| 1. |
- Scott, Robert A., et al.
(författare)
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Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways
- 2012
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:9, s. 991-1005
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 2. |
- Frazier-Wood, Alexis C., et al.
(författare)
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Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses
- 2016
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Ingår i: Nature Genetics. - : Nature Research (part of Springer Nature). - 1061-4036 .- 1546-1718. ; 48, s. 624-
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Tidskriftsartikel (refereegranskat)abstract
- Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (vertical bar(p) over cap vertical bar approximate to 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.
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| 3. |
- Dekkers, Bas J W, et al.
(författare)
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The Arabidopsis DELAY OF GERMINATION 1 gene affects ABSCISIC ACID INSENSITIVE 5 (ABI5) expression and genetically interacts with ABI3 during Arabidopsis seed development
- 2016
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Ingår i: The Plant Journal. - : Wiley-Blackwell. - 0960-7412 .- 1365-313X. ; 85:4, s. 451-465
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Tidskriftsartikel (refereegranskat)abstract
- The seed expressed gene DELAY OF GERMINATION (DOG) 1 is absolutely required for the induction of dormancy. Next to a non-dormant phenotype, the dog1-1 mutant is also characterized by a reduced seed longevity suggesting that DOG1 may affect additional seed processes as well. This aspect however, has been hardly studied and is poorly understood. To uncover additional roles of DOG1 in seeds we performed a detailed analysis of the dog1 mutant using both transcriptomics and metabolomics to investigate the molecular consequences of a dysfunctional DOG1 gene. Further, we used a genetic approach taking advantage of the weak aba insensitive (abi) 3-1 allele as a sensitized genetic background in a cross with dog1-1. DOG1 affects the expression of hundreds of genes including LATE EMBRYOGENESIS ABUNDANT and HEAT SHOCK PROTEIN genes which are affected by DOG1 partly via control of ABI5 expression. Furthermore, the content of a subset of primary metabolites, which normally accumulate during seed maturation, was found to be affected in the dog1-1 mutant. Surprisingly, the abi3-1 dog1-1 double mutant produced green seeds which are highly ABA insensitive, phenocopying severe abi3 mutants, indicating that dog1-1 acts as an enhancer of the weak abi3-1 allele and thus revealing a genetic interaction between both genes. Analysis of the dog1 and dog1 abi3 mutants revealed additional seed phenotypes and therefore we hypothesize that DOG1 function is not limited to dormancy but that it is required for multiple aspects of seed maturation, in part by interfering with ABA signalling components.
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| 4. |
- Fall, Tove, et al.
(författare)
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The Role of Adiposity in Cardiometabolic Traits : A Mendelian Randomization Analysis
- 2013
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Ingår i: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 10:6, s. e1001474-
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Tidskriftsartikel (refereegranskat)abstract
- Background: The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach. Methods and Findings: We used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index (BMI) in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses. Age-and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and BMI (n = 198,502), (ii) rs9939609 and 24 traits, and (iii) BMI and 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared to the BMI-trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03-1.39) and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1-1.4; all p<0.05). For quantitative traits, our results provide novel evidence for a causal effect of adiposity on the liver enzymes alanine aminotransferase and gamma-glutamyl transferase and confirm previous reports of a causal effect of adiposity on systolic and diastolic blood pressure, fasting insulin, 2-h post-load glucose from the oral glucose tolerance test, C-reactive protein, triglycerides, and high-density lipoprotein cholesterol levels (all p<0.05). The estimated causal effects were in agreement with traditional observational measures in all instances except for type 2 diabetes, where the causal estimate was larger than the observational estimate (p = 0.001). Conclusions: We provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.
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| 5. |
- Horikoshi, Momoko, et al.
(författare)
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Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation.
- 2015
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 11:7
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Tidskriftsartikel (refereegranskat)abstract
- Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency ≥0.5% across European ancestry populations. Within the European Network for Genetic and Genomic Epidemiology (ENGAGE) Consortium, we have undertaken the first large-scale meta-analysis of genome-wide association studies (GWAS), supplemented by 1000G imputation, for four quantitative glycaemic and obesity-related traits, in up to 87,048 individuals of European ancestry. We identified two loci for body mass index (BMI) at genome-wide significance, and two for fasting glucose (FG), none of which has been previously reported in larger meta-analysis efforts to combine GWAS of European ancestry. Through conditional analysis, we also detected multiple distinct signals of association mapping to established loci for waist-hip ratio adjusted for BMI (RSPO3) and FG (GCK and G6PC2). The index variant for one association signal at the G6PC2 locus is a low-frequency coding allele, H177Y, which has recently been demonstrated to have a functional role in glucose regulation. Fine-mapping analyses revealed that the non-coding variants most likely to drive association signals at established and novel loci were enriched for overlap with enhancer elements, which for FG mapped to promoter and transcription factor binding sites in pancreatic islets, in particular. Our study demonstrates that 1000G imputation and genetic fine-mapping of common and low-frequency variant association signals at GWAS loci, integrated with genomic annotation in relevant tissues, can provide insight into the functional and regulatory mechanisms through which their effects on glycaemic and obesity-related traits are mediated.
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| 6. |
- Schultz, Iman J, et al.
(författare)
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Gene expression analysis for the prediction of recurrence in patients with primary Ta urothelial cell carcinoma
- 2007
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Ingår i: European Urology. - : Elsevier BV. - 0302-2838 .- 1873-7560. ; 51:2, s. 416-423
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Tidskriftsartikel (refereegranskat)abstract
- Objectives The individual recurrence-free period after primary surgery of patients with Ta urothelial cell carcinoma (UCC) cannot be predicted accurately. This study aims at discriminating between patients with primary Ta UCC and long or short recurrence-free periods. Methods We investigated mRNA expression of 23 genes in 44 primary Ta tumours (23 and 21 tumours were from patients with long [≥4 yr] or short [≤2 yr] recurrence-free periods, respectively), using real-time quantitative polymerase chain reaction. The genes were selected from previously published studies and showed a relationship with tumour recurrence in patients with UCC. Results Differential mRNA expression between the two patient groups indicated statistical significance only for the gene survivin (p = 0.0011). Its recurrence predictive value could not be increased by a combination with any of the other genes. Comparison of the receiver operating characteristic curves for survivin expression between patients with long or short recurrence-free intervals revealed an area under the curve of 0.79 (95%CI, 0.65–0.92). Using the median expression (0.84) as cut-off level, survivin identified 71.4% (95%CI, 47.8–88.7) and 69.6% (95%CI, 47.1–86.8) of the patients with long or short recurrence-free periods, respectively. Conclusions Our study identifies survivin as the most promising candidate to distinguish between patients with primary Ta UCC and long or short recurrence-free intervals. Therefore, survivin mRNA expression analysis might help the urologist to individualise patient treatment and prevent unnecessary cystoscopies in a subgroup of these patients.
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| 7. |
- Schultz, Iman J., et al.
(författare)
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Simultaneous proteomic and genomic analysis of primary Ta urothelial cell carcinomas for the prediction of tumor recurrence
- 2007
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Ingår i: Anticancer Research. - 0250-7005 .- 1791-7530. ; 27:2, s. 1051-1058
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Tidskriftsartikel (refereegranskat)abstract
- Background: The prediction of tumor recurrence in patients with Ta urothelial cell carcinoma is inaccurate and new prognostic markers are desirable. Materials and Methods: Surface-enhanced laser-desorption ionization time-of-flight mass spectrometry (SELDI-TOF MS) was performed on 33 primary Ta tumors (16 and 17 tumors were from patients with long and short recurrence-free periods, respectively) and data were compared to previously obtained mRNA expression profiles of 49 genes. Results: The intensities of a protein peak at m/z 33331 varied most significantly between the two patient groups (p=0.0048). This was comparable to survivin, whose mRNA expression differed most significantly (p=0.0042) of the 49 genes. ROC analysis revealed an area under the curve for protein peak 33331 and survivin of 0.78 (95% CI, 0.62-0.94) and 0.79 (95% CI, 0.63-0.94), respectively. Protein peak 33331 and survivin identified 3 (17%) and 8 (47%) patients with a recurrence-free period of at least 4 years, respectively, without generating false-negatives. Conclusion: These findings indicate that SELDI-TOF MS and real-time Q-PCR analysis on the same tissue can result in the identification of markers with comparable differential expression. Such combined analyses may yield combinations of several markers that might improve disease prognosis.
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| 8. |
- Schultz, Iman J., et al.
(författare)
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The Prognostic Role of the STK15 T91A Polymorphism and of STK15 mRNA Expression in Patients with Urothelial Cell Carcinoma
- 2007
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Ingår i: Anticancer Research. - 0250-7005 .- 1791-7530. ; 27:2, s. 1025-1030
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Tidskriftsartikel (refereegranskat)abstract
- Background: The prognostic role of the STK15 T91A polymorphism and of STK15 mRNA expression was investigated in patients with urothelial cell carcinoma (UCC). Materials and Methods: The STK15 genotype with respect to the T91A polymorphism was assessed by restriction fragment length polymorphism in 135 patients. STK15 mRNA expression was measured in tumor tissues of 103 patients, using real-time quantitative PCR. Results: The T91A polymorphism lacked any prognostic information in our patient cohort. Interestingly though, STK15 mRNA expression was increased in invasive and high-grade tumors (p-values of 0.009 and 0.0001, respectively). Additionally, patients with superficial UCC (n=82) who had a tumor recurrence in the first year after surgery displayed elevated STK15 mRNA expression levels (p=0.009). Kaplan-Meier survival analysis revealed an increased risk of tumor progression for patients with Ta tumors (n=62) and high STK15 expression (log-rank p=0.04). Furthermore, a decreased overall (log-rank p=0.006) and UCC-specific survival (log-rank p=0.001) were shown for patients with elevated STK15 mRNA levels. Conclusion: Patients with UCC and elevated levels of STK15 mRNA generally showed a more adverse disease course than patients with low levels. This may help in identifying patients in need of more aggressive treatment.
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