Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development

A novel Alzheimer disease locus located near the gene encoding tau protein

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this recordAPOE ε4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ε4+ (10 352 cases and 9207 controls) and APOE ε4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ε4 status. Suggestive associations (P<1 × 10-4) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ε4+: 1250 cases and 536 controls; APOE ε4-: 718 cases and 1699 controls). Among APOE ε4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10-9). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ε4+ subjects (CR1 and CLU) or APOE ε4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10-7) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P≤1.3 × 10-8), frontal cortex (P≤1.3 × 10-9) and temporal cortex (P≤1.2 × 10-11). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10-6) and temporal cortex (P=2.6 × 10-6). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ε4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted

The European Union and regional integration. A comparative perspective and lessons for the Americas.

Regional integration processes are meant to provide a peaceful arena in which sovereign countries voluntarily combine their efforts in areas of mutual concern, creating common regional interests and objectives. Models and ideas, however, do not always result in concrete actions or significant accomplishments. Even the most developed institutional exercise of regional integration, the European Union (EU), is commonly overwhelmed by the contradictions and obstacles of the institutional architecture and the interests of the member states. The construction of the EU has continued for more than five decades and remains an unfinished project. Despite its ebbs and flows, the assessment of the European integration process is positive and still at the forefront of regional integration experiences. In that regard, what lessons can be learned in the Americas from the European experience? What are the peculiarities and prospects of the integration processes in the Western Hemisphere? What are the conditions necessary for developing integration processes? Some ideas and responses to these questions are provided in the articles of this book, grouped in four sections: hemispheric integration, North America, Central America and the Caribbean, and South America. The contributors demonstrate that integration in the sub-regions of the Americas has progressed in varying degrees, and that each integration process is characterized by particular circumstances that constrain further institutional developments, legitimacy and credibility. Regional integration in both Europe and the Americas is a work in progress, and therefore, scholarly exercises of the kind included in this book serve not only as a reflection and analysis of what currently exists and how it has developed, but also as a consideration for future developments

Improvement of the Helioseismic and Magnetic Imager (HMI) Vector Magnetic Field Inversion Code

Abstract A spectral line inversion code, Very Fast Inversion of the Stokes Vector (VFISV), has been used since 2010 May to infer the solar atmospheric parameters from the spectropolarimetric observations taken by the Helioseismic and Magnetic Imager (HMI) on board the Solar Dynamics Observatory. The magnetic filling factor, the fraction of the surface with a resolution element occupied by magnetic field, is set to have a constant value of 1 in the current version of VFISV. This report describes an improved inversion strategy for the spectropolarimetric data observed with HMI for magnetic field strengths of intermediate values in areas spatially not fully resolved. The VFISV inversion code has been modified to enable inversion of the Stokes profiles with two different components: one magnetic and one nonmagnetic. In this scheme, both components share the atmospheric components except for the magnetic field vector. In order to determine whether the new strategy is useful, we evaluate the inferred parameters inverted with one magnetic component (the original version of the HMI inversion) and with two components (the improved version) using a Bayesian analysis. In pixels with intermediate magnetic field strengths (e.g., plages), the new version provides statistically significant values of filling fraction and magnetic field vector. Not only does the fitting of the Stokes profile improve, but also the inference of the magnetic parameters and line-of-sight velocity are obtained uniquely. The new strategy is also proven to be effective for mitigating the anomalous hemispheric bias in the east–west magnetic field component in moderate field regions

Recovery after open versus laparoscopic pyloromyotomy for pyloric stenosis: a double-blind multicentre randomised controlled trial

BackgroundA laparoscopic approach to pyloromyotomy for infantile pyloric stenosis has gained popularity but its effectiveness remains unproven. We aimed to compare outcomes after open or laparoscopic pyloromyotomy for the treatment of pyloric stenosis.MethodsWe did a multicentre international, double-blind, randomised, controlled trial between June, 2004, and May, 2007, across six tertiary paediatric surgical centres. 180 infants were randomly assigned to open (n=93) or laparoscopic pyloromyotomy (n=87) with minimisation for age, weight, gestational age at birth, bicarbonate at initial presentation, feeding type, preoperative duration of symptoms, and trial centre. Infants with a diagnosis of pyloric stenosis were eligible. Primary outcomes were time to achieve full enteral feed and duration of postoperative recovery. We aimed to recruit 200 infants (100 per group); however, the data monitoring and ethics committee recommended halting the trial before full recruitment because of significant treatment benefit in one group at interim analysis. Participants, parents, and nursing staff were unaware of treatment. Data were analysed on an intention-to-treat basis with regression analysis. The trial is registered with ClinicalTrials.gov, number NCT00144924.FindingsTime to achieve full enteral feeding in the open pyloromyotomy group was (median [IQR]) 23·9 h (16·0–41·0) versus 18·5 h (12·3–24·0; p=0·002) in the laparoscopic group; postoperative length of stay was 43·8 h (25·3–55·6) versus 33·6 h (22·9–48·1; p=0·027). Postoperative vomiting, and intra-operative and postoperative complications were similar between the two groups.InterpretationBoth open and laparoscopic pyloromyotomy are safe procedures for the management of pyloric stenosis. However, laparoscopy has advantages over open pyloromyotomy, and we recommend its use in centres with suitable laparoscopic experience.FundingSir Arthur Halley Stewart Trust

Author Correction: Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing (Nature Genetics, (2019), 51, 3, (414-430), 10.1038/s41588-019-0358-2)

An amendment to this paper has been published and can be accessed via a link at the top of the paper