| 61. |
|
|
| 62. |
- Liu, LL, et al.
(författare)
-
Genetic regulation of serum IgA levels and susceptibility to common immune, infectious, kidney, and cardio-metabolic traits
- 2022
-
Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1, s. 6859-
-
Tidskriftsartikel (refereegranskat)abstract
- Immunoglobulin A (IgA) mediates mucosal responses to food antigens and the intestinal microbiome and is involved in susceptibility to mucosal pathogens, celiac disease, inflammatory bowel disease, and IgA nephropathy. We performed a genome-wide association study of serum IgA levels in 41,263 individuals of diverse ancestries and identified 20 genome-wide significant loci, including 9 known and 11 novel loci. Co-localization analyses with expression QTLs prioritized candidate genes for 14 of 20 significant loci. Most loci encoded genes that produced immune defects and IgA abnormalities when genetically manipulated in mice. We also observed positive genetic correlations of serum IgA levels with IgA nephropathy, type 2 diabetes, and body mass index, and negative correlations with celiac disease, inflammatory bowel disease, and several infections. Mendelian randomization supported elevated serum IgA as a causal factor in IgA nephropathy. African ancestry was consistently associated with higher serum IgA levels and greater frequency of IgA-increasing alleles compared to other ancestries. Our findings provide novel insights into the genetic regulation of IgA levels and its potential role in human disease.
|
|
| 63. |
|
|
| 64. |
|
|
| 65. |
- Sakaue, S, et al.
(författare)
-
Dimensionality reduction reveals fine-scale structure in the Japanese population with consequences for polygenic risk prediction
- 2020
-
Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 1569-
-
Tidskriftsartikel (refereegranskat)abstract
- The diversity in our genome is crucial to understanding the demographic history of worldwide populations. However, we have yet to know whether subtle genetic differences within a population can be disentangled, or whether they have an impact on complex traits. Here we apply dimensionality reduction methods (PCA, t-SNE, PCA-t-SNE, UMAP, and PCA-UMAP) to biobank-derived genomic data of a Japanese population (n = 169,719). Dimensionality reduction reveals fine-scale population structure, conspicuously differentiating adjacent insular subpopulations. We further enluciate the demographic landscape of these Japanese subpopulations using population genetics analyses. Finally, we perform phenome-wide polygenic risk score (PRS) analyses on 67 complex traits. Differences in PRS between the deconvoluted subpopulations are not always concordant with those in the observed phenotypes, suggesting that the PRS differences might reflect biases from the uncorrected structure, in a trait-dependent manner. This study suggests that such an uncorrected structure can be a potential pitfall in the clinical application of PRS.
|
|
| 66. |
- Suzuki, K., et al.
(författare)
-
Liver function and prognosis, and influence of sacubitril/valsartan in patients with heart failure with reduced ejection fraction
- 2020
-
Ingår i: European Journal of Heart Failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 22:9, s. 1662-1671
-
Tidskriftsartikel (refereegranskat)abstract
- AIMS: The prevalence of liver function abnormalities is common in patients with heart failure (HF) with reduced ejection fraction (HFrEF). We assessed the impact of liver function on prognosis and the effect of sacubitril/valsartan on measures of liver function in patients with HFrEF. METHODS AND RESULTS: The PARADIGM-HF trial was a randomized, double-blind, active treatment-controlled trial. We included 8232 HFrEF patients with available measures of liver function, including transaminases, alkaline phosphatase (ALP) and bilirubin; the primary endpoint was a composite of HF hospitalization and cardiovascular (CV) death. At screening, 11.6% of study patients had total bilirubin above the upper limit of normal (20.5 mumol/L) and 9.2% had ALP above the upper limit of normal (123 IU/L). Although ALP and albumin were associated with an increased risk of outcomes, among conventional test of liver function, total bilirubin was the strongest predictor for the primary endpoint [hazard ratio (HR) 1.10; 95% confidence interval (CI) 1.04-1.15; P < 0.001], HF hospitalization (HR 1.14; 95% CI 1.07-1.22; P < 0.001); CV death (HR 1.07; 95% CI 1.00-1.14; P = 0.040), and all-cause death (HR 1.08; 95% CI 1.02-1.14; P = 0.009). All conventional measures of liver function were significantly improved in the sacubitril/valsartan group compared with the enalapril group after randomization (between-group reduction: total bilirubin 2.4%, 95% CI 0.7-4.2%, P = 0.007; aspartate aminotransferase 7.9%, 95% CI 6.7-9.0%, P < 0.001; alanine aminotransferase 7.7%; 95% CI 6.2-9.3%, P < 0.001; ALP 5.4%, 95% CI 4.4-6.4%, P < 0.001). CONCLUSION: Total bilirubin was a significant and independent predictor of CV death or HF hospitalization and all-cause mortality in patients with HFrEF enrolled in PARADIGM-HF. Sacubitril/valsartan improved measures of liver function compared with enalapril.
|
|
| 67. |
- Sønderby, Ida E., et al.
(författare)
-
1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans
- 2021
-
Ingår i: Translational Psychiatry. - : Nature Publishing Group. - 2158-3188. ; 11:1
-
Tidskriftsartikel (refereegranskat)abstract
- Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.
|
|
| 68. |
|
|
| 69. |
|
|
| 70. |
- Baron, P., et al.
(författare)
-
Potential for the measurement of mesosphere and lower thermosphere (MLT) wind, temperature, density and geomagnetic field with Superconducting Submillimeter-Wave Limb-Emission Sounder 2 (SMILES-2)
- 2020
-
Ingår i: Atmospheric Measurement Techniques. - : Copernicus GmbH. - 1867-1381 .- 1867-8548. ; 13:1, s. 219-237
-
Tidskriftsartikel (refereegranskat)abstract
- Submillimeter-Wave Limb-Emission Sounder 2 (SMILES-2) is a satellite mission proposed in Japan to probe the middle and upper atmosphere (20-160 km). The main instrument is composed of 4K cooled radiometers operating near 0.7 and 2 THz. It could measure the diurnal changes of the horizontal wind above 30 km, temperature above 20 km, ground-state atomic oxygen above 90 km and atmospheric density near the mesopause, as well as abundance of about 15 chemical species. In this study we have conducted simulations to assess the wind, temperature and density retrieval performance in the mesosphere and lower thermosphere (60- 110 km) using the radiometer at 760 GHz. It contains lines of water vapor (H2O), molecular oxygen (O2) and nitric oxide (NO) that are the strongest signals measured with SMILES-2 at these altitudes. The Zeeman effect on the O2 line due to the geomagnetic field (B) is considered; otherwise, the retrieval errors would be underestimated by a factor of 2 above 90 km. The optimal configuration for the radiometer's polarization is found to be vertical linear. Considering a retrieval vertical resolution of 2.5 km, the line-of-sight wind is retrieved with a precision of 2-5ms-1 up to 90 km and 30ms-1 at 110 km. Temperature and atmospheric density are retrieved with a precision better than 5K and 7% up to 90 km (30K and 20% at 110 km). Errors induced by uncertainties on the vector B are mitigated by retrieving it. The retrieval of B is described as a side-product of the mission. At high latitudes, precisions of 30-100 nT on the vertical component and 100-300 nT on the horizontal one could be obtained at 85 and 105 km (vertical resolution of 20 km). SMILES-2 could therefore provide the first measurements of B close to the electrojets' altitude, and the precision is enough to measure variations induced by solar storms in the auroral regions.
|
|
