A Variant in LDLR is Associated with Abdominal Aortic Aneurysm

Background—Abdominal aortic aneurysm (AAA) is a common cardiovascular disease among older people and demonstrates significant heritability. In contrast to similar complex diseases, relatively few genetic associations with AAA have been confirmed. We reanalysed our genome-wide study and carried through to replication suggestive discovery associations at a lower level of significance.

Methods and Results—A genome-wide association study was conducted using 1,830 cases from the UK, New Zealand and Australia with infra-renal aorta diameter =30mm or ruptured AAA and 5,435 unscreened controls from the 1958 Birth Cohort and National Blood Service cohort from the Wellcome Trust Case Control Consortium. Eight suggestive associations with P<1x10-4 were carried through to in silico replication in 1,292 AAA cases and 30,503 controls. One SNP associated with P<0.05 after Bonferroni correction in the in silico study underwent further replication (706 AAA cases and 1,063 controls from the UK, 507 AAA cases and 199 controls from Denmark and 885 AAA cases and 1,000 controls from New Zealand). Low density lipoprotein receptor (LDLR) rs6511720 A, was significantly associated overall and in three of five individual replication studies. The full study showed an association that reached genome-wide significance (odds ratio 0.76; 95% confidence interval 0.70 to 0.83; P=2.08x10-10).

Conclusions—LDLR rs6511720 is associated with abdominal aortic aneurysm. This finding is consistent with established effects of this variant on coronary artery disease. Shared aetiological pathways with other cardiovascular diseases may present novel opportunities for preventative and therapeutic strategies for AAA.

Genome-wide association analysis identifies 13 new risk loci for schizophrenia

Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-analysis with previous schizophrenia GWAS (8,832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls and 581 parent-offspring trios). We identified 22 loci associated at genome-wide significance; 13 of these are new, and 1 was previously implicated in bipolar disorder. Examination of candidate genes at these loci suggests the involvement of neuronal calcium signaling. We estimate that 8,300 independent, mostly common SNPs (95% credible interval of 6,300-10,200 SNPs) contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability. Common genetic variation has an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this disorder.

Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture

Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.

Large-scale association analysis identifies new risk loci for coronary artery disease

Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r(2)

Synthesis by extrusion: continuous, large-scale preparation of MOFs using little or no solvent

Grinding solid reagents under solvent-free or low-solvent conditions (mechanochemistry) is emerging as a general synthetic technique which is an alternative to conventional solvent-intensive methods. However, it is essential to find ways to scale-up this type of synthesis if its promise of cleaner manufacturing is to be realised. Here, we demonstrate the use of twin screw and single screw extruders for the continuous synthesis of various metal complexes, including Ni(salen), Ni(NCS)(2)(PPh3)(2) as well as the commercially important metal organic frameworks (MOFs) Cu-3(BTC)(2) (HKUST-1), Zn(2-methylimidazolate)(2) (ZIF-8, MAF-4) and Al(fumarate)(OH). Notably, Al(fumarate)(OH) has not previously been synthesised mechanochemically. Quantitative conversions occur to give products at kg h(-1) rates which, after activation, exhibit surface areas and pore volumes equivalent to those of materials produced by conventional solvent-based methods. Some reactions can be performed either under completely solvent-free conditions whereas others require the addition of small amounts of solvent (typically 3-4 mol equivalents). Continuous neat melt phase synthesis is also successfully demonstrated by both twin screw and single screw extrusion for ZIF-8. The latter technique provided ZIF-8 at 4 kg h(-1). The space time yields (STYs) for these methods of up to 144 x 10(3) kg per m(3) per day are orders of magnitude greater than STYs for other methods of making MOFs. Extrusion methods clearly enable scaling of mechanochemical and melt phase synthesis under solvent-free or low-solvent conditions, and may also be applied in synthesis more generally.

Robert Graves

Robert Graves was a British writer who enlisted in August 1914. He fought at the Battle of Loos in 1915, and was wounded at the Somme in 1916. He published his first volumes of poems during the war, and his bestselling war memoir, Goodbye to All That, in 1929.