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  • 1
    Keywords: EXPRESSION ; DISEASES ; RISK ; POLYMORPHISMS ; DNA-REPAIR GENES ; METAANALYSIS ; UROTHELIAL CELL-CARCINOMA ; imputation ; CONFERS SUSCEPTIBILITY ; SEQUENCE VARIANT
    Abstract: Genome-wide association studies (GWAS) of urinary bladder cancer (UBC) have yielded common variants at 12 loci that associate with risk of the disease. We report here the results of a GWAS of UBC including 1670 UBC cases and 90 180 controls, followed by replication analysis in additional 5266 UBC cases and 10 456 controls. We tested a dataset containing 34.2 million variants, generated by imputation based on whole-genome sequencing of 2230 Icelanders. Several correlated variants at 20p12, represented by rs62185668, show genome-wide significant association with UBC after combining discovery and replication results (OR = 1.19, P = 1.5 x 10(-11) for rs62185668-A, minor allele frequency = 23.6%). The variants are located in a non-coding region approximately 300 kb upstream from the JAG1 gene, an important component of the Notch signaling pathways that may be oncogenic or tumor suppressive in several forms of cancer. Our results add to the growing number of UBC risk variants discovered through GWAS.
    Type of Publication: Journal article published
    PubMed ID: 24861552
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  • 2
    Keywords: EXPRESSION ; BREAST-CANCER ; REDUCED RISK ; SKIN-CANCER ; CASP8 GENE ; GENOME-WIDE ASSOCIATION ; COMMON VARIANTS ; SEQUENCE VARIANTS ; INACTIVATING MUTATIONS ; GENETIC-VARIANTS
    Abstract: In an ongoing screen for DNA sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conduct a genome-wide association study (GWAS) of 24,988,228 SNPs and small indels detected through whole-genome sequencing of 2,636 Icelanders and imputed into 4,572 BCC patients and 266,358 controls. Here we show the discovery of four new BCC susceptibility loci: 2p24 MYCN (rs57244888[C], OR=0.76, P=4.7 x 10(-12)), 2q33 CASP8-ALS2CR12 (rs13014235[C], OR=1.15, P=1.5 x 10(-9)), 8q21 ZFHX4 (rs28727938[G], OR=0.70, P=3.5 x 10(-12)) and 10p14 GATA3 (rs73635312[A], OR=0.74, P=2.4 x 10(-16)). Fine mapping reveals that two variants correlated with rs73635312[A] occur in conserved binding sites for the GATA3 transcription factor. In addition, expression microarrays and RNA-seq show that rs13014235[C] and a related SNP rs700635[C] are associated with expression of CASP8 splice variants in which sequences from intron 8 are retained.
    Type of Publication: Journal article published
    PubMed ID: 25855136
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  • 3
    Abstract: The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to approximately 370,000 women, we identify 389 independent signals (P 〈 5 x 10-8) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain approximately 7.4% of the population variance in age at menarche, corresponding to approximately 25% of the estimated heritability. We implicate approximately 250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.
    Type of Publication: Journal article published
    PubMed ID: 28436984
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  • 4
    ISSN: 1432-1971
    Keywords: Key words: Coarctation of the aorta — Hypertension — Recoarctation — Exercise testing
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. The purpose of this investigation was to study exercise-induced hypertension after surgical repair of coarctation of the aorta (CoA). Groups of 27 patients with CoA and 27 healthy control subjects, 6–21 years old, were exercised to exhaustion using the Bruce protocol. Fourteen patients had undergone surgery during the first year of life (group A), and 13 patients had been operated on later (group B). The pulse rate and systolic blood pressures (BP) in the arm and leg were measured before, during, and after exercise to evaluate changes in the BP and the arm/leg BP gradient with exercise. The systolic BP was significantly higher in the patients than in the controls at all stages of the exercise test (p 〈 0.01), as was the arm/leg BP gradient both before and after exercise (p 〈 0.01); the latter increased significantly with exercise in the patient group (p 〈 0.05). We found hypertension to be a more common and severe problem in group B patients, who had higher blood pressures than their controls at rest and during exercise (p 〈 0.05). Exercise-induced hypertension was also more common in group B (23%) than in group A (7%). We conclude that exercise-induced hypertension and recoarctation are problems in postoperative CoA patients. Moreover, exercise-induced hypertension is more common in patients with CoA operated on after the first year of life.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-1971
    Keywords: Key words: Coarctation — Left ventricular function — Exercise — Hypertension
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. Postoperative coarctation (CoA) patients are often found to have signs of persistent myocardial dysfunction. M-mode echocardiography was performed to study left ventricular (LV) size, mass, and systolic function and Doppler ultrasonography to study LV filling and flow velocity in the LV outflow tract and aorta in 28 ``healthy'' postoperative CoA patients (5–21 years) and 28 age- and sex-matched controls. The early (E) and late (A) diastolic transmitral velocities were significantly higher in the patient group than in the controls (p 〈 0.05). Other diastolic parameters (isovolumic relaxation time, E/A ratio, and deceleration time of the early diastolic velocity) were similar in the two groups (p= NS). The left atrial diameter, LV wall average, end-diastolic diameter of the LV and LV mass were higher in the patients than controls (p 〈 0.05). The patients also had a higher stroke volume, cardiac output, and cardiac index than the controls (p 〈 0.01). The fractional shortening was similar in the two groups (p= NS). Blood flow velocities in both the LV outflow tract and aorta were higher in the patients than the controls (p 〈 0.0002). We found LV hypertrophy with signs of a hyperdynamic circulation (increased cardiac index and stroke volume) in our patients. An increase in A is associated with LV hypertrophy and seems to be a sensitive marker of diastolic abnormality. The rise in E is paradoxical but has been seen in other studies. The increased blood flow velocity in the LV outflow tract suggests obstruction to LV outflow and increased flow in the descending aorta is due to residual coarctation.
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Springer
    Pediatric cardiology 20 (1999), S. 195-199 
    ISSN: 1432-1971
    Keywords: Key words: Atrial septal defects — Spontaneous closure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. Atrial septal defects (ASDs) are found more frequently in the pediatric population than in adults, and improved diagnostic techniques with echocardiography (2DE) and Doppler facilitate diagnosis so that repair is possible at an optimal time. The purpose of our investigation was to study the size of ASDs at diagnosis, how size changes during follow-up, and to explore the relationship between size at diagnosis and need for surgery. We reviewed the medical records of all patients in Iceland with the diagnosis of ASD born between 1984 and 1993. ASD was confirmed by 2DE in all patients and defects smaller than 4 mm were excluded. ASD size was measured by 2DE from subxyphoid long and short axis views. There were 91 patients—29 males and 62 females. Four patients died from causes other than the heart defect and had not been operated upon. Seven patients with ASD primum and sinus venosus defects were excluded from analysis. There were 29 patients with a 4 mm defect, 17 patients with 5 or 6 mm defects, 8 patients with 7 or 8 mm defects, and 26 patients had defects 〉8 mm. In the 4 mm group, in 26 patients (89%) the ASD closed spontaneously or decreased in size, and 1 patient had been operated upon. In the 5 or 6 mm group, 15 of 19 ASDs (79%) had closed spontaneously, and 2 patients (9.5%) had been operated upon. In the 7 or 8 mm group, 1 of 6 ASDs (16.6%) had closed spontaneously and 3 had been closed surgically. In the 〉8 mm group, 1 of 24 ASDs had closed spontaneously and 20 (91%) had been closed surgically. We conclude that defects smaller than 6 mm in diameter are very likely to close spontaneously although follow-up is necessary. Defects larger than 8 mm have a high probability requiring operative closure.
    Type of Medium: Electronic Resource
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  • 7
    Publication Date: 2012-08-24
    Description: Mutations generate sequence diversity and provide a substrate for selection. The rate of de novo mutations is therefore of major importance to evolution. Here we conduct a study of genome-wide mutation rates by sequencing the entire genomes of 78 Icelandic parent-offspring trios at high coverage. We show that in our samples, with an average father's age of 29.7, the average de novo mutation rate is 1.20 x 10(-8) per nucleotide per generation. Most notably, the diversity in mutation rate of single nucleotide polymorphisms is dominated by the age of the father at conception of the child. The effect is an increase of about two mutations per year. An exponential model estimates paternal mutations doubling every 16.5 years. After accounting for random Poisson variation, father's age is estimated to explain nearly all of the remaining variation in the de novo mutation counts. These observations shed light on the importance of the father's age on the risk of diseases such as schizophrenia and autism.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3548427/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3548427/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kong, Augustine -- Frigge, Michael L -- Masson, Gisli -- Besenbacher, Soren -- Sulem, Patrick -- Magnusson, Gisli -- Gudjonsson, Sigurjon A -- Sigurdsson, Asgeir -- Jonasdottir, Aslaug -- Jonasdottir, Adalbjorg -- Wong, Wendy S W -- Sigurdsson, Gunnar -- Walters, G Bragi -- Steinberg, Stacy -- Helgason, Hannes -- Thorleifsson, Gudmar -- Gudbjartsson, Daniel F -- Helgason, Agnar -- Magnusson, Olafur Th -- Thorsteinsdottir, Unnur -- Stefansson, Kari -- MH071425/MH/NIMH NIH HHS/ -- R01 MH071425/MH/NIMH NIH HHS/ -- England -- Nature. 2012 Aug 23;488(7412):471-5. doi: 10.1038/nature11396.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉deCODE Genetics, Sturlugata 8, 101 Reykjavik, Iceland. kong@decode.is〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22914163" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Autistic Disorder/epidemiology/etiology/*genetics ; Chromosomes, Human/genetics ; Female ; *Genetic Predisposition to Disease ; Genome, Human/genetics ; Humans ; Iceland/epidemiology ; Male ; Middle Aged ; Mothers ; *Mutation Rate ; Ovum/metabolism ; *Paternal Age ; Pedigree ; Polymorphism, Single Nucleotide/genetics ; Risk Factors ; Schizophrenia/epidemiology/etiology/*genetics ; Selection, Genetic/genetics ; Sequence Analysis, DNA ; Spermatozoa/metabolism ; Young Adult
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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