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 1/42,000, 1/43,700 and 1/49,500 SNPs explained 1/421%, 1/424% and 1/429% 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/I 2-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.

The Politics of Observation:Radical Psychiatry and Social Documentary

How did the counter-cultural aims of Radical Psychiatry coincide with those of documentary filmmaking in the 1960s? Where the forms and structures of new approaches to the documentary necessarily complicit in promoting the clinical and anti-clinical practices, and wider political agenda, of Radical Psychiatry? How did the documentary deal with the ethical, aesthetic, and audience-related issues associated with filming personalities and environments associated with Radical Psychiatry? How did Radical Psychiatry and the documentary shape postwar discourses on trauma, especially within conflict and post-conflict (PTSD) contexts? What is the legacy of Radical Pschiatry today, and how has it been explored by contemporary documentray film?

This article addresses these question by examining a range of documentaries dealing with the radical and 'anti-psychiatric' ideas and methods of figures such as R.D.Laing, David Cooper, Jan Bastiaans, Timothy Leary, and Franco Basaglia. Films analysed include Peter Robinson's Asylum (1972) and Psychiatry and Violence (1973); Ah, Sunflower (Klinkert and Sinclair, 1967); Anatomy of Violence (Davis, 1967); Turn On, Tune In, Drop Out (Robin Clarke, 1967), W. R. - Mysteries of the Organism (Makavejev, 1971); Raymond Depardon's San Clemente (1980) and Urgences (1988); and Louis van Gasteren's trilogy Now Do You Get it Why I am Crying (1969), The Price of Survival (2003), and There is No Plane to Zagreb (2012). 
The article concludes with a discussion of Nicolas Philibert's Every Little Thing (1997) within the context of the French documentary tradition and the film's more immediate subject - the famous clinic at La Borde established by Jean Oury, and associated with the methods and theories of figures such as Jacques
 Lacan, Francesc Tosquelles, Franz Fanon, and Félix Guattari.

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.

FoodCAP: acid-labile protein adducts of heterocyclic amines in human blood are not viable biomarkers of HCA dietary exposure

Intake of heterocyclic amines (HCAs, carcinogens produced during cooking of meat/fish, the most abundant being PhIP, DiMeIQx and MeIQx) is influenced by many factors including type/thickness of meat and cooking method/temperature/duration. Thus, assessment of HCA dietary exposure is difficult. Protein adducts of HCAs have been proposed as potential medium-term biomarkers of exposure, e.g. PhIP adducted to serum albumin or haemoglobin. However, evidence is still lacking that HCA adducts are viable biomarkers in humans consuming normal diets. The FoodCAP project, supported by World Cancer Research Fund, developed a highly sensitive mass spectrometric method for hydrolysis, extraction and detection of acid-labile HCAs in blood and assessed their validity as biomarkers of exposure. Multiple acid/alkaline hydrolysis conditions were assessed, followed by liquid-liquid extraction, clean-up by cation-exchange SPE and quantification by UPLC-ESI-MS/ MS. Blood was analysed from volunteers who completed food diaries to estimate HCA intake based on the US National Cancer Institute’s CHARRED database. Standard HCAs were recovered quantitatively from fortified blood. In addition, PhIP/MeIQx adducts bound to albumin and haemoglobin prepared in vitro using a human liver microsome system were also detectable in blood fortified at low ppt concentrations. However, except for one sample (5pg/ml PhIP), acid-labile PhIP, 7,8-DiMeIQx, 4,8-DiMeIQx and MeIQx were not observed above the 2pg/ml limit of detection in plasma (n=35), or in serum, whole blood or purified albumin, even in volunteers with high meat consumption (nominal HCA intake >2µg/day). It is concluded that HCA blood protein adducts are not viable biomarkers of exposure. Untargeted metabolomic analyses may facilitate discovery of suitable markers.

Phylogeny and ancient DNA of Sus provides insights into neolithic expansion in Island Southeast Asia and Oceania

Human settlement of Oceania marked the culmination of a global colonization process that began when humans first left Africa at least 90,000 years ago. The precise origins and dispersal routes of the Austronesian peoples and the associated Lapita culture remain contentious, and numerous disparate models of dispersal (based primarily on linguistic, genetic, and archeological data) have been proposed. Here, through the use of mtDNA from 781 modern and ancient Sus specimens, we provide evidence for an early human-mediated translocation of the Sulawesi warty pig (Sus celebensis) to Flores and Timor and two later separate human-mediated dispersals of domestic pig (Sus scrofa) through Island Southeast Asia into Oceania. Of the later dispersal routes, one is unequivocally associated with the Neolithic (Lapita) and later Polynesian migrations and links modern and archeological Javan, Sumatran, Wallacean, and Oceanic pigs with mainland Southeast Asian S. scrofa. Archeological and genetic evidence shows these pigs were certainly introduced to islands east of the Wallace Line, including New Guinea, and that so-called "wild" pigs within this region are most likely feral descendants of domestic pigs introduced by early agriculturalists. The other later pig dispersal links mainland East Asian pigs to western Micronesia, Taiwan, and the Philippines. These results provide important data with which to test current models for human dispersal in the region. © 2007 by The National Academy of Sciences of the USA.

Effectiveness of a Multifaceted Intervention for Potentially Inappropriate Prescribing in Older Patients in Primary Care: A Cluster-Randomized Controlled Trial (OPTI-SCRIPT Study)

PURPOSE Potentially inappropriate prescribing (PIP) is common in older people and can result in increased morbidity, adverse drug events, and hospitalizations. The OPTI-SCRIPT study (Optimizing Prescribing for Older People in Primary Care, a cluster-randomized controlled trial) tested the effectiveness of a multifaceted intervention for reducing PIP in primary care.

METHODS We conducted a cluster-randomized controlled trial among 21 general practitioner practices and 196 patients with PIP. Intervention participants received a complex, multifaceted intervention incorporating academic detailing; review of medicines with web-based pharmaceutical treatment algorithms that provide recommended alternative-treatment options; and tailored patient information leaflets. Control practices delivered usual care and received simple, patient-level PIP feedback. Primary outcomes were the proportion of patients with PIP and the mean number of potentially inappropriate prescriptions. We performed intention-to-treat analysis using random-effects regression.

RESULTS All 21 practices and 190 patients were followed. At intervention completion, patients in the intervention group had significantly lower odds of having PIP than patients in the control group (adjusted odds ratio = 0.32; 95% CI, 0.15–0.70; P = .02). The mean number of PIP drugs in the intervention group was 0.70, compared with 1.18 in the control group (P = .02). The intervention group was almost one-third less likely than the control group to have PIP drugs at intervention completion, but this difference was not significant (incidence rate ratio = 0.71; 95% CI, 0.50–1.02; P = .49). The intervention was effective in reducing proton pump inhibitor prescribing (adjusted odds ratio = 0.30; 95% CI, 0.14–0.68; P = .04).

CONCLUSIONS The OPTI-SCRIPT intervention incorporating academic detailing with a pharmacist, and a review of medicines with web-based pharmaceutical treatment algorithms, was effective in reducing PIP, particularly in modifying prescribing of proton pump inhibitors, the most commonly occurring PIP drugs nationally.

Heterogeneity and clinical significance of ETV1 translocations in human prostate cancer

A fluorescence in situ hybridisation (FISH) assay has been used to screen for ETV1 gene rearrangements in a cohort of 429 prostate cancers from patients who had been diagnosed by trans-urethral resection of the prostate. The presence of ETV1 gene alterations (found in 23 cases, 5.4%) was correlated with higher Gleason Score (P=0.001), PSA level at diagnosis (P=<0.0001) and clinical stage (P=0.017) but was not linked to poorer survival. We found that the six previously characterised translocation partners of ETV1 only accounted for 34% of ETV1 re-arrangements (eight out of 23) in this series, with fusion to the androgen-repressed gene C15orf21 representing the commonest event (four out of 23). In 5'-RACE experiments on RNA extracted from formalin-fixed tissue we identified the androgen-upregulated gene ACSL3 as a new 5'-translocation partner of ETV1. These studies report a novel fusion partner for ETV1 and highlight the considerable heterogeneity of ETV1 gene rearrangements in human prostate cancer.

Exposure to Political Violence in Northern Ireland and Outcome of First Episode Psychosis

The impact of political violence on individuals presenting with an episode of first episode psychosis has not been examined. Individuals were assessed for exposure to political violence in Northern Ireland (the “Troubles”) by asking for a response to 2 questions: one asked about the impact of violence “on your area”; the second about the impact of violence “on you or your family’s life.” The participants were separated into 2 groups (high and low impact) for each question. Symptom profiles and rates of substance misuse were compared across the groups at baseline and at 3-year follow up. Of the 178 individuals included in the study 66 (37.1%) reported a high impact of the “Troubles” on their life and 81 (45.5%) a high impact of the “Troubles” on their area. There were no significant differences in symptom profile or rates of substance misuse between high and low groups at presentation. At 3-year follow-up high impact of the “Troubles” on life was associated with higher Positive and Negative Symptom Scale (PANSS) Total (P = .01), PANSS-Positive (P < .05), and PANSS-General (P < .01) scores and lower global assessment of functioning disability (P < .05) scores, after adjusting for confounding factors. Impact of the “Troubles” on area was not associated with differences in symptom outcomes. This finding adds to the evidence that outcomes in psychosis are significantly impacted by environmental factors and suggests that greater attention should be paid to therapeutic strategies designed to address the impact of trauma.

Integration of copy number and transcriptomics provides risk stratification in prostate cancer: A discovery and validation cohort study

BACKGROUND: Understanding the heterogeneous genotypes and phenotypes of prostate cancer is fundamental to improving the way we treat this disease. As yet, there are no validated descriptions of prostate cancer subgroups derived from integrated genomics linked with clinical outcome.

METHODS: In a study of 482 tumour, benign and germline samples from 259 men with primary prostate cancer, we used integrative analysis of copy number alterations (CNA) and array transcriptomics to identify genomic loci that affect expression levels of mRNA in an expression quantitative trait loci (eQTL) approach, to stratify patients into subgroups that we then associated with future clinical behaviour, and compared with either CNA or transcriptomics alone.

FINDINGS: We identified five separate patient subgroups with distinct genomic alterations and expression profiles based on 100 discriminating genes in our separate discovery and validation sets of 125 and 103 men. These subgroups were able to consistently predict biochemical relapse (p = 0.0017 and p = 0.016 respectively) and were further validated in a third cohort with long-term follow-up (p = 0.027). We show the relative contributions of gene expression and copy number data on phenotype, and demonstrate the improved power gained from integrative analyses. We confirm alterations in six genes previously associated with prostate cancer (MAP3K7, MELK, RCBTB2, ELAC2, TPD52, ZBTB4), and also identify 94 genes not previously linked to prostate cancer progression that would not have been detected using either transcript or copy number data alone. We confirm a number of previously published molecular changes associated with high risk disease, including MYC amplification, and NKX3-1, RB1 and PTEN deletions, as well as over-expression of PCA3 and AMACR, and loss of MSMB in tumour tissue. A subset of the 100 genes outperforms established clinical predictors of poor prognosis (PSA, Gleason score), as well as previously published gene signatures (p = 0.0001). We further show how our molecular profiles can be used for the early detection of aggressive cases in a clinical setting, and inform treatment decisions.

INTERPRETATION: For the first time in prostate cancer this study demonstrates the importance of integrated genomic analyses incorporating both benign and tumour tissue data in identifying molecular alterations leading to the generation of robust gene sets that are predictive of clinical outcome in independent patient cohorts.