| 301. |
- Scott, Robert A., et al.
(författare)
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An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans
- 2017
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 66:11, s. 2888-2902
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Tidskriftsartikel (refereegranskat)abstract
- To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 x 10(-8)), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.
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| 302. |
- Skelton, Alasdair, et al.
(författare)
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Hydrochemical Changes Before and After Earthquakes Based on Long-Term Measurements of Multiple Parameters at Two Sites in Northern IcelandA Review
- 2019
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Ingår i: Journal of Geophysical Research - Solid Earth. - 2169-9313 .- 2169-9356. ; 124:3, s. 2702-2720
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Forskningsöversikt (refereegranskat)abstract
- Hydrochemical changes before and after earthquakes have been reported for over 50years. However, few reports provide sufficient data for an association to be verified statistically. Also, no mechanism has been proposed to explain why hydrochemical changes are observed far from earthquake foci where associated strains are small (<10(-8)). Here we address these challenges based on time series of multiple hydrochemical parameters from two sites in northern Iceland. We report hydrochemical changes before and after M >5 earthquakes in 2002, 2012, and 2013. The longevity of the time series (10 and 16years) permits statistical verification of coupling between hydrochemical changes and earthquakes. We used a Student t test to find significant hydrochemical changes and a binomial test to confirm association with earthquakes. Probable association was confirmed for preseismic changes based on five parameters (Na, Si, K, O-18, and H-2) and postseismic changes based on eight parameters (Ca, Na, Si, Cl, F, SO4, O-18, and H-2). Using concentration ratios and stable isotope values, we showed that (1) gradual preseismic changes were caused by source mixing, which resulted in a shift from equilibrium and triggered water-rock interaction; (2) postseismic changes were caused by rapid source mixing; and (3) longer-term hydrochemical changes were caused by source mixing and mineral growth. Because hydrochemical changes occur at small earthquake-related strains, we attribute source mixing and water-rock interaction to microscale fracturing. Because fracture density and size scale inversely, we infer that mixing of nearby sources and water-rock interaction are feasible responses to small earthquake-related strains. Plain Language Summary Changes in groundwater chemistry before and after earthquakes have been reported for over 50years. However, few studies have been able to prove that the earthquakes caused these changes. Also, no study has explained why these changes are often reported far from where the earthquake occurred. Here we address these challenges based on measurements of groundwater chemistry made at two sites in northern Iceland over time periods of 10 and 16years. We used statistical methods to prove that the earthquakes caused changes of ground water chemistry both before and after the earthquakes. We showed that changes of groundwater chemistry before earthquakes were caused by slow mixing between different groundwaters, which triggered reactions with the wall rock that changed groundwater chemistry, and that changes of groundwater chemistry after earthquakes were causes by rapid mixing between different groundwaters. That these changes were detected far from where the earthquakes occurred suggests that cracking of the wall rock at a very small scale was all that was needed for mixing of different groundwaters and reactions with the wall rock to occur.
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| 303. |
- Small, K. S., et al.
(författare)
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Identification of an imprinted master trans regulator at the KLF14 locus related to multiple metabolic phenotypes
- 2011
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Ingår i: Nat Genet. ; 43:6, s. 561-4
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have identified many genetic variants associated with complex traits. However, at only a minority of loci have the molecular mechanisms mediating these associations been characterized. In parallel, whereas cis regulatory patterns of gene expression have been extensively explored, the identification of trans regulatory effects in humans has attracted less attention. Here we show that the type 2 diabetes and high-density lipoprotein cholesterol-associated cis-acting expression quantitative trait locus (eQTL) of the maternally expressed transcription factor KLF14 acts as a master trans regulator of adipose gene expression. Expression levels of genes regulated by this trans-eQTL are highly correlated with concurrently measured metabolic traits, and a subset of the trans-regulated genes harbor variants directly associated with metabolic phenotypes. This trans-eQTL network provides a mechanistic understanding of the effect of the KLF14 locus on metabolic disease risk and offers a potential model for other complex traits.
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| 304. |
- Solé Navais, Pol, et al.
(författare)
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Genetic effects on the timing of parturition and links to fetal birth weight.
- 2023
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Ingår i: Nature genetics. - 1546-1718. ; 55:4, s. 559-567
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Tidskriftsartikel (refereegranskat)abstract
- The timing of parturition is crucial for neonatal survival and infant health. Yet, its genetic basis remains largely unresolved. We present a maternal genome-wide meta-analysis of gestational duration (n = 195,555), identifying 22 associated loci (24 independent variants) and an enrichment in genes differentially expressed during labor. A meta-analysis of preterm delivery (18,797 cases, 260,246 controls) revealed six associated loci and large genetic similarities with gestational duration. Analysis of the parental transmitted and nontransmitted alleles (n = 136,833) shows that 15 of the gestational duration genetic variants act through the maternal genome, whereas 7 act both through the maternal and fetal genomes and 2 act only via the fetal genome. Finally, the maternal effects on gestational duration show signs of antagonistic pleiotropy with the fetal effects on birth weight: maternal alleles that increase gestational duration have negative fetal effects on birth weight. The present study provides insights into the genetic effects on the timing of parturition and the complex maternal-fetal relationship between gestational duration and birth weight.
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| 305. |
- Spears, Dean, et al.
(författare)
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Additively-separable and rank-discounted variable-population social welfare functions : A characterization
- 2021
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Ingår i: Economics Letters. - : Elsevier BV. - 0165-1765 .- 1873-7374. ; 203
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Tidskriftsartikel (refereegranskat)abstract
- Economic policy evaluations require social welfare functions for variable-size populations. Two important candidates are critical-level generalized utilitarianism (CLGU) and rank-discounted critical-level generalized utilitarianism, which was recently characterized by Asheim and Zuber (2014) (AZ). AZ introduce a novel axiom, existence of egalitarian equivalence (EEE). First, we show that, under some uncontroversial criteria for a plausible social welfare relation, EEE suffices to rule out the Repugnant Conclusion of population ethics (without AZ’s other novel axioms). Second, we provide a new characterization of CLGU: AZ’s set of axioms is equivalent to CLGU when EEE is replaced by the axiom same-number independence.
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| 306. |
- Spears, Dean, et al.
(författare)
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What calibrating variable-value population ethics suggests
- 2024
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Ingår i: Economics and Philosophy. - 0266-2671 .- 1474-0028.
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Tidskriftsartikel (refereegranskat)abstract
- Variable-Value axiologies avoid Parfit's Repugnant Conclusion while satisfying some weak instances of the Mere Addition principle. We apply calibration methods to two leading members of the family of Variable-Value views conditional upon: first, a very weak instance of Mere Addition and, second, some plausible empirical assumptions about the size and welfare of the intertemporal world population. We find that such facts calibrate these two Variable-Value views to be nearly totalist, and therefore imply conclusions that should seem repugnant to anyone who opposes Total Utilitarianism only due to the Repugnant Conclusion.
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| 307. |
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| 308. |
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| 309. |
- Stacey, Simon N, et al.
(författare)
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Ancestry-shift refinement mapping of the C6orf97-ESR1 breast cancer susceptibility locus.
- 2010
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Ingår i: PLoS genetics. - : Public Library of Science. - 1553-7404. ; 6:7, s. e1001029-
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Tidskriftsartikel (refereegranskat)abstract
- We used an approach that we term ancestry-shift refinement mapping to investigate an association, originally discovered in a GWAS of a Chinese population, between rs2046210[T] and breast cancer susceptibility. The locus is on 6q25.1 in proximity to the C6orf97 and estrogen receptor alpha (ESR1) genes. We identified a panel of SNPs that are correlated with rs2046210 in Chinese, but not necessarily so in other ancestral populations, and genotyped them in breast cancer case:control samples of Asian, European, and African origin, a total of 10,176 cases and 13,286 controls. We found that rs2046210[T] does not confer substantial risk of breast cancer in Europeans and Africans (OR = 1.04, P = 0.099, and OR = 0.98, P = 0.77, respectively). Rather, in those ancestries, an association signal arises from a group of less common SNPs typified by rs9397435. The rs9397435[G] allele was found to confer risk of breast cancer in European (OR = 1.15, P = 1.2 x 10(-3)), African (OR = 1.35, P = 0.014), and Asian (OR = 1.23, P = 2.9 x 10(-4)) population samples. Combined over all ancestries, the OR was 1.19 (P = 3.9 x 10(-7)), was without significant heterogeneity between ancestries (P(het) = 0.36) and the SNP fully accounted for the association signal in each ancestry. Haplotypes bearing rs9397435[G] are well tagged by rs2046210[T] only in Asians. The rs9397435[G] allele showed associations with both estrogen receptor positive and estrogen receptor negative breast cancer. Using early-draft data from the 1,000 Genomes project, we found that the risk allele of a novel SNP (rs77275268), which is closely correlated with rs9397435, disrupts a partially methylated CpG sequence within a known CTCF binding site. These studies demonstrate that shifting the analysis among ancestral populations can provide valuable resolution in association mapping.
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| 310. |
- Steele, Katie, et al.
(författare)
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Belief Revision for Growing Awareness
- 2021
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Ingår i: Mind. - : Oxford University Press (OUP). - 0026-4423 .- 1460-2113. ; 130:520, s. 1207-1232
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Tidskriftsartikel (refereegranskat)abstract
- The Bayesian maxim for rational learning could be described as conservative change from one probabilistic belief or credence function to another in response to new information. Roughly: ‘Hold fixed any credences that are not directly affected by the learning experience.’ This is precisely articulated for the case when we learn that some proposition that we had previously entertained is indeed true (the rule of conditionalization). But can this conservative-change maxim be extended to revising one’s credences in response to entertaining propositions or concepts of which one was previously unaware? The economists Karni and Vierø (2013, 2015) make a proposal in this spirit. Philosophers have adopted effectively the same rule: revision in response to growing awareness should not affect the relative probabilities of propositions in one’s ‘old’ epistemic state. The rule is compelling, but only under the assumptions that its advocates introduce. It is not a general requirement of rationality, or so we argue. We provide informal counterexamples. And we show that, when awareness grows, the boundary between one’s ‘old’ and ‘new’ epistemic commitments is blurred. Accordingly, there is no general notion of conservative change in this setting.
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