Hypomethylation of FAM63B in bipolar disorder patients

Bipolar disorder (BD) and schizophrenia (SZ) are known to share common genetic and psychosocial risk factors. A recent epigenome-wide association study performed on blood samples from SZ patients found significant hypomethylation of FAM63B in exon 9. Here, we used iPLEX-based methylation analysis to investigate two CpG sites in FAM63B in blood samples from 459 BD cases and 268 controls. Both sites were significantly hypomethylated in BD cases (lowest p value = 3.94 × 10−8). The methylation levels at the two sites were correlated, and no strong correlation was found with nearby single nucleotide polymorphisms (SNPs), suggesting that methylation differences at these sites are not readably picked up by genome-wide association studies. Overall, FAM63B hypomethylation was found in BD patients, thus replicating the initial finding in SZ patients. This study suggests that FAM63B is a shared epigenetic risk gene for the two disorders

CACNA1C hypermethylation is associated with bipolar disorder

The CACNA1C gene, encoding a subunit of the L-type voltage-gated calcium channel is one of the best-supported susceptibility genes for bipolar disorder (BD). Genome-wide association studies have identified a cluster of non-coding single-nucleotide polymorphisms (SNPs) in intron 3 to be highly associated with BD and schizophrenia. The mechanism by which these SNPs confer risk of BD appears to be through an altered regulation of CACNA1C expression. The role of CACNA1C DNA methylation in BD has not yet been addressed. The aim of this study was to investigate if CACNA1C DNA methylation is altered in BD. First, the methylation status of five CpG islands (CGIs) across CACNA1C in blood from BD subjects (n=40) and healthy controls (n=38) was determined. Four islands were almost completely methylated or completely unmethylated, while one island (CGI 3) in intron 3 displayed intermediate methylation levels. In the main analysis, the methylation status of CGI 3 was analyzed in a larger sample of BD subjects (n=582) and control individuals (n=319). Out of six CpG sites that were investigated, five sites showed significant hypermethylation in cases (lowest P=1.16 × 10(-7) for CpG35). Nearby SNPs were found to influence the methylation level, and we identified rs2238056 in intron 3 as the strongest methylation quantitative trait locus (P=2.6 × 10(-7)) for CpG35. In addition, we found an increased methylation in females, and no difference between bipolar I and II. In conclusion, we find that CACNA1C methylation is associated with BD and suggest that the regulatory effect of the non-coding risk variants involves a shift in DNA methylation

Long-term halocarbon observations from a coastal and an inland site in Sabah, Malaysian Borneo

Abstract. Short-lived halocarbons are believed to have important sources in the tropics, where rapid vertical transport could provide a significant source to the stratosphere. In this study, quasi-continuous measurements of short-lived halocarbons are reported for two tropical sites in Sabah (Malaysian Borneo), one coastal and one inland (rainforest). We present the observations for C2Cl4, CHBr3, CH2Br2* (actually ~80% CH2Br2 and ~20% CHBrCl2) and CH3I from November 2008 to January 2010 made using our μDirac gas chromatographs with electron capture detection (GC-ECD). We focus on the first 15 months of observations, showing over one annual cycle for each compound and therefore adding significantly to the few limited-duration observational studies that have been conducted thus far in southeast Asia. The main feature in the C2Cl4 behaviour at both sites is its annual cycle, with the winter months being influenced by northerly flow with higher concentrations, typical of the Northern Hemisphere, and with the summer months influenced by southerly flow and lower concentrations representative of the Southern Hemisphere. No such clear annual cycle is seen for CHBr3, CH2Br2* or CH3I. The baseline values for CHBr3 and CH2Br2* are similar at the coastal (overall median: CHBr3 1.7 ppt, CH2Br2* 1.4 ppt) and inland sites (CHBr3 1.6 ppt, CH2Br2* 1.1 ppt), but periods with elevated values are seen at the coast (overall 95th percentile: CHBr3 4.4 ppt, CH2Br2ast 1.9 ppt), presumably resulting from the stronger influence of coastal emissions. Overall median bromine values from [CHBr3 × 3] + [CH2Br2* × 2] are 8.0 ppt at the coast and 6.8 ppt inland. The median values reported here are largely consistent with other limited tropical data and imply that southeast Asia generally is not, as has been suggested, a hot spot for emissions of these compounds. These baseline values are consistent with the most recent emissions found for southeast Asia using the p-TOMCAT (Toulouse Off-line Model of Chemistry And Transport) model. CH3I, which is only observed at the coastal site, is the shortest-lived compound measured in this study, and the observed atmospheric variations reflect this, with high variability throughout the study period. This work was supported by a NERC consortium grant to the OP3 team, by NCAS, by the European Commission through the SCOUT-O3 project (505390-GOCE-CF2004) and by NERC western Pacific grant number NE/F020341/1 and NERC CAST grant number NE/J006246/1. L. M. O’Brien and M. J. Ashfold thank NERC for research studentships. A. D. Robinson acknowledges NERC for their support through small grant project NE/D008085/1. N. R. P. Harris is supported by a NERC Advanced Research Fellowship. We thank the Sabah Foundation, Danum Valley Field Centre and the Royal Society (Glen Reynolds) for field site support. The research leading to these results has received funding from the European Union’s Seventh Framework Programme FP7/2007–2013 under grant agreement no. 226224 – SHIVA. We thank David Oram and Stephen Humphrey at UEA for their assistance in checking the calibration of our Aculife cylinder in May 2009. This is paper number 626 of the Royal Society’s South East Asian Rainforest Research Programme.This is the final published version. It first appeared at http://www.atmos-chem-phys.net/14/8369/2014/acp-14-8369-2014.html

Using Abbreviated Injury Scale (AIS) codes to classify Computed Tomography (CT) features in the Marshall System

<p>Abstract</p> <p>Background</p> <p>The purpose of Abbreviated Injury Scale (AIS) is to code various types of Traumatic Brain Injuries (TBI) based on their anatomical location and severity. The Marshall CT Classification is used to identify those subgroups of brain injured patients at higher risk of deterioration or mortality. The purpose of this study is to determine whether and how AIS coding can be translated to the Marshall Classification</p> <p>Methods</p> <p>Initially, a Marshall Class was allocated to each AIS code through cross-tabulation. This was agreed upon through several discussion meetings with experts from both fields (clinicians and AIS coders). Furthermore, in order to make this translation possible, some necessary assumptions with regards to coding and classification of mass lesions and brain swelling were essential which were all approved and made explicit.</p> <p>Results</p> <p>The proposed method involves two stages: firstly to determine all possible Marshall Classes which a given patient can attract based on allocated AIS codes; via cross-tabulation and secondly to assign one Marshall Class to each patient through an algorithm.</p> <p>Conclusion</p> <p>This method can be easily programmed in computer softwares and it would enable future important TBI research programs using trauma registry data.</p

TLR7-mediated skin inflammation remotely triggers chemokine expression and leukocyte accumulation in the brain

Background: The relationship between the brain and the immune system has become increasingly topical as, although it is immune-specialised, the CNS is not free from the influences of the immune system. Recent data indicate that peripheral immune stimulation can significantly affect the CNS. But the mechanisms underpinning this relationship remain unclear. The standard approach to understanding this relationship has relied on systemic immune activation using bacterial components, finding that immune mediators, such as cytokines, can have a significant effect on brain function and behaviour. More rarely have studies used disease models that are representative of human disorders. Methods: Here we use a well-characterised animal model of psoriasis-like skin inflammation—imiquimod—to investigate the effects of tissue-specific peripheral inflammation on the brain. We used full genome array, flow cytometry analysis of immune cell infiltration, doublecortin staining for neural precursor cells and a behavioural read-out exploiting natural burrowing behaviour. Results: We found that a number of genes are upregulated in the brain following treatment, amongst which is a subset of inflammatory chemokines (CCL3, CCL5, CCL9, CXCL10, CXCL13, CXCL16 and CCR5). Strikingly, this model induced the infiltration of a number of immune cell subsets into the brain parenchyma, including T cells, NK cells and myeloid cells, along with a reduction in neurogenesis and a suppression of burrowing activity. Conclusions: These findings demonstrate that cutaneous, peripheral immune stimulation is associated with significant leukocyte infiltration into the brain and suggest that chemokines may be amongst the key mediators driving this response

Whole-exome sequencing of individuals from an isolated population implicates rare risk variants in bipolar disorder

Bipolar disorder affects about 1% of the world's population, and its estimated heritability is about 75%. Only few whole genome or whole-exome sequencing studies in bipolar disorder have been reported, and no rare coding variants have yet been robustly identified. The use of isolated populations might help finding variants with a recent origin, more likely to have drifted to higher frequency by chance. Following this approach, we investigated 28 bipolar cases and 214 controls from the Faroe Islands by whole exome sequencing, and the results were followed-up in a British sample of 2025 cases and 1358 controls. Seventeen variants in 16 genes in the single-variant analysis, and 3 genes in the gene-based statistics surpassed exome-wide significance in the discovery phase. The discovery findings were supported by enrichment analysis of common variants from genome-wide association studies (GWAS) data and interrogation of protein-protein interaction networks. The replication in the British sample confirmed the association with NOS1 (missense variant rs79487279) and NCL (gene-based test). A number of variants from the discovery set were not present in the replication sample, including a novel PITPNM2 missense variant, which is located in a highly significant schizophrenia GWAS locus. Likewise, PIK3C2A identified in the gene-based analysis is located in a combined bipolar and schizophrenia GWAS locus. Our results show support both for existing findings in the literature, as well as for new risk genes, and identify rare variants that might provide additional information on the underlying biology of bipolar disorder

The critical role of second-order normative beliefs in predicting energy conservation

This is the author accepted manuscript. The final version is available from Springer Nature via the DOI in this recordSustaining large-scale public goods requires individuals to make environmentally friendly decisions today to benefit future generations. Recent research suggests that second-order normative beliefs are more powerful predictors of behaviour than first-order personal beliefs. We explored the role that second-order normative beliefs—the belief that community members think that saving energy helps the environment—play in curbing energy use. We first analysed a data set of 211 independent, randomized controlled trials conducted in 27 US states by Opower, a company that uses comparative information about energy consumption to reduce household energy usage (pooled N = 16,198,595). Building off the finding that the energy savings varied between 0.81% and 2.55% across states, we matched this energy use data with a survey that we conducted of over 2,000 individuals in those same states on their first-order personal and second-order normative beliefs. We found that second-order normative beliefs predicted energy savings but first-order personal beliefs did not. A subsequent pre-registered experiment provides causal evidence for the role of second-order normative beliefs in predicting energy conservation above first-order personal beliefs. Our results suggest that second-order normative beliefs play a critical role in promoting energy conservation and have important implications for policymakers concerned with curbing the detrimental consequences of climate change

A neighbourhood Output Area Classification from the 2021 and 2022 UK censuses

UK-wide multivariate neighbourhood classifications have been built using small area population data following every census since 1971, and have been built using Output Area geographies since 2001. Policy makers in both the public and private sectors find such taxonomies, typically arranged into hierarchies of Supergroups, Groups and Subgroups, useful across a wide range of applications in business and service planning. Recent and forthcoming releases of small area census statistics pose new methodological challenges. For example, the 2022 Scottish Census was carried out a year after those in other UK nations, and some of the variables now collected across different jurisdictions do not bear direct comparison with one another. Here we develop a methodology to accommodate these issues alongside the more established procedures of variable selection, standardisation, transformation, class definition and labelling