| 1. |
- Mishra, A., et al.
(författare)
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Stroke genetics informs drug discovery and risk prediction across ancestries
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 611, s. 115-123
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Tidskriftsartikel (refereegranskat)abstract
- Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
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| 4. |
- Silventoinen, K., et al.
(författare)
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Differences in genetic and environmental variation in adult BMI by sex, age, time period, and region : An individual-based pooled analysis of 40 twin cohorts
- 2017
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Ingår i: American Journal of Clinical Nutrition. - : Oxford University Press. - 0002-9165 .- 1938-3207. ; 106:2, s. 457-466
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Tidskriftsartikel (refereegranskat)abstract
- Background: Genes and the environment contribute to variation in adult body mass index [BMI (in kg/m2)], but factors modifying these variance components are poorly understood.Objective: We analyzed genetic and environmental variation in BMI between men and women from young adulthood to old age from the 1940s to the 2000s and between cultural-geographic regions representing high (North America and Australia), moderate (Europe), and low (East Asia) prevalence of obesity.Design: We used genetic structural equation modeling to analyze BMI in twins ≥20 y of age from 40 cohorts representing 20 countries (140,379 complete twin pairs).Results: The heritability of BMI decreased from 0.77 (95% CI: 0.77, 0.78) and 0.75 (95% CI: 0.74, 0.75) in men and women 20-29 y of age to 0.57 (95% CI: 0.54, 0.60) and 0.59 (95% CI: 0.53, 0.65) in men 70-79 y of age and women 80 y of age, respectively. The relative influence of unique environmental factors correspondingly increased. Differences in the sets of genes affecting BMI in men and women increased from 20-29 to 60-69 y of age. Mean BMI and variances in BMI increased from the 1940s to the 2000s and were greatest in North America and Australia, followed by Europe and East Asia. However, heritability estimates were largely similar over measurement years and between regions. There was no evidence of environmental factors shared by co-twins affecting BMI.Conclusions: The heritability of BMI decreased and differences in the sets of genes affecting BMI in men and women increased from young adulthood to old age. The heritability of BMI was largely similar between cultural-geographic regions and measurement years, despite large differences in mean BMI and variances in BMI. Our results show a strong influence of genetic factors on BMI, especially in early adulthood, regardless of the obesity level in the population.
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| 5. |
- Heid, Iris M, et al.
(författare)
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Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 949-960
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Tidskriftsartikel (refereegranskat)abstract
- Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
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| 6. |
- Ahlm, Lars, et al.
(författare)
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Modeling the thermodynamics and kinetics of sulfuric acid-dimethylamine-water nanoparticle growth in the CLOUD chamber
- 2016
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Ingår i: Aerosol Science and Technology. - : Informa UK Limited. - 0278-6826 .- 1521-7388. ; 50:10, s. 1017-1032
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Tidskriftsartikel (refereegranskat)abstract
- Dimethylamine (DMA) has a stabilizing effect on sulfuric acid (SA) clusters, and the SA and DMA molecules and clusters likely play important roles in both aerosol particle formation and growth in the atmosphere. We use the monodisperse particle growth model for acid-base chemistry in nanoparticle growth (MABNAG) together with direct and indirect observations from the CLOUD4 and CLOUD7 experiments in the cosmics leaving outdoor droplets (CLOUD) chamber at CERN to investigate the size and composition evolution of freshly formed particles consisting of SA, DMA, and water as they grow to 20nm in dry diameter. Hygroscopic growth factors are measured using a nano-hygroscopicity tandem differential mobility analyzer (nano-HTDMA), which combined with simulations of particle water uptake using the thermodynamic extended-aerosol inorganics model (E-AIM) constrain the chemical composition. MABNAG predicts a particle-phase ratio between DMA and SA molecules of 1.1-1.3 for a 2nm particle and DMA gas-phase mixing ratios between 3.5 and 80 pptv. These ratios agree well with observations by an atmospheric-pressure interface time-of-flight (APi-TOF) mass spectrometer. Simulations with MABNAG, direct observations of the composition of clusters <2nm, and indirect observations of the particle composition indicate that the acidity of the nucleated particles decreases as they grow from approximate to 1 to 20nm. However, MABNAG predicts less acidic particles than suggested by the indirect estimates at 10nm diameter using the nano-HTDMA measurements, and less acidic particles than observed by a thermal desorption chemical ionization mass spectrometer (TDCIMS) at 10-30nm. Possible explanations for these discrepancies are discussed.
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| 7. |
- Kim, J., et al.
(författare)
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Hygroscopicity of nanoparticles produced from homogeneous nucleation in the CLOUD experiments
- 2016
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Ingår i: Atmospheric Chemistry And Physics. - : Copernicus GmbH. - 1680-7316 .- 1680-7324. ; 16:1, s. 293-304
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Tidskriftsartikel (refereegranskat)abstract
- Sulfuric acid, amines and oxidized organics have been found to be important compounds in the nucleation and initial growth of atmospheric particles. Because of the challenges involved in determining the chemical composition of objects with very small mass, however, the properties of the freshly nucleated particles and the detailed pathways of their formation processes are still not clear. In this study,we focus on a challenging size range, i.e., particles that have grown to diameters of 10 and 15 nm following nucleation, and measure their water uptake. Water uptake is useful information for indirectly obtaining chemical composition of aerosol particles. We use a nanometer-hygroscopicity tandem differential mobility analyzer (nano-HTDMA) at sub-saturated conditions (ca. 90% relative humidity at 293 K) to measure the hygroscopicity of particles during the seventh Cosmics Leaving OUtdoor Droplets (CLOUD7) campaign performed at CERN in 2012. In CLOUD7, the hygroscopicity of nucleated nanoparticles was measured in the presence of sulfuric acid, sulfuric acid-dimethylamine, and sulfuric acid-organics derived from alpha-pinene oxidation. The hygroscopicity parameter kappa decreased with increasing particle size, indicating decreasing acidity of particles. No clear effect of the sulfuric acid concentration on the hygroscopicity of 10 nm particles produced from sulfuric acid and dimethylamine was observed, whereas the hygroscopicity of 15 nm particles sharply decreased with decreasing sulfuric acid concentrations. In particular, when the concentration of sulfuric acid was 5.1 x 10(6) molecules cm(-3) in the gas phase, and the dimethylamine mixing ratio was 11.8 ppt, the measured kappa of 15 nm particles was 0.31 +/- 0.01: close to the value reported for dimethylaminium sulfate (DMAS) (kappa(DMAS) similar to 0.28). Furthermore, the difference in kappa between sulfuric acid and sulfuric acid-dimethylamine experiments increased with increasing particle size. The kappa values of particles in the presence of sulfuric acid and organics were much smaller than those of particles in the presence of sulfuric acid and dimethylamine. This suggests that the organics produced from alpha-pinene ozonolysis play a significant role in particle growth even at 10 nm sizes.
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| 9. |
- Smith, D. L., et al.
(författare)
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Lifetime measurements of the negative-parity 7(-) and 8(-) states in Cd-122
- 2008
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Ingår i: Physical Review C. Nuclear Physics. - 0556-2813 .- 1089-490X. ; 77:1, s. 014309-
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Tidskriftsartikel (refereegranskat)abstract
- The Advanced Time-Delayed beta gamma gamma(t) method was used to measure lifetimes of selected high-spin states in Cd-122 populated from beta(-) decay of the J(pi)=(9(-)) isomer in Ag-122. From the gamma gamma coincidences, a new energy level was established at 2616.6 keV with a suggested spin-parity assignment of 8(-). Lifetimes were determined for the high-spin states at 2616.6 and 2502.7 keV as T-1/2=1.35(29) ns and 0.24(6) ns, respectively. The transition rates for gamma rays de-exciting the 7(-) states in the N=74 isotones of Cd-122, Sn-124, and Te-126 were found to be very similar.
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| 10. |
- Speliotes, Elizabeth K., et al.
(författare)
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Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 937-948
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ~2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10−8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
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