排序方式: 共有20条查询结果,搜索用时 15 毫秒
1.
Suhre K Shin SY Petersen AK Mohney RP Meredith D Wägele B Altmaier E;CARDIoGRAM Deloukas P Erdmann J Grundberg E Hammond CJ de Angelis MH Kastenmüller G Köttgen A Kronenberg F Mangino M Meisinger C Meitinger T Mewes HW Milburn MV Prehn C Raffler J Ried JS Römisch-Margl W Samani NJ Small KS Wichmann HE Zhai G Illig T Spector TD Adamski J Soranzo N Gieger C 《Nature》2011,477(7362):54-60
Genome-wide association studies (GWAS) have identified many risk loci for complex diseases, but effect sizes are typically small and information on the underlying biological processes is often lacking. Associations with metabolic traits as functional intermediates can overcome these problems and potentially inform individualized therapy. Here we report a comprehensive analysis of genotype-dependent metabolic phenotypes using a GWAS with non-targeted metabolomics. We identified 37 genetic loci associated with blood metabolite concentrations, of which 25 show effect sizes that are unusually high for GWAS and account for 10-60% differences in metabolite levels per allele copy. Our associations provide new functional insights for many disease-related associations that have been reported in previous studies, including those for cardiovascular and kidney disorders, type 2 diabetes, cancer, gout, venous thromboembolism and Crohn's disease. The study advances our knowledge of the genetic basis of metabolic individuality in humans and generates many new hypotheses for biomedical and pharmaceutical research. 相似文献
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Döring A Gieger C Mehta D Gohlke H Prokisch H Coassin S Fischer G Henke K Klopp N Kronenberg F Paulweber B Pfeufer A Rosskopf D Völzke H Illig T Meitinger T Wichmann HE Meisinger C 《Nature genetics》2008,40(4):430-436
Serum uric acid concentrations are correlated with gout and clinical entities such as cardiovascular disease and diabetes. In the genome-wide association study KORA (Kooperative Gesundheitsforschung in der Region Augsburg) F3 500K (n = 1,644), the most significant SNPs associated with uric acid concentrations mapped within introns 4 and 6 of SLC2A9, a gene encoding a putative hexose transporter (effects: -0.23 to -0.36 mg/dl per copy of the minor allele). We replicated these findings in three independent samples from Germany (KORA S4 and SHIP (Study of Health in Pomerania)) and Austria (SAPHIR; Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk), with P values ranging from 1.2 x 10(-8) to 1.0 x 10(-32). Analysis of whole blood RNA expression profiles from a KORA F3 500K subgroup (n = 117) showed a significant association between the SLC2A9 isoform 2 and urate concentrations. The SLC2A9 genotypes also showed significant association with self-reported gout. The proportion of the variance of serum uric acid concentrations explained by genotypes was about 1.2% in men and 6% in women, and the percentage accounted for by expression levels was 3.5% in men and 15% in women. 相似文献
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Roscioli T Kamsteeg EJ Buysse K Maystadt I van Reeuwijk J van den Elzen C van Beusekom E Riemersma M Pfundt R Vissers LE Schraders M Altunoglu U Buckley MF Brunner HG Grisart B Zhou H Veltman JA Gilissen C Mancini GM Delrée P Willemsen MA Ramadža DP Chitayat D Bennett C Sheridan E Peeters EA Tan-Sindhunata GM de Die-Smulders CE Devriendt K Kayserili H El-Hashash OA Stemple DL Lefeber DJ Lin YY van Bokhoven H 《Nature genetics》2012,44(5):581-585
Walker-Warburg syndrome (WWS) is an autosomal recessive multisystem disorder characterized by complex eye and brain abnormalities with congenital muscular dystrophy (CMD) and aberrant a-dystroglycan glycosylation. Here we report mutations in the ISPD gene (encoding isoprenoid synthase domain containing) as the second most common cause of WWS. Bacterial IspD is a nucleotidyl transferase belonging to a large glycosyltransferase family, but the role of the orthologous protein in chordates is obscure to date, as this phylum does not have the corresponding non-mevalonate isoprenoid biosynthesis pathway. Knockdown of ispd in zebrafish recapitulates the human WWS phenotype with hydrocephalus, reduced eye size, muscle degeneration and hypoglycosylated a-dystroglycan. These results implicate ISPD in a-dystroglycan glycosylation in maintaining sarcolemma integrity in vertebrates. 相似文献
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Saenz HL Engel P Stoeckli MC Lanz C Raddatz G Vayssier-Taussat M Birtles R Schuster SC Dehio C 《Nature genetics》2007,39(12):1469-1476
The bacterial genus Bartonella comprises 21 pathogens causing characteristic intraerythrocytic infections. Bartonella bacilliformis is a severe pathogen representing an ancestral lineage, whereas the other species are benign pathogens that evolved by radial speciation. Here, we have used comparative and functional genomics to infer pathogenicity genes specific to the radiating lineage, and we suggest that these genes may have facilitated adaptation to the host environment. We determined the complete genome sequence of Bartonella tribocorum by shotgun sequencing and functionally identified 97 pathogenicity genes by signature-tagged mutagenesis. Eighty-one pathogenicity genes belong to the core genome (1,097 genes) of the radiating lineage inferred from genome comparison of B. tribocorum, Bartonella henselae and Bartonella quintana. Sixty-six pathogenicity genes are present in B. bacilliformis, and one has been lost by deletion. The 14 pathogenicity genes specific for the radiating lineage encode two laterally acquired type IV secretion systems, suggesting that these systems have a role in host adaptability. 相似文献
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Thye T Owusu-Dabo E Vannberg FO van Crevel R Curtis J Sahiratmadja E Balabanova Y Ehmen C Muntau B Ruge G Sievertsen J Gyapong J Nikolayevskyy V Hill PC Sirugo G Drobniewski F van de Vosse E Newport M Alisjahbana B Nejentsev S Ottenhoff TH Hill AV Horstmann RD Meyer CG 《Nature genetics》2012,44(3):257-259
After imputation of data from the 1000 Genomes Project into a genome-wide dataset of Ghanaian individuals with tuberculosis and controls, we identified a resistance locus on chromosome 11p13 downstream of the WT1 gene (encoding Wilms tumor 1). The strongest signal was obtained at the rs2057178 SNP (P = 2.63 × 10(-9)). Replication in Gambian, Indonesian and Russian tuberculosis case-control study cohorts increased the significance level for the association with this SNP to P = 2.57 × 10(-11). 相似文献
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Cao J Schneeberger K Ossowski S Günther T Bender S Fitz J Koenig D Lanz C Stegle O Lippert C Wang X Ott F Müller J Alonso-Blanco C Borgwardt K Schmid KJ Weigel D 《Nature genetics》2011,43(10):956-963
The plant Arabidopsis thaliana occurs naturally in many different habitats throughout Eurasia. As a foundation for identifying genetic variation contributing to adaptation to diverse environments, a 1001 Genomes Project to sequence geographically diverse A. thaliana strains has been initiated. Here we present the first phase of this project, based on population-scale sequencing of 80 strains drawn from eight regions throughout the species' native range. We describe the majority of common small-scale polymorphisms as well as many larger insertions and deletions in the A. thaliana pan-genome, their effects on gene function, and the patterns of local and global linkage among these variants. The action of processes other than spontaneous mutation is identified by comparing the spectrum of mutations that have accumulated since A. thaliana diverged from its closest relative 10 million years ago with the spectrum observed in the laboratory. Recent species-wide selective sweeps are rare, and potentially deleterious mutations are more common in marginal populations. 相似文献
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A discoidin domain receptor 1 knock-out mouse as a novel model for osteoarthritis of the temporomandibular joint 总被引:1,自引:1,他引:0
Boris Schminke Hayat Muhammad Christa Bode Boguslawa Sadowski Regina Gerter Nikolaus Gersdorff Ralf Bürgers Efrat Monsonego-Ornan Vicki Rosen Nicolai Miosge 《Cellular and molecular life sciences : CMLS》2014,71(6):1081-1096
Discoidin domain receptor 1 (DDR-1)-deficient mice exhibited a high incidence of osteoarthritis (OA) in the temporomandibular joint (TMJ) as early as 9 weeks of age. They showed typical histological signs of OA, including surface fissures, loss of proteoglycans, chondrocyte cluster formation, collagen type I upregulation, and atypical collagen fibril arrangements. Chondrocytes isolated from the TMJs of DDR-1-deficient mice maintained their osteoarthritic characteristics when placed in culture. They expressed high levels of runx-2 and collagen type I, as well as low levels of sox-9 and aggrecan. The expression of DDR-2, a key factor in OA, was increased. DDR-1-deficient chondrocytes from the TMJ were positively influenced towards chondrogenesis by a three-dimensional matrix combined with a runx-2 knockdown or stimulation with extracellular matrix components, such as nidogen-2. Therefore, the DDR-1 knock-out mouse can serve as a novel model for temporomandibular disorders, such as OA of the TMJ, and will help to develop new treatment options, particularly those involving tissue regeneration. 相似文献
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Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome
Flück CE Tajima T Pandey AV Arlt W Okuhara K Verge CF Jabs EW Mendonça BB Fujieda K Miller WL 《Nature genetics》2004,36(3):228-230
Deficient activities of multiple steroidogenic enzymes have been reported without and with Antley-Bixler syndrome (ABS), but mutations of corresponding cytochrome P450 enzymes have not been found. We identified mutations in POR, encoding P450 oxidoreductase, the obligate electron donor for these enzymes, in a woman with amenorrhea and three children with ABS, even though knock-out of POR is embryonically lethal in mice. Mutations of POR also affect drug-metabolizing P450 enzymes, explaining the association of ABS with maternal fluconazole ingestion. 相似文献
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