New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Genetic architecture of human plasma lipidome and its link to cardiovascular disease

Understanding genetic architecture of plasma lipidome could provide better insights into lipid metabolism and its link to cardiovascular diseases (CVDs). Here, we perform genome-wide association analyses of 141 lipid species (n = 2,181 individuals), followed by phenome-wide scans with 25 CVD related phenotypes (n = 511,700 individuals). We identify 35 lipid-species-associated loci (P <5 x10(-8)), 10 of which associate with CVD risk including five new loci-COL5A1, GLTPD2, SPTLC3, MBOAT7 and GALNT16 (false discovery rate<0.05). We identify loci for lipid species that are shown to predict CVD e.g., SPTLC3 for CER(d18:1/24:1). We show that lipoprotein lipase (LPL) may more efficiently hydrolyze medium length triacylglycerides (TAGs) than others. Polyunsaturated lipids have highest heritability and genetic correlations, suggesting considerable genetic regulation at fatty acids levels. We find low genetic correlations between traditional lipids and lipid species. Our results show that lipidomic profiles capture information beyond traditional lipids and identify genetic variants modifying lipid levels and risk of CVD

Active HOMs Excitation in the First Prototypes of Superstructure

An alternative layout of the TESLA collider [1], based on superstructures [2], reduces investment cost for the main accelerator due to a much lower number of input couplers and resulting from that, a simplification in the RF distribution system. In May 2002, two first Nb prototypes of the superstructure (P1, P2) were installed next to the injector in the TESLA Test Facility linac (TTF) at DESY to verify experimentally the predictedRF-properties. Part of the experimental program was devoted to the damping of Higher Order Modes (HOM). Good suppression of HOMs in both prototypes has been achieved with HOM couplers based on the coaxial line technique [3]. A several methods have been applied to measure impedances Z=(R/Q)·Qext of parasitic modes. We report here mainly on results of the active mode excitation method and the measurements of HOMs’ parameters by means of a Network Analyzer, which we performed on cold- and on warm prototypes. The other method, HOMs excitation by charge modulation, is reported in more detail in [4]