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.

British Society of Gastroenterology guidelines on the diagnosis and management of Barrett's oesophagus

These guidelines provide a practical and evidence-based resource for the management of patients with Barrett's oesophagus and related early neoplasia. The Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument was followed to provide a methodological strategy for the guideline development. A systematic review of the literature was performed for English language articles published up until December 2012 in order to address controversial issues in Barrett's oesophagus including definition, screening and diagnosis, surveillance, pathological grading for dysplasia, management of dysplasia, and early cancer including training requirements. The rigour and quality of the studies was evaluated using the SIGN checklist system. Recommendations on each topic were scored by each author using a five-tier system (A+, strong agreement, to D+, strongly disagree). Statements that failed to reach substantial agreement among authors, defined as >80% agreement (A or A+), were revisited and modified until substantial agreement (>80%) was reached. In formulating these guidelines, we took into consideration benefits and risks for the population and national health system, as well as patient perspectives. For the first time, we have suggested stratification of patients according to their estimated cancer risk based on clinical and histopathological criteria. In order to improve communication between clinicians, we recommend the use of minimum datasets for reporting endoscopic and pathological findings. We advocate endoscopic therapy for high-grade dysplasia and early cancer, which should be performed in high-volume centres. We hope that these guidelines will standardise and improve management for patients with Barrett's oesophagus and related neoplasia.

North Atlantic surface ocean 14C variability between 30 – 40 kyr. BP

The Faroe-Shetland channel is situated in the main path of the inflow of warm North Atlantic surface water to the Nordic seas and further provides an escape route for the cold Norwegian Sea Deep Water. AMS 14C dates of planktonic foraminifera covering Marine Isotope Stage 3 from two cores in the Faroe-Shetland channel will be used to trace past variability of the Atlantic Meridional Overturning Circulation (AMOC). The reservoir age R shows considerable variability ranging between 50 to 2750 14C years. In particular high R values are observed during Heinrich event 4 (H4) with values around 1550 14C years and during the Laschamp magnetic excursion with R values as high as 2700 14C years. The period between Greenland interstadial 8 (GI8) and GI5 show highly variable R values with interstadial R values around 500 – 650 14C years, i.e. slightly higher than ‘normal’, whereas stadials show either significantly higher or lower R values. From GI5 towards the Last Glacial Maximum R values are generally around 1000 14C years or higher. Using magnetic susceptibility, IRD and δ13C and δ18O values measured on the planktic foraminifera species Neogloboquadrina pachyderma, we compare the observed R variability with reconstructed changes in the Atlantic Meridional Overturning Circulation (AMOC). Furthermore a climate model of intermediate complexity (GENIE) including 14C is used as conceptual tool for identifying oceanographic configuration explaining the observed R variability.

Late-Glacial and early Holocene marine 14C reservoir ages off North Iceland (16-9 cal kyr BP)

Tephrochronological age models and 48 14C age determinations on molluscs and foraminifera (planktonic and benthic) are applied for the calculation of marine 14C reservoir age variability during a time period covering the Heinrich event H1 to early Holocene (16–9 cal kyr BP). Our data source consists of four high-resolution marine sediment cores (HM107-04, HM107-05, MD99-2271, MD99-2275) from the North Icelandic shelf. The marine reservoir age (ΔR) is found to be extremely variable, ranging from 385 to 1065 14C years. Extreme ΔR values occur at the end of H1, with values around 1000 14C years (~15 cal kyr BP), probably due to reduced northward flow of well-ventilated subtropical surface waters and a southward expansion of polar waters, as well as an expansion of sea ice limiting air-sea gas exchange. With the onset of the Bølling-Allerød interstadial, the ΔR values decrease towards 0 14C years suggesting a more vigorous North Atlantic Current and an active meridional overturning circulation system. During the Younger Dryas stadial, ΔR values are consistently around 700 14C years suggesting e renewed expansion of polar waters and a weakened meridional overtuning circulation. Interestingly, ΔR values remain high (~200 14C years) at the onset of the Holocene suggesting continued high influence of polar waters. Subsequently, ΔR values rapidly decrease to ~¬ 250 14C years around 11 cal kyr BP, indicating increased air-sea CO2 exchange with the coeval atmosphere. The ΔR values average around 0 14C years from around 10.5 to 9.0 cal kyr BP.

Pleiotropic analysis of cancer risk loci on esophageal adenocarcinoma risk

Background: Several cancer-associated loci identified from genome-wide association studies (GWAS) have been associated with risks of multiple cancer sites, suggesting pleiotropic effects. We investigated whether GWAS-identified risk variants for other common cancers are associated with risk of esophageal adenocarcinoma (EA) or its precursor, Barrett's esophagus. 

Methods: We examined the associations between risks of EA and Barrett's esophagus and 387 SNPs that have been associated with risks of other cancers, by using genotype imputation data on 2,163 control participants and 3,885 (1,501 EA and 2,384 Barrett's esophagus) case patients from the Barrett's and Esophageal Adenocarcinoma Genetic Susceptibility Study, and investigated effect modification by smoking history, body mass index (BMI), and reflux/heartburn. 

Results: After correcting for multiple testing, none of the tested 387 SNPs were statistically significantly associated with risk of EA or Barrett's esophagus. No evidence of effect modification by smoking, BMI, or reflux/heartburn was observed. 

Conclusions: Genetic risk variants for common cancers identified from GWAS appear not to be associated with risks of EA or Barrett's esophagus. 

Impact: To our knowledge, this is the first investigation of pleiotropic genetic associations with risks of EA and Barrett's esophagus.

Genome-wide association studies in oesophageal adenocarcinoma and Barrett's oesophagus: a large-scale meta-analysis

Background: Esophageal adenocarcinoma (EA) is one of the fastest rising cancers in western countries. Barrett’s Esophagus (BE) is the premalignant precursor of EA. However, only a subset of BE patients develop EA, which complicates the clinical management in the absence of valid predictors. Genetic risk factors for BE and EA are incompletely understood. This study aimed to identify novel genetic risk factors for BE and EA.Methods: Within an international consortium of groups involved in the genetics of BE/EA, we performed the first meta-analysis of all genome-wide association studies (GWAS) available, involving 6,167 BE patients, 4,112 EA patients, and 17,159 representative controls, all of European ancestry, genotyped on Illumina high-density SNP-arrays, collected from four separate studies within North America, Europe, and Australia. Meta-analysis was conducted using the fixed-effects inverse variance-weighting approach. We used the standard genome-wide significant threshold of 5×10-8 for this study. We also conducted an association analysis following reweighting of loci using an approach that investigates annotation enrichment among the genome-wide significant loci. The entire GWAS-data set was also analyzed using bioinformatics approaches including functional annotation databases as well as gene-based and pathway-based methods in order to identify pathophysiologically relevant cellular pathways.Findings: We identified eight new associated risk loci for BE and EA, within or near the CFTR (rs17451754, P=4·8×10-10), MSRA (rs17749155, P=5·2×10-10), BLK (rs10108511, P=2·1×10-9), KHDRBS2 (rs62423175, P=3·0×10-9), TPPP/CEP72 (rs9918259, P=3·2×10-9), TMOD1 (rs7852462, P=1·5×10-8), SATB2 (rs139606545, P=2·0×10-8), and HTR3C/ABCC5 genes (rs9823696, P=1·6×10-8). A further novel risk locus at LPA (rs12207195, posteriori probability=0·925) was identified after re-weighting using significantly enriched annotations. This study thereby doubled the number of known risk loci. The strongest disease pathways identified (P<10-6) belong to muscle cell differentiation and to mesenchyme development/differentiation, which fit with current pathophysiological BE/EA concepts. To our knowledge, this study identified for the first time an EA-specific association (rs9823696, P=1·6×10-8) near HTR3C/ABCC5 which is independent of BE development (P=0·45).Interpretation: The identified disease loci and pathways reveal new insights into the etiology of BE and EA. Furthermore, the EA-specific association at HTR3C/ABCC5 may constitute a novel genetic marker for the prediction of transition from BE to EA. Mutations in CFTR, one of the new risk loci identified in this study, cause cystic fibrosis (CF), the most common recessive disorder in Europeans. Gastroesophageal reflux (GER) belongs to the phenotypic CF-spectrum and represents the main risk factor for BE/EA. Thus, the CFTR locus may trigger a common GER-mediated pathophysiology.