Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery

Rare truncating variants in the sarcomeric protein titin associate with familial and early-onset atrial fibrillation

Common genetic variants in structural proteins contribute to risk of atrial fibrillation (AF). Here, using whole-exome sequencing, the authors identify rare truncating variants in TTN that associate with familial and early-onset AF and show defects in cardiac sarcomere assembly in ttn.2-mutant zebrafish

A saturated map of common genetic variants associated with human height

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes(1). Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel(2)) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants

Methylotrophic methanogenic Thermoplasmata implicated in reduced methane emissions from bovine rumen

Rumen methanogens are major sources of anthropogenic methane emissions, and these archaea are targets in strategies aimed at reducing methane emissions. Here we show that the poorly characterised Thermoplasmata archaea in bovine rumen are methylotrophic methanogens and that they are reduced upon dietary supplementation with rapeseed oil in lactating cows. In a metatranscriptomic survey, Thermoplasmata 16S rRNA and methyl-coenzyme M reductase (mcr) transcripts decreased concomitantly with mRNAs of enzymes involved in methanogenesis from methylamines that were among the most abundant archaeal transcripts, indicating that these Thermoplasmata degrade methylamines. Their methylotrophic methanogenic lifestyle was corroborated by in vitro incubations, showing enhanced growth of these organisms upon methylamine supplementation paralleled by elevated methane production. The Thermoplasmata have a high potential as target in future strategies to mitigate methane emissions from ruminant livestock. Our findings and the findings of others also indicate a wider distribution of methanogens than previously anticipated

Juggling multiple accountability systems: how three principals manage these tensions in Ontario, Canada

Accountability in education is not new. Schools have always been accountable in one way or another to the communities they serve, regardless of the policy environment of the time (Elmore, The Educational Forum, 69:134–142, 2005). This article explores how three principals from Ontario, Canada manage the tensions of multiple accountability systems in their work. Findings indicate that the principals were able to find ways to be accountable to a variety of communities and ideals by prioritizing and honoring local needs and beliefs within the larger provincial mandate. Principals could not ignore the various accountability pressures; indeed, their success hinged on the ability to negotiate them. This delicate balancing act requires school principals to develop skills necessary to successfully juggle these competing demands

Methane Emission from Enteric Fermentation: Methanogenesis and Fermentation

Rumen fermentation of carbohydrates plays a fundamental role in ruminant metabolism as the main source of energy. Acetic, propionic and butyric acids (namely, volatile fatty acids, VFA) are the main products of the rumen fermentation of structural and nonstructural carbohydrates con- tained in the ruminant’s diet. The metabolic pathways involved in VFA production are strictly linked to methane emission, because hydrogen is actively produced during the fermentation of structural carbohydrates, and it is rapidly metabolised by methanogens, in order to maintain the optimal thermodynamic condition for the metabolism of the microbe consortium in the rumen. Hydrogen plays also a fundamental role in the maintenance of the equilibrium among VFA pathways and in their interconversion. In this chapter, after a brief chemical description of dietary carbohydrates, individual VFA pathways are described in order to put in evidence the thermodynamic control points of each pathway and the production of energy and reductive equivalent. Then, the relationship between hydrogen, VFA and methane production has been reviewed, considering the role of some dietary factors, the substrate competition between different meta- bolic pathways and the models of VFA estimation