排序方式: 共有17条查询结果,搜索用时 15 毫秒
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Hüffmeier U Uebe S Ekici AB Bowes J Giardina E Korendowych E Juneblad K Apel M McManus R Ho P Bruce IN Ryan AW Behrens F Lascorz J Böhm B Traupe H Lohmann J Gieger C Wichmann HE Herold C Steffens M Klareskog L Wienker TF Fitzgerald O Alenius GM McHugh NJ Novelli G Burkhardt H Barton A Reis A 《Nature genetics》2010,42(11):996-999
Psoriatic arthritis (PsA) is an inflammatory joint disease that is distinct from other chronic arthritides and which is frequently accompanied by psoriasis vulgaris (PsV) and seronegativity for rheumatoid factor. We conducted a genome-wide association study in 609 German individuals with PsA (cases) and 990 controls with replication in 6 European cohorts including a total of 5,488 individuals. We replicated PsA associations at HLA-C and IL12B and identified a new association at TRAF3IP2 (rs13190932, P = 8.56 × 10?1?). TRAF3IP2 was also associated with PsV in a German cohort including 2,040 individuals (rs13190932, P = 1.95 × 10?3). Sequencing of the exons of TRAF3IP2 identified a coding variant (p.Asp10Asn, rs33980500) as the most significantly associated SNP (P = 1.13 × 10?2?, odds ratio = 1.95). Functional assays showed reduced binding of this TRAF3IP2 variant to TRAF6, suggesting altered modulation of immunoregulatory signals through altered TRAF interactions as a new and shared pathway for PsA and PsV. 相似文献
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Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy 总被引:20,自引:0,他引:20
Gerull B Heuser A Wichter T Paul M Basson CT McDermott DA Lerman BB Markowitz SM Ellinor PT MacRae CA Peters S Grossmann KS Drenckhahn J Michely B Sasse-Klaassen S Birchmeier W Dietz R Breithardt G Schulze-Bahr E Thierfelder L 《Nature genetics》2004,36(11):1162-1164
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with fibrofatty replacement of cardiac myocytes, ventricular tachyarrhythmias and sudden cardiac death. In 32 of 120 unrelated individuals with ARVC, we identified heterozygous mutations in PKP2, which encodes plakophilin-2, an essential armadillo-repeat protein of the cardiac desmosome. In two kindreds with ARVC, disease was incompletely penetrant in most carriers of PKP2 mutations. 相似文献
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Lee K Jeong J Kwak I Yu CT Lanske B Soegiarto DW Toftgard R Tsai MJ Tsai S Lydon JP DeMayo FJ 《Nature genetics》2006,38(10):1204-1209
The hedgehog family of morphogens are regulators of cell proliferation, differentiation and cell-cell communication. These morphogens have been shown to have important roles in organogenesis, spermatogenesis, stem cell maintenance and oncogenesis. Indian hedgehog (encoded by Ihh) has been shown to be expressed in the uterine epithelium under the control of the steroid hormone, progesterone. Although in vivo and in vitro studies have shown that progesterone achieves its effects on uterine function through epithelial-stromal cross-talk, molecular mediator(s) for this cellular communication pathway have not been elucidated. Using new experimental approaches that ablate Ihh specifically in Pgr-positive uterine cells of the mouse, we demonstrate that Ihh is an essential mediator of Pgr action in the uterus, and expression of this factor is critical in mediating the communication between the uterine epithelium and stroma required for embryo implantation. 相似文献
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Taal HR St Pourcain B Thiering E Das S Mook-Kanamori DO Warrington NM Kaakinen M Kreiner-Møller E Bradfield JP Freathy RM Geller F Guxens M Cousminer DL Kerkhof M Timpson NJ Ikram MA Beilin LJ Bønnelykke K Buxton JL Charoen P Chawes BL Eriksson J Evans DM Hofman A Kemp JP Kim CE Klopp N Lahti J Lye SJ McMahon G Mentch FD Müller-Nurasyid M O'Reilly PF Prokopenko I Rivadeneira F Steegers EA Sunyer J Tiesler C Yaghootkar H;Cohorts for Heart Aging Research in Genetic Epidemiology Consortium 《Nature genetics》2012,44(5):532-538
To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 × 10(-9)) and rs1042725 on chromosome 12q15 (P = 2.8 × 10(-10)) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height, their effects on infant head circumference were largely independent of height (P = 3.8 × 10(-7) for rs7980687 and P = 1.3 × 10(-7) for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 × 10(-6)). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume, Parkinson's disease and other neurodegenerative diseases, indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life. 相似文献
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RA Scott V Lagou RP Welch E Wheeler ME Montasser J Luan R Mägi RJ Strawbridge E Rehnberg S Gustafsson S Kanoni LJ Rasmussen-Torvik L Yengo C Lecoeur D Shungin S Sanna C Sidore PC Johnson JW Jukema T Johnson A Mahajan N Verweij G Thorleifsson JJ Hottenga S Shah AV Smith B Sennblad C Gieger P Salo M Perola NJ Timpson DM Evans BS Pourcain Y Wu JS Andrews J Hui LF Bielak W Zhao M Horikoshi P Navarro A Isaacs JR O'Connell K Stirrups V Vitart C Hayward T Esko E Mihailov RM Fraser T Fall BF Voight 《Nature genetics》2012,44(9):991-1005
Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control. 相似文献
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Constitutive mechanistic explanations are said to refer to mechanisms that constitute the phenomenon-to-be-explained. The most prominent approach of how to understand this relation is Carl Craver's mutual manipulability approach (MM) to constitutive relevance. Recently, MM has come under attack (Baumgartner and Casini 2017; Baumgartner and Gebharter 2015; Harinen 2014; Kästner 2017; Leuridan 2012; Romero 2015). It is argued that MM is inconsistent because, roughly, it is spelled out in terms of interventionism (which is an approach to causation), whereas constitutive relevance is said to be a non-causal relation. In this paper, I will discuss a strategy of how to resolve this inconsistency—so-called fat-handedness approaches (Baumgartner and Casini 2017; Baumgartner and Gebharter 2015; Romero 2015). I will argue that these approaches are problematic. I will present a novel suggestion for how to consistently define constitutive relevance in terms of interventionism. My approach is based on a causal interpretation of manipulability in terms of causal relations between the mechanism's components and what I will call temporal EIO-parts of the phenomenon. Still, this interpretation accounts for the fundamental difference between constitutive relevance and causal relevance. 相似文献
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Cornelius F Boerkoel Hiroshi Takashima Joy John Jiong Yan Pawel Stankiewicz Lisa Rosenbarker Jean-Luc André Radovan Bogdanovic Antoine Burguet Sandra Cockfield Isabel Cordeiro Stefan Fründ Friederike Illies Mark Joseph Ilkka Kaitila Giuliana Lama Chantal Loirat D Ross McLeod David V Milford Elizabeth M Petty Francisco Rodrigo Jorge M Saraiva Beate Schmidt Graham C Smith Jürgen Spranger Anja Stein Hannelore Thiele Jane Tizard Rosanna Weksberg James R Lupski David W Stockton 《Nature genetics》2002,30(2):215-220
Schimke immuno-osseous dysplasia (SIOD, MIM 242900) is an autosomal-recessive pleiotropic disorder with the diagnostic features of spondyloepiphyseal dysplasia, renal dysfunction and T-cell immunodeficiency. Using genome-wide linkage mapping and a positional candidate approach, we determined that mutations in SMARCAL1 (SWI/SNF2-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1), are responsible for SIOD. Through analysis of data from persons with SIOD in 26 unrelated families, we observed that affected individuals from 13 of 23 families with severe disease had two alleles with nonsense, frameshift or splicing mutations, whereas affected individuals from 3 of 3 families with milder disease had a missense mutation on each allele. These observations indicate that some missense mutations allow retention of partial SMARCAL1 function and thus cause milder disease. 相似文献
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A genome-wide transgenic RNAi library for conditional gene inactivation in Drosophila 总被引:1,自引:0,他引:1
Dietzl G Chen D Schnorrer F Su KC Barinova Y Fellner M Gasser B Kinsey K Oppel S Scheiblauer S Couto A Marra V Keleman K Dickson BJ 《Nature》2007,448(7150):151-156
Forward genetic screens in model organisms have provided important insights into numerous aspects of development, physiology and pathology. With the availability of complete genome sequences and the introduction of RNA-mediated gene interference (RNAi), systematic reverse genetic screens are now also possible. Until now, such genome-wide RNAi screens have mostly been restricted to cultured cells and ubiquitous gene inactivation in Caenorhabditis elegans. This powerful approach has not yet been applied in a tissue-specific manner. Here we report the generation and validation of a genome-wide library of Drosophila melanogaster RNAi transgenes, enabling the conditional inactivation of gene function in specific tissues of the intact organism. Our RNAi transgenes consist of short gene fragments cloned as inverted repeats and expressed using the binary GAL4/UAS system. We generated 22,270 transgenic lines, covering 88% of the predicted protein-coding genes in the Drosophila genome. Molecular and phenotypic assays indicate that the majority of these transgenes are functional. Our transgenic RNAi library thus opens up the prospect of systematically analysing gene functions in any tissue and at any stage of the Drosophila lifespan. 相似文献