of disease, but the holy grail of human genetics research has been the identification of the genes responsible for common diseases. The development of genome-wide association (GWA) studies has revolutionized this field, and led to an explosion in the number of genes identified that are definitely involved in musculoskeletal disease pathogenesis. However, this approach will not identify all common disease genes, and although the current progress is exciting and proves the potential of this research discipline, other approaches will be required to identify many of the types of genetic variation likely to be involved.

Genome-Wide Gene Expression Analysis Reveals a Dynamic Interplay between Luteotropic and Luteolytic Factors in the Regulation of Corpus Luteum Function in the Bonnet Monkey (Macaca radiata)

Although LH is essential for survival and function of the corpus luteum (CL) in higher primates, luteolysis occurs during nonfertile cycles without a discernible decrease in circulating LH levels. Using genome-wide expression analysis, several experiments were performed to examine the processes of luteolysis and rescue of luteal function in monkeys. Induced luteolysis with GnRH receptor antagonist (Cetrorelix) resulted in differential regulation of 3949 genes, whereas replacement with exogenous LH (Cetrorelix plus LH) led to regulation of 4434 genes (1563 down-regulation and 2871 up-regulation). A model system for prostaglandin (PG) F-2 alpha-induced luteolysis in the monkey was standardized and demonstrated that PGF(2 alpha) regulated expression of 2290 genes in the CL. Analysis of the LH-regulated luteal transcriptome revealed that 120 genes were regulated in an antagonistic fashion by PGF(2 alpha). Based on the microarray data, 25 genes were selected for validation by real-time RT-PCR analysis, and expression of these genes was also examined in the CL throughout the luteal phase and from monkeys treated with human chorionic gonadotropin (hCG) to mimic early pregnancy. The results indicated changes in expression of genes favorable to PGF(2 alpha) action during the late to very late luteal phase, and expressions of many of these genes were regulated in an opposite manner by exogenous hCG treatment. Collectively, the findings suggest that curtailment of expression of downstream LH-target genes possibly through PGF(2 alpha) action on the CL is among the mechanisms underlying cross talk between the luteotropic and luteolytic signaling pathways that result in the cessation of luteal function, but hCG is likely to abrogate the PGF(2 alpha)-responsive gene expression changes resulting in luteal rescue crucial for the maintenance of early pregnancy. (Endocrinology 150: 1473-1484, 2009)

World Wide Web korpuksena kielitieteellisen tutkimusaineiston haku verkkosivuilta

Tämä tutkielma käsittelee World Wide Webin sisältämien verkkosivujen sisältöjen käyttöä korpusmaisesti kielitieteellisenä tutkimusaineistona. World Wide Web sisältää moninkertaisesti enemmän tekstiä kuin suurimmat olemassa olevat perinteiset tekstikorpukset, joten verkkosivuilta voi todennäköisesti löytää paljon esiintymiä sellaisista sanoista ja rakenteista, jotka ovat perinteisissä korpuksissa harvinaisia. Verkkosivuja voidaan käyttää aineistona kahdella eri tavalla: voidaan kerätä satunnainen otos verkkosivuista ja luoda itsenäinen korpus niiden sisällöistä, tai käyttää koko World Wide Webiä korpuksena verkkohakukoneiden kautta. Verkkosivuja on käytetty tutkimusaineistona monilla eri kielitieteen aloilla, kuten leksikograafisessa tutkimuksessa, syntaktisten rakenteiden tutkimuksessa, pedagogisena materiaalina ja vähemmistökielten tutkimuksessa. Verkkosivuilla on perinteisiin korpuksiin verrattuna useita haitallisia ominaisuuksia, jotka pitää ottaa huomioon, kun niitä käytetään aineistona. Kaikki sivut eivät sisällä kelvollista tekstiä, ja sivut ovat usein esimerkiksi HTML-muotoisia, jolloin ne pitää muuttaa helpommin käsiteltävissä olevaan muotoon. Verkkosivut sisältävät enemmän kielellisiä virheitä kuin perinteiset korpukset, ja niiden tekstityypit ja aihepiirit ovat runsaslukuisempia kuin perinteisten korpusten. Aineiston keräämiseen verkkosivuilta tarvitaan tehokkaita ohjelmatyökaluja. Näistä yleisimpiä ovat kaupalliset verkkohakukoneet, joiden kautta on mahdollista päästä nopeasti käsiksi suureen määrään erilaisia sivuja. Näiden lisäksi voidaan käyttää erityisesti kielitieteellisiin tarpeisiin kehitettyjä työkaluja. Tässä tutkielmassa esitellään ohjelmatyökalut WebCorp, WebAsCorpus.org, BootCaT ja Web as Corpus Toolkit, joiden avulla voi hakea aineistoa verkkosivuilta nimenomaan kielitieteellisiin tarkoituksiin.

Weed management in wide-row cropping systems: a review of current practices and risks for Australian farming systems.

Growing agricultural crops in wide row spacings has been widely adopted to conserve water, to control pests and diseases, and to minimise problems associated with sowing into stubble. The development of herbicide resistance combined with the advent of precision agriculture has resulted in a further reason for wide row spacings to be adopted: weed control. Increased row spacing enables two different methods of weed control to be implemented with non-selective chemical and physical control methods utilised in the wide inter-row zone, with or without selective chemicals used on the on-row only. However, continual application of herbicides and tillage on the inter-row zone brings risks of herbicide resistance, species shifts and/or changes in species dominance, crop damage, increased costs, yield losses, and more expensive weed management technology.

Tiedonhakustrategiat World Wide Webissä

Tutkimuksen tarkoituksena on selvittää, millaisia tiedonhakustrategioita tiedonhakijatkäyttävät etsiessään tietoa Internetistä. Käyttäjät luokitellaan kolmeen ryhmään tiedonhakustrategiansa mukaan. Haku-suuntautuneet käyttäjät käyttävät enimmäkseen hakukoneita, niin koko Internetin kattavia kuin sivustojen sisäisiäkin. Linkkisuuntautuneet taas joko tietävät tai arvaavat kohdesivuston osoitteen tai käyttävät laajoja hierarkkisia hakemistoja tiedon löytämiseen. He navigoivat mielummin sivustollakin linkkejä käyttäen eivätkä yleensä käytä hakutoimintoa. Eriytyneet käyttäjät eivät säännönmukaisesti suosi kumpaakaan tapaa, vaan valitsevat strategian tehtävän mukaan. Tietoa kerättiin kahdella tavalla: WWW-sivulla olleella kyselylomakkeella ja tiedonhakutestillä, jossa käyttäjille annettiin suoritettavaksi erilaisia tiedonhakutehtäviä. Tiedonhakutehtävät lajiteltiin kolmeen ryhmään sen mukaan, mitä strategiaa ne suosivat: hakustrategiaa suosivat, linkkistrategiaa suosivat ja neutraalit tehtävät. Tutkimusongelmana oli selvittää, kuinka tehtävän tyyppi ja ATK- ja Internet-kokemus vaikuttavat tiedonhakustrategian valintaan. Kävi ilmi, ettei käyttäjien suuntautuneisuus tiettyyn strategiaan vaikuta tiedonhakustrategian valintaan, vaan ainoastaan tehtävän tyyppi oli merkitsevä tekijä. Aikaisemman tutkimustiedon valossa kokeenet suosivat haku-suuntautunutta strategiaa. Tässä tutkimuksessa havaittiin, että kokemus lisäsi molempien strategioiden käyttöä yhtäläisesti, mutta tämä ilmiö oli havaittavissa ainoastaan kysely-lomakkeen pohjalta, ei testeissä. Molempien tiedonhakustrategioiden käyttö lisääntyy kokemuksen myötä, mutta suhteelliset osuudet pysyvät samoina. Syyksi sille, että kokeneet eivät suosineet hakustrategiaa, esitetään sitä, että tehtävät olivat liian helppoja, jolloin kokemus ei pääse auttamaan. Oleellisia eroja suoritusajoissa tai hakustrategian vaihdon tiheydessä ei havaittu suhteessa kokemukseen, ainoastaan suhteessa tehtävän tyyppiin.Tämäkin selitettiin toisentyyppisten tehtävien helppoudella. Tutkimuksessa pohditaan lisäksi asiantuntijuuden syntyä tiedonhakukontekstissa sekä esitetään metatietohypoteesi, jonka mukaan tiedonhakustrategian valintaan vaikuttaa tärkeänä tekijänä käyttäjän metatieto hakupalveluista. Metatietoon kuuluu tieto siitä, mitä hakukoneita on saatavilla, mitä tietoa verkosta kannattaa hakea, millä yrityksillä ja yhteisöillä on sisältörikkaat sivut jne, ja minkä tyyppistä tietoa yleensä on saatavilla. Kaikenkaikkiaan strategian valintaan esitetään taustalle kolmen tason tiedon vaikutusta: 1) oma asiantuntemus haettavasta alasta, 2) metatieto Internetin tiedonhakupalveluista sekä 3) tekninen tieto siitä, kuinka hakukoneet toimivat. Avainsanat: tiedonhaku, tiedonhakustrategia, hakukone, WWW, metatieto, kognitiivinen psykologia

Sense of Community in Web Environment

The study of social phenomena in the World Wide Web has been rather fragmentary, andthere is no coherent, reseach-based theory about sense of community in Web environment. Sense of community means part of one's self-concept that has to do with perceiving oneself belonging to, and feeling affinity to a certain social grouping. The present study aimed to find evidence for sense of community in Web environment, and specifically find out what the most critical psychological factors of sense of community would be. Based on known characteristics of real life communities and sense of community, and few occational studies of Web-communities, it was hypothesized that the following factors would be the most critical ones and that they could be grouped as prerequisites, facilitators and consequences of sense of community: awareness and social presence (prerequisites), criteria for membership and borders, common purpose, social interaction and reciprocity, norms and conformity, common history (facilitators), trust and accountability (consequences). In addition to critical factors, the present study aimed to find out if this kind of grouping would be valid. Furthermore, the effect of Web-community members' background variables to sense of community was of interest. In order to answer the questions, an online-questionnaire was created and tested. It included propositions that reflect factors that precede, facilitate and follow the sense of community in Web environment. A factor analysis was calculated to find out the critical factors and analyses of variance were calculated to see if the grouping to prerequisites, facilitators and consequences was right and how the background variables would affect the sense of community in Web environment. The results indicated that the psychological structure of sense of community in Web environment could not be presented with critical variables grouped as prerequisites, facilitators and consequences. Most factors did facilitate the sense of community, but based on this data it could not be argued that some of the factors chronologically precedesense of community and some follow it. Instead, the factor analysis revealed that the most critical factors in sense of community in Web environment are 1) reciprocal involvement, 2) basic trust for others, 3) similarity and common purpose of members, and 4) shared history of members. The most influencing background variables were the member's own participation activity (indicated with reading and writing messages) and the phase in membership lifecycle (from visitor to leader). The more the member participated and the further in membership life cycle he was, the more he felt sense of community. There are many descreptions of sense of community, but the present study was one of the first to actually measure the phenomenon in Web environment, and that gained well documented, valid results based on large data, proving that sense of community in Web environment is possible, and clarifying its psychological structure, thus enhancing the understanding of sense of community in Web environment. Keywords: sense of community, Web-community, psychology of the Internet

Podcast: Community wide interventions for increasing physical activity

If the amount of physical activity in a society increased, it should improve public health; but uncertainties remain about how to achieve this. Professor Philip Baker from the Queensland University of Technology in Australia describes the findings from the January 2015 update of the Cochrane review of the evidence on community-wide interventions.

#20 [updated] Community wide interventions for increasing physical activity - Clinical Version

People who are physically active have higher levels of health related fitness, and a lower risk profile for developing a number of disabling medical conditions and chronic diseases. However, despite considerable evidence of the benefits of regular physical activity, global levels of physical inactivity remain stubbornly high. In response, governments are looking to find ways to increase the physical activity of their populations.

A simple, wide-range, linear thermistor-based temperature indicator

A novel thermistor-based temperature indicator using an RC oscillator and an up/down counter has been developed and described. The indicator provides linear performance over a wide dynamic temperature range of 0-100°C. This indicator is free from the error due to lead resistances of the thermistor and gives a maximum error of ±0 · 1°C in the range 0-100°C. Test results are given to support the theory.