DNA methylation in a Scottish family multiply affected by bipolar disorder and major depressive disorder

Background: Bipolar disorder (BD) is a severe, familial psychiatric condition. Progress in understanding the aetiology of BD has been hampered by substantial phenotypic and genetic heterogeneity. We sought to mitigate these confounders by studying a multi-generational family multiply affected by BD and major depressive disorder (MDD), who carry an illness-linked haplotype on chromosome 4p. Within a family, aetiological heterogeneity is likely to be reduced, thus conferring greater power to detect illness-related changes. As accumulating evidence suggests that altered DNA methylation confers risk for BD and MDD, we compared genome-wide methylation between (i) affected carriers of the linked haplotype (ALH) and married-in controls (MIs), (ii) well unaffected haplotype carriers (ULH) and MI, (iii) ALH and ULH and (iv) all haplotype carriers (LH) and MI.Results: Nominally significant differences in DNA methylation were observed in all comparisons, with differences withstanding correction for multiple testing when the ALH or LH group was compared to the MIs. In both comparisons, we observed increased methylation at a locus in FANCI, which was accompanied by increased FANCI expression in the ALH group. FANCI is part of the Fanconi anaemia complementation (FANC) gene family, which are mutated in Fanconi anaemia and participate in DNA repair. Interestingly, several FANC genes have been implicated in psychiatric disorders. Regional analyses of methylation differences identified loci implicated in psychiatric illness by genome-wide association studies, including CACNB2 and the major histocompatibility complex. Gene ontology analysis revealed enrichment for methylation differences in neurologically relevant genes.Conclusions: Our results highlight altered DNA methylation as a potential mechanism by which the linked haplotype might confer risk for mood disorders. Differences in the phenotypic outcome of haplotype carriers might, in part, arise from additional changes in DNA methylation that converge on neurologically important pathways. Further work is required to investigate the underlying mechanisms and functional consequences of the observed differences in methylation

Alpha 2 agonists for sedation to produce better outcomes from critical illness (A2B Trial): protocol for a multicentre phase 3 pragmatic clinical and cost-effectiveness randomised trial in the UK

Introduction: Almost all patients receiving mechanical ventilation (MV) in intensive care units (ICUs) require analgesia and sedation. The most widely used sedative drug is propofol, but there is uncertainty whether alpha2-agonists are superior. The alpha 2 agonists for sedation to produce better outcomes from critical illness (A2B) trial aims to determine whether clonidine or dexmedetomidine (or both) are clinically and cost-effective in MV ICU patients compared with usual care.Methods and analysis: Adult ICU patients within 48 hours of starting MV, expected to require at least 24 hours further MV, are randomised in an open-label three arm trial to receive propofol (usual care) or clonidine or dexmedetomidine as primary sedative, plus analgesia according to local practice. Exclusions include patients with primary brain injury; postcardiac arrest; other neurological conditions; or bradycardia. Unless clinically contraindicated, sedation is titrated using weight-based dosing guidance to achieve a Richmond-Agitation-Sedation score of −2 or greater as early as considered safe by clinicians. The primary outcome is time to successful extubation. Secondary ICU outcomes include delirium and coma incidence/duration, sedation quality, predefined adverse events, mortality and ICU length of stay. Post-ICU outcomes include mortality, anxiety and depression, post-traumatic stress, cognitive function and health-related quality of life at 6-month follow-up. A process evaluation and health economic evaluation are embedded in the trial.The analytic framework uses a hierarchical approach to maximise efficiency and control type I error. Stage 1 tests whether each alpha2-agonist is superior to propofol. If either/both interventions are superior, stages 2 and 3 testing explores which alpha2-agonist is more effective. To detect a mean difference of 2 days in MV duration, we aim to recruit 1437 patients (479 per group) in 40–50 UK ICUs.Ethics and dissemination: The Scotland A REC approved the trial (18/SS/0085). We use a surrogate decision-maker or deferred consent model consistent with UK law. Dissemination will be via publications, presentations and updated guidelines

Impact of cross-disorder polygenic risk on frontal brain activation with specific effect of schizophrenia risk

AbstractEvidence suggests that there is shared genetic aetiology across the major psychiatric disorders conferred by additive effects of many common variants. Measuring their joint effects on brain function may identify common neural risk mechanisms. We investigated the effects of a cross-disorder polygenic risk score (PGRS), based on additive effects of genetic susceptibility to the five major psychiatric disorders, on brain activation during performance of a language-based executive task. We examined this relationship in healthy individuals with (n=82) and without (n=57) a family history of bipolar disorder to determine whether this effect was additive or interactive dependent on the presence of family history. We demonstrate a significant interaction for polygenic loading×group in left lateral frontal cortex (BA9, BA6). Further examination indicated that this was driven by a significant positive correlation in those without a family history (i.e. healthy unrelated volunteers), with no significant relationships in the familial group. We then examined the effect of the individual diagnoses contributing to the PGRS to determine evidence of disorder-specificity. We found a significant association with the schizophrenia polygenic score only, with no other significant relationships. These findings indicate differences in left lateral frontal brain activation in association with increased cross-disorder PGRS in individuals without a family history of psychiatric illness. Lack of effects in the familial group may reflect epistatic effects, shared environmental influences or effects not captured by the PGRS. The specific relationship with loading for schizophrenia is notably consistent with frontal cortical inefficiency as a circumscribed phenotype of psychotic disorders

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Microbial and plant-derived compounds both contribute to persistent soil organic carbon in temperate soils

Our study tests the emerging paradigm that biochemical recalcitrance does not affect substantially long-term (50 years) SOC persistence. We analyzed the molecular composition of SOC in archived soils originating from four European long-term bare fallow experiments (Askov, Rothamsted, Versailles and Ultuna). The soils had been collected after various periods (up to 53 years) under bare fallow. With increasing duration of bare fallow without new organic inputs, the relative abundance of cutin- and suberin-derived compounds declined substantially, and the abundance of lignin-derived compounds was close to zero. Conversely, the relative abundance of plant-derived long-chain alkanes remained almost constant or increased during the bare fallow period. The relative abundance of N-containing compounds, considered to be abundant in SOC derived from microbial activity, increased consistently illustrating that microbial turnover of SOC continues even when plant inputs are stopped. The persistence of the different families of plant-derived compounds differed markedly over the scale of half a century, which may be ascribed to their contrasting chemical characteristics and recalcitrance, or to differences in their interactions with the soil mineral matrix, and likely some combination since chemical composition drives the degree of mineral association. Using soil from this unique set of long-term bare fallow experiments, we provide direct evidence that multi-decadal scale persistent SOC is enriched in microbe-derived compounds but also includes a substantial fraction of plant-derived compounds

The energetic and chemical fingerprints of persistent soil organic carbon. Soil 6th International Symposium on Soil Organic Matter

The absence of convincing physical or chemical procedures to characterize or isolate relatively labile versus persistent soil organic carbon (SOC) pools makes the study of persistent SOC difficult. Long-term bare fallow (BF) experiments, in which C inputs have been stopped for decades, provide a unique opportunity to study persistent SOC without the inherent artefacts induced by extraction procedures, the hypothesis being that SOC is gradually enriched in persistent C with time as labile components decompose. We determined the evolution of thermal and chemical characteristics of bulk SOC in five long-term BF experiments across Europe (Askov, Grignon, Rothamsted, Ultuna and Versailles), using a multi-technique approach involving Rock-Eval pyrolysis (RE), thermogravimetry and differential scanning calorimetry (TG-DSC), Near Edge X-Ray Absorption Fine Structure (NEXAFS) and pyrolysis gas chromatography-mass spectrometry (TMAH-Py-GC-MS). Results of RE andTG analyses showed that the temperature needed to combust the SOC increased with BF duration at all sites.Conversely, SOC energy density (in mJ mg-1 C) measured by DSC decreased with BF duration. RE results showed that hydrogen index (HI) tended to decrease with BF duration whereas the oxygen index (OI) did not show consistent trends across sites. NEXAFS signals presented little differences and were dominated by carboxyl peak. TMAH-Py-GC-MS results showed a strong relative decrease in lignin-derived compounds with BF duration and a small decline in cutin and suberin-derived compounds. Conversely, the relative intensity of alkanes increased with bare fallow duration. Our results showed that in spite of the heterogeneity of the soils at the 5 long-term BF sites, SOC that has persisted in soils for several decades have similar and defined thermal and energetic properties: persistent SOC burns at higher temperature and its combustion generates less energy. Persistent SOC in the studied temperate soils also shares some chemical properties: it has a lower HI values and is depleted in lignin-derived compounds. The increased burning temperature and lower energy density of persistent SOC suggest that SOC stability may be a function of the high energy cost and low energy gain from decomposition of this material