A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer

Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.

Making the profitable transition towards sustainable business practice

The last three decades have been difficult for companies and industry. In an increasingly competitive international business climate with shifting national environmental regulations, higher standards are being demanded by the consumer and community groups, not-to-mention the escalating cost of primary resources such as water, steel and minerals. The cause of these pressures is the traditional notion held by business executives and engineers that there is an inherent trade off between eco-efficiency and improving the economic bottom line. However there is significant evidence and examples of best practice to show that there is in fact no trade-off between the environment and the economy if sustainable development through continual improvement is adopted. It is highly possible therefore for companies to make a profitable transition towards sustainable business practice, where along the transition significant business opportunities can be taken advantage of. Companies are by their very nature dynamic, influential and highly capable of adapting to change. Making an organisational transformation to a sustainable business is not outside the capacity of the typical company, who know much of what is needed already to change their activities to satisfy current market demands while achieving competitiveness. However in order to make the transition towards sustainable business practice companies require some key mechanisms such as accurate information on methodologies and opportunities, understanding of the financial and non-financial incentives, permission from stakeholders and shareholders, understanding of the emerging market opportunities, a critical mass of leaders in their sector and demonstrated case studies, and awarding appropriate risk-taking activities undertaken by engineers and CEOs. Satisfying these requirements will adopt an innovative culture within the company that strives for continual improvement and successfully transforms itself to achieve competitiveness in the 21st Century. This paper will summarise the experiences of The Natural Edge Project (TNEP) and its partners in assisting organisations to make a profitable transition towards sustainable business practice through several initiatives. The Natural Advantage of Nations publication provides the critical information required by business leaders and engineers to set the context of sustainable business practice. The Profiting in a Carbon Constrained World report, developed with Natural Capitalism Inc led by Hunter Lovins, summarises the opportunities available to companies to take advantage of the carbon trading market mechanisms such as the Chicago Climate Exchange and European Climate Exchange. The Sustainability Helix then guides the company through the transition by identifying the key tools and methodologies required by companies to reduce environmental loading while dramatically improving resource productivity and achieving competitiveness. Finally, the Engineering Sustainable Solutions Program delivers the key engineering information required by companies and university departments to deliver sustainable engineering solutions. The initiatives are of varying complexity and level of application, however all are designed to provide key staff the critical information required to make a profitable transition towards sustainable business practice. It is then their responsibility to apply and teach their knowledge to the rest of the organisation.

Michael Kirby's challenge: Intellectual property, HIV/AIDS, and human rights

In July 2014, Melbourne hosted the 20th International AIDS Conference. The event opened, paying tribute to the late Dutch HIV/AIDS researcher Professor Joep Lange, with his image projected onto a screen, with the accompanying quotation: ‘If we can bring a bottle of Coke to every corner of Africa, we should be able to also deliver antiretroviral drugs.’

Genome-wide association analysis identifies 11 risk variants associated with the asthma with hay fever phenotype

Background To date, no genome-wide association study (GWAS) has considered the combined phenotype of asthma with hay fever. Previous analyses of family data from the Tasmanian Longitudinal Health Study provide evidence that this phenotype has a stronger genetic cause than asthma without hay fever. Objective We sought to perform a GWAS of asthma with hay fever to identify variants associated with having both diseases. Methods We performed a meta-analysis of GWASs comparing persons with both physician-diagnosed asthma and hay fever (n = 6,685) with persons with neither disease (n = 14,091). Results At genome-wide significance, we identified 11 independent variants associated with the risk of having asthma with hay fever, including 2 associations reaching this level of significance with allergic disease for the first time: ZBTB10 (rs7009110; odds ratio [OR], 1.14; P = 4 × 10−9) and CLEC16A (rs62026376; OR, 1.17; P = 1 × 10−8). The rs62026376:C allele associated with increased asthma with hay fever risk has been found to be associated also with decreased expression of the nearby DEXI gene in monocytes. The 11 variants were associated with the risk of asthma and hay fever separately, but the estimated associations with the individual phenotypes were weaker than with the combined asthma with hay fever phenotype. A variant near LRRC32 was a stronger risk factor for hay fever than for asthma, whereas the reverse was observed for variants in/near GSDMA and TSLP. Single nucleotide polymorphisms with suggestive evidence for association with asthma with hay fever risk included rs41295115 near IL2RA (OR, 1.28; P = 5 × 10−7) and rs76043829 in TNS1 (OR, 1.23; P = 2 × 10−6). Conclusion By focusing on the combined phenotype of asthma with hay fever, variants associated with the risk of allergic disease can be identified with greater efficiency.

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.

Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution

Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10−9 to P = 1.8 × 10−40) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10−3 to P = 1.2 × 10−13). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.

Genome-wide association study of prostate cancer-specific survival

BACKGROUND: Unnecessary intervention and overtreatment of indolent disease are common challenges in clinical management of prostate cancer. Improved tools to distinguish lethal from indolent disease are critical. METHODS: We performed a genome-wide survival analysis of cause-specific death in 24,023 prostate cancer patients (3,513 disease-specific deaths) from the PRACTICAL and BPC3 consortia. Top findings were assessed for replication in a Norwegian cohort (CONOR). RESULTS: We observed no significant association between genetic variants and prostate cancer survival. CONCLUSIONS: Common genetic variants with large impact on prostate cancer survival were not observed in this study. IMPACT: Future studies should be designed for identification of rare variants with large effect sizes or common variants with small effect sizes.