Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke

Genetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 × 10 -11; odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28-1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes.

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.

William James, Sciences of Mind, and Anti-imperial Discourse

In the past few decades, the humanities and social sciences have developed new methods of reorienting their conceptual frameworks in a “world without frontiers.” In this book, Bernadette M. Baker offers an innovative approach to rethinking sciences of mind as they formed at the turn of the twentieth century, via the concerns that have emerged at the turn of the twenty-first. The less-visited texts of Harvard philosopher and psychologist William James provide a window into contemporary debates over principles of toleration, anti-imperial discourse, and the nature of ethics. Baker revisits Jamesian approaches to the formation of scientific objects including the child mind, exceptional mental states, and the ghost to explore the possibilities and limits of social scientific thought dedicated to mind development and discipline formation around the construct of the West.

"You must trust somebody" : Valtio, liberalismi ja sotatarviketeollisuus Britanniassa 1884-1905

Tutkielmassa on tarkasteltu Britannian sotilasviranomaisten ja maan sotatarviketeollisuuden välisiä suhteita vuosina 1884-1905. Kiihtyvän kilpavarustelun myötä Britannian sotilasbudjetit kasvoivat nopeasti, mikä johti maan sotatarviketeollisuuden saamien tilausten määrän nopeaan kasvuun samalla kun tuotteiden teknologinen kehitys oli nopeaa. Sotilasmenojen nopea kasvu antoi sotamateriaalihankinnoista vastaaville viranomaisille mahdollisuuden vaikuttaa yksityisen teollisuuden kehitykseen. Keskittämällä tilaukset vain luotettavina pitämilleen yrityksille viranomaiset loivat näiden kanssa puolivirallisia yhteistyösuhteita ja edistivät samalla voimakkaasti alan keskittymistä. Toisaalta muutamien suuryritysten hallitsemasta sotatarviketuotannosta muodostui yksi niistä harvoista teollisuuden aloista, joilla Britannian nopeasti kasvavat kilpailijat eivät pystyneet ohittamaan sitä enempää tuotteiden teknologisessa tasossa kuin markkinaosuuksien suuruudessakaan. Tiettyjen yritysten suosimisen taustalla ei ollut vain maanpuolustuksen kannalta rationaalinen pyrkimys hankkia riittävän laadukasta ja kehittynyttä sotamateriaalia, vaan asiaan vaikutti myös upseerien ja sotilasministeriöiden siviilivirkamiesten perinteiset aristokraattiset ajattelu- ja toimintamallit. Taloudellisen liberalismin hengessä tapahtuneet pyrkimykset uudistaa hankintamenettelyä vastaamaan enemmän vapaan kilpailun ja taloudellisuuden ihanteita jäivät yleensä tuloksettomiksi. Sotamateriaalihankintoihin liittyvä päätöksenteko vaati suurta asiantuntemusta, mikä johti sotaministeriön ja amiraliteetin virkamiesten vaikutusvallan kasvamiseen. Sotateollisuuden laajeneminen kytkeytyy läheisesti 1900-luvun alussa Britannian yhteiskunnallisessa elämässä tapahtuneeseen muutokseen, jota yleensä on luonnehdittu laissez fairen lopuksi. Jo 1880-luvulla alkaneella puuttumisellaan yksityisten sotateollisuusyritysten kehitykseen viranomaiset olivat alkaneet harjoittaa suunniteltua teollisuuspolitiikkaa, jonka tuloksena syntynyt puolivirallinen sotilasteollinen sektori oli aatteellisesti liberaaliin yhteiskuntaan soveltumaton ilmiö. Aseteollisuudessa Britannian valtio oli siten joutunut ensimmäisen kerran läheiseen vuorovaikutussuhteeseen modernien suuryritysten kanssa. Kytkentä, joka 1900-luvun kuluessa levisi yhä uusille aloille samalla kun valtion roolia talouselämässä alettiin vahvistaa. Tutkimuksen varsinaisen lähdemateriaalin muodostavat Britannian parlamentin pöytäkirjat ja sen komiteoiden raportit Niiden ohella on käytetty päätöksien tekemiseen osallistuneiden tai niihin vaikuttamiseen pyrkineiden poliitikkojen ja sotilaiden painettuja puheita, kirjekokoelmia, päiväkirjoja ja muistelmia sekä eräitä aikakauden historiaa koskevia dokumenttikokoelmia ja tilastojulkaisuja. Oleellista valaistusta asiaan tuovat osaltaan aikalaisten kirjoittamat teokset sekä lehdistö, joista kuvastuu ajalle ominainen ajattelutapa. Aihetta suoranaisesti koskevaa, tieteellisen tutkimusten kriteerit täyttävää aikaisempaa tutkimusta on vähän, mutta aihetta sivuavien tutkimusten määrä on erittäin suuri. Sotamateriaalihankintoja ja niiden taustalla olevia syitä voidaan tarkastella niin talous-, sota- aate-, kuin poliittisen historiankin näkökulmista, mutta yksinään mikään niistä ei ole riittävä tämän tutkimuksen kysymyksenasettelun kannalta. Siten tutkielmaa varten on perehdytty laajasti aikakautta koskevaan tutkimuskirjallisuuteen.

Stenotaphrum secundatum, Buffalo Grass 'Sir James'

Spontaneous mutation: discovered in February 2001 as a superior plant growing among “Common” buffalo grass growing on the breeder’s property at Saltash in the Hunter Valley (NSW). The selected material has smaller (finer) leaves and showed better growth and colour than the parent variety with minimal inputs (water, fertiliser) under stressful climatic conditions. Subsequently, it also showed better leaf colour retention than the parent variety during winter. A vegetative plug taken from the original plant has now undergone four subsequent vegetative divisions to expand the original material for performance trials in NSW and Queensland without showing any discernible off types. Main selection criteria: winter colour retention, small leaves, low fertiliser requirement. Propagation: vegetative. Breeder: Brent Redman, Maitland North, NSW. PBR Certificate Number 2715, Application Number 2002/283, granted 18 March 2005.

Portrait of Ralph and Joan Grahme with Ralph's sister Ilse Schuster nee Gottschalk and her husband James at restaurant "Old Vienna"; London, England.

Left to right: Ralph Grahme, Joan Grahme, Ilse Schuster nee Gottschalk, and James Schuster;

New genetic loci link adipose and insulin biology to body fat distribution

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10−8). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

Genetic studies of body mass index yield new insights for obesity biology

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10−8), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ~2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

Defining the role of common variation in the genomic and biological architecture of adult human height

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated approximately 2,000, approximately 3,700 and approximately 9,500 SNPs explained approximately 21%, approximately 24% and approximately 29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/beta-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

FTO genotype is associated with phenotypic variability of body mass index

There is evidence across several species for genetic control of phenotypic variation of complex traits1, 2, 3, 4, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using ~170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype)5, 6, 7, is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of ~0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI8, possibly mediated by DNA methylation9, 10. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.

Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index

Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and approximately 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 x 10(-)(8)), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.