| 1. |
- Estrada, Karol, et al.
(författare)
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Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.
- 2012
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:5, s. 491-501
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Tidskriftsartikel (refereegranskat)abstract
- Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
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| 2. |
- 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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| 3. |
- Almeida, Joao, et al.
(författare)
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Molecular understanding of sulphuric acid-amine particle nucleation in the atmosphere
- 2013
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 502:7471, s. 359-
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Tidskriftsartikel (refereegranskat)abstract
- Nucleation of aerosol particles from trace atmospheric vapours is thought to provide up to half of global cloud condensation nuclei(1). Aerosols can cause a net cooling of climate by scattering sunlight and by leading to smaller but more numerous cloud droplets, which makes clouds brighter and extends their lifetimes(2). Atmospheric aerosols derived from human activities are thought to have compensated for a large fraction of the warming caused by greenhouse gases(2). However, despite its importance for climate, atmospheric nucleation is poorly understood. Recently, it has been shown that sulphuric acid and ammonia cannot explain particle formation rates observed in the lower atmosphere(3). It is thought that amines may enhance nucleation(4-16), but until now there has been no direct evidence for amine ternary nucleation under atmospheric conditions. Here we use the CLOUD (Cosmics Leaving OUtdoor Droplets) chamber at CERN and find that dimethylamine above three parts per trillion by volume can enhance particle formation rates more than 1,000-fold compared with ammonia, sufficient to account for the particle formation rates observed in the atmosphere. Molecular analysis of the clusters reveals that the faster nucleation is explained by a base-stabilization mechanism involving acid-amine pairs, which strongly decrease evaporation. The ion-induced contribution is generally small, reflecting the high stability of sulphuric acid-dimethylamine clusters and indicating that galactic cosmic rays exert only a small influence on their formation, except at low overall formation rates. Our experimental measurements are well reproduced by a dynamical model based on quantum chemical calculations of binding energies of molecular clusters, without any fitted parameters. These results show that, in regions of the atmosphere near amine sources, both amines and sulphur dioxide should be considered when assessing the impact of anthropogenic activities on particle formation.
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| 4. |
- Geissbuehler, M., et al.
(författare)
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Triplet imaging of oxygen consumption during the contraction of a single smooth muscle cell (A7r5)
- 2012
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Ingår i: Oxygen Transport to Tissue XXXIII. - New York, NY : Springer Science+Business Media B.V.. - 9781461415657 ; , s. 263-268
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Konferensbidrag (refereegranskat)abstract
- Triplet imaging is a novel optical technique that allows investigating oxygen metabolism at the single cell and the sub-cellular level. The method combines high temporal and spatial resolutions which are required for the monitoring of fast kinetics of oxygen concentration in living cells. Calibration and validation are demonstrated with a titration experiment using l-ascorbic acid with the enzyme ascorbase oxidase. The method was applied to a biological cell system, employing as reporter a cytosolic fusion protein of β-galactosidase with a SNAP-tag labeled with tetramethylrhodamine. Oxygen consumption in single smooth muscle cells A7r5 during an [Arg8]-vasopressin- induced contraction is measured. The triplet lifetime images over time can be related to an intracellular oxygen consumption corresponding to a mono-exponentially decaying intracellular oxygen concentration. This is in good agreement with previously reported measurements of oxygen consumption in skeletal muscle fibers.
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| 5. |
- Leinonen, Ville, et al.
(författare)
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Diagnostic effectiveness of quantitative [¹⁸F]flutemetamol PET imaging for detection of fibrillar amyloid β using cortical biopsy histopathology as the standard of truth in subjects with idiopathic normal pressure hydrocephalus.
- 2014
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Ingår i: Acta neuropathologica communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 2, s. 46-
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: PET imaging of amyloid-β (Aβ) in vivo holds promise for aiding in earlier diagnosis and intervention in Alzheimer's disease (AD) and mild cognitive impairment. AD-like Aβ pathology is a common comorbidity in patients with idiopathic normal pressure hydrocephalus (iNPH). Fifty patients with iNPH needing ventriculo-peritoneal shunting or intracranial pressure monitoring underwent [18F]flutemetamol PET before (N = 28) or after (N = 22) surgery. Cortical uptake of [18F]flutemetamol was assessed visually by blinded reviewers, and also quantitatively via standard uptake value ratio (SUVR) in specific neocortical regions in relation to either cerebellum or pons reference region: the cerebral cortex of (prospective studies) or surrounding (retrospective studies) the biopsy site, the contralateral homolog, and a calculated composite brain measure. Aβ pathology in the biopsy specimen (standard of truth [SoT]) was measured using Bielschowsky silver and thioflavin S plaque scores, percentage area of grey matter positive for monoclonal antibody to Aβ (4G8), and overall pathology impression. We set out to find (1) which pair(s) of PET SUVR and pathology SoT endpoints matched best, (2) whether quantitative measures of [18F]flutemetamol PET were better for predicting the pathology outcome than blinded image examination (BIE), and (3) whether there was a better match between PET image findings in retrospective vs. prospective studies.RESULTS: Of the 24 possible endpoint/SoT combinations, the one with composite-cerebellum SUVR and SoT based on overall pathology had the highest Youden index (1.000), receiver operating characteristic area under the curve (1.000), sensitivity (1.000), specificity (1.000), and sum of sensitivity and specificity for the pooled data as well as for the retrospective and prospective studies separately (2.00, for all 3). The BIE sum of sensitivity and specificity, comparable to that for quantitation, was highest using Bielschowsky silver as SoT for all SUVRs (ipsilateral, contralateral, and composite, for both reference regions). The composite SUVR had a 100% positive predictive value (both reference regions) for the overall pathology diagnosis. All SUVRs had a 100% negative predictive value for the Bielschowsky silver result.CONCLUSION: Bielschowsky silver stain and overall pathology judgment showed the strongest associations with imaging results.
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| 6. |
- Sandholm, Niina, et al.
(författare)
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Genome-wide association study of urinary albumin excretion rate in patients with type 1 diabetes
- 2014
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Ingår i: Diabetologia. - Berlin Heidelberg : Springer-Verlag. - 0012-186X .- 1432-0428. ; 57:6, s. 1143-1153
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: An abnormal urinary albumin excretion rate (AER) is often the first clinically detectable manifestation of diabetic nephropathy. Our aim was to estimate the heritability and to detect genetic variation associated with elevated AER in patients with type 1 diabetes.METHODS: The discovery phase genome-wide association study (GWAS) included 1,925 patients with type 1diabetes and with data on 24 h AER. AER was analysed as a continuous trait and the analysis was stratified by the use of antihypertensive medication. Signals with a p value <10(-4) were followed up in 3,750 additional patients withtype 1 diabetes from seven studies.RESULTS: The narrow-sense heritability, captured with our genotyping platform, was estimated to explain 27.3% of the total AER variability, and 37.6% after adjustment for covariates. In the discovery stage, five single nucleotide polymorphisms in the GLRA3 gene were strongly associated with albuminuria (p < 5 × 10(-8)). In the replication group, a nominally significant association (p = 0.035) was observed between albuminuria and rs1564939 in GLRA3, but this was in the opposite direction. Sequencing of the surrounding genetic region in 48 Finnish and 48 UK individuals supported the possibility that population-specific rare variants contribute to the synthetic associationobserved at the common variants in GLRA3. The strongest replication (p = 0.026) was obtained for rs2410601 between the PSD3 and SH2D4A genes. Pathway analysis highlighted natural killer cell mediated immunity processes.CONCLUSIONS/INTERPRETATION: This study suggests novel pathways and molecular mechanisms for the pathogenesis of albuminuria in type 1 diabetes.
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| 7. |
- Sandholm, Niina, et al.
(författare)
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New susceptibility loci associated with kidney disease in type 1 diabetes
- 2012
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Ingår i: PLOS Genetics. - San Francisco, USA : Public Library of Science, PLOS. - 1553-7390 .- 1553-7404. ; 8:9, s. e1002921-
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Tidskriftsartikel (refereegranskat)abstract
- Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genomewide association studies (GWAS) of T1D DN comprising similar to 2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2 x 10(-8)) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0 x 10(-9)). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-beta 1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1 x 10(-7)), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.
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| 8. |
- Taal, H. Rob, et al.
(författare)
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Common variants at 12q15 and 12q24 are associated with infant head circumference
- 2012
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:5, s. 532-538
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Tidskriftsartikel (refereegranskat)abstract
- 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 x 10(-9)) and rs1042725 on chromosome 12q15 (P = 2.8 x 10(-10)) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height(1), their effects on infant head circumference were largely independent of height (P = 3.8 x 10(-7) for rs7980687 and P = 1.3 x 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 x 10(-6)). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume(2), Parkinson's disease and other neurodegenerative diseases(3-5), indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.
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| 9. |
- Tyrrell, Jessica, et al.
(författare)
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Genetic variation in the 15q25 nicotinic acetylcholine receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) interacts with maternal self-reported smoking status during pregnancy to influence birth weight.
- 2012
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Ingår i: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 21:24, s. 5344-5358
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Tidskriftsartikel (refereegranskat)abstract
- Maternal smoking during pregnancy is associated with low birth weight. Common variation at rs1051730 is robustly associated with smoking quantity and was recently shown to influence smoking cessation during pregnancy, but its influence on birth weight is not clear. We aimed to investigate the association between this variant and birth weight of term, singleton offspring in a well-powered meta-analysis. We stratified 26 241 European origin study participants by smoking status (women who smoked during pregnancy versus women who did not smoke during pregnancy) and, in each stratum, analysed the association between maternal rs1051730 genotype and offspring birth weight. There was evidence of interaction between genotype and smoking (P = 0.007). In women who smoked during pregnancy, each additional smoking-related T-allele was associated with a 20 g [95% confidence interval (95% CI): 4-36 g] lower birth weight (P = 0.014). However, in women who did not smoke during pregnancy, the effect size estimate was 5 g per T-allele (95% CI: -4to 14 g; P = 0.268). To conclude, smoking status during pregnancy modifies the association between maternal rs1051730 genotype and offspring birth weight. This strengthens the evidence that smoking during pregnancy is causally related to lower offspring birth weight and suggests that population interventions that effectively reduce smoking in pregnant women would result in a reduced prevalence of low birth weight.
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| 10. |
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