| 1. |
- Aad, G, et al.
(författare)
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- 2015
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swepub:Mat__t
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| 2. |
- Kanai, M, et al.
(författare)
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- 2023
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swepub:Mat__t
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| 3. |
- Bombarda, F., et al.
(författare)
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Runaway electron beam control
- 2019
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Ingår i: Plasma Physics and Controlled Fusion. - : IOP Publishing. - 1361-6587 .- 0741-3335. ; 61:1
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Tidskriftsartikel (refereegranskat)
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| 4. |
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- 2018
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Ingår i: Nuclear Fusion. - : IOP Publishing. - 1741-4326 .- 0029-5515. ; 58:1
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Forskningsöversikt (refereegranskat)
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| 5. |
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- 2019
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Tidskriftsartikel (refereegranskat)
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| 6. |
- Craddock, Nick, et al.
(författare)
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Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7289, s. 713-720
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Tidskriftsartikel (refereegranskat)abstract
- Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed,19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated similar to 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
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| 7. |
- Palmer, Nicholette D, et al.
(författare)
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A genome-wide association search for type 2 diabetes genes in African Americans.
- 2012
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Ingår i: PloS one. - San Francisco : Public Library of Science (PLoS). - 1932-6203. ; 7:1, s. e29202-
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Tidskriftsartikel (refereegranskat)abstract
- African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
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| 8. |
- Fich, M., et al.
(författare)
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Herschel-PACS spectroscopy of the intermediate mass protostar NGC 7129 FIRS 2
- 2010
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 518:Article Number: L86
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Tidskriftsartikel (refereegranskat)abstract
- Aims. We present preliminary results of the first Herschel spectroscopic observations of NGC 7129 FIRS2, an intermediate mass star-forming region. We attempt to interpret the observations in the framework of an in-falling spherical envelope. Methods. The PACS instrument was used in line spectroscopy mode ( R = 1000-5000) with 15 spectral bands between 63 and 185 mu m. This provided good detections of 26 spectral lines seen in emission, including lines of H2O, CO, OH, O I, and C II. Results. Most of the detected lines, particularly those of H2O and CO, are substantially stronger than predicted by the spherical envelope models, typically by several orders of magnitude. In this paper we focus on what can be learned from the detected CO emission lines. Conclusions. It is unlikely that the much stronger than expected line emission arises in the (spherical) envelope of the YSO. The region hot enough to produce such high excitation lines within such an envelope is too small to produce the amount of emission observed. Virtually all of this high excitation emission must arise in structures such as as along the walls of the outflow cavity with the emission produced by a combination of UV photon heating and/or non-dissociative shocks.
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| 9. |
- Lis, D. C., et al.
(författare)
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Herschel/HIFI discovery of interstellar chloronium (H2Cl+)
- 2010
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 521:1
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Tidskriftsartikel (refereegranskat)abstract
- We report the first detection of chloronium, H_2Cl^+, in the interstellar medium, using the HIFI instrument aboard the Herschel Space Observatory. The 2_12-1_01 lines of ortho-H\_2^35Cl^+ and ortho-H\_2^37Cl^+ are detected in absorption towards NGC 6334I, and the 1_11-0_00 transition of para-H\_2^35Cl^+ is detected in absorption towards NGC 6334I and Sgr B2(S). The H_2Cl^+ column densities are compared to those of the chemically-related species HCl. The derived HCl/H_2Cl^+ column density ratios, ~1-10, are within the range predicted by models of diffuse and dense photon dominated regions (PDRs). However, the observed H_2Cl^+ column densities, in excess of 10^13 cm^-2, are significantly higher than the model predictions. Our observations demonstrate the outstanding spectroscopic capabilities of HIFI for detecting new interstellar molecules and providing key constraints for astrochemical models.
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| 10. |
- Horikoshi, Momoko, et al.
(författare)
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New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism.
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:1
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Tidskriftsartikel (refereegranskat)abstract
- Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.
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| 11. |
- Lis, D. C., et al.
(författare)
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Herschel/HIFI measurements of the ortho/para ratio in water towards Sagittarius B2(M) and W31C
- 2010
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 521:1, s. Article Number: L26 -
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Tidskriftsartikel (refereegranskat)abstract
- We present Herschel/HIFI observations of the fundamental rotational transitions of ortho- and para-H216O and H218O in absorption towards Sagittarius B2(M) and W31C. The ortho/para ratio in water in the foreground clouds on the line of sight towards these bright continuum sources is generally consistent with the statistical high-temperature ratio of 3, within the observational uncertainties. However, somewhat unexpectedly, we derive a low ortho/para ratio of 2.35 +/- 0.35, corresponding to a spin temperature of similar to 27 K, towards Sagittarius B2(M) at velocities of the expanding molecular ring. Water molecules in this region appear to have formed with, or relaxed to, an ortho/para ratio close to the value corresponding to the local temperature of the gas and dust.
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| 12. |
- Flannick, Jason, et al.
(författare)
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Data Descriptor : Sequence data and association statistics from 12,940 type 2 diabetes cases and controls
- 2017
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Ingår i: Scientific Data. - : Springer Science and Business Media LLC. - 2052-4463. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (> 80% of low-frequency coding variants in similar to ~82 K Europeans via the exome chip, and similar to ~90% of low-frequency non-coding variants in similar to ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.
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| 13. |
- Fuchsberger, Christian, et al.
(författare)
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The genetic architecture of type 2 diabetes
- 2016
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 536:7614, s. 41-47
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Tidskriftsartikel (refereegranskat)abstract
- The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.
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| 14. |
- 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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| 15. |
- Tobias, Deirdre K, et al.
(författare)
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Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine
- 2023
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Ingår i: Nature Medicine. - 1546-170X. ; 29:10, s. 2438-2457
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Forskningsöversikt (refereegranskat)abstract
- Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.
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| 16. |
- Wyrowski, F., et al.
(författare)
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Variations in H2O+/H2O ratios toward massive star-forming regions
- 2010
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 521, s. L34-
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Tidskriftsartikel (refereegranskat)abstract
- Early results from the Herschel Space Observatory revealed the water cation H2O+ to be an abundant ingredient of the interstellar medium. Here we present new observations of the H2O and H2O+ lines at 1113.3 and 1115.2 GHz using the Herschel Space Observatory toward a sample of high-mass star-forming regions to observationally study the relation between H2O and H2O+. Nine out of ten sources show absorption from H2O+ in a range of environments: the molecular clumps surrounding the forming and newly formed massive stars, bright high-velocity outflows associated with the massive protostars, and unrelated low-density clouds along the line of sight. Column densities per velocity component of H2O+ are found in the range of 10(12) to a few 10(13) cm(-2). The highest N(H2O+) column densities are found in the outflows of the sources. The ratios of H2O+/H2O are determined in a range from 0.01 to a few and are found to differ strongly between the observed environments with much lower ratios in the massive (proto) cluster envelopes (0.01-0.1) than in outflows and diffuse clouds. Remarkably, even for source components detected in H2O in emission, H2O+ is still seen in absorption.
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| 17. |
- Hudson, Thomas J., et al.
(författare)
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International network of cancer genome projects
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7291, s. 993-998
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Tidskriftsartikel (refereegranskat)abstract
- The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.
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| 18. |
- Rolffs, R., et al.
(författare)
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Reversal of infall in SgrB2(M) revealed by Herschel/HIFI observations of HCN lines at THz frequencies
- 2010
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 521:1, s. Article Number: L46 -
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Tidskriftsartikel (refereegranskat)abstract
- Aims. To investigate the accretion and feedback processes in massive star formation, we analyze the shapes of emission lines from hot molecular cores, whose asymmetries trace infall and expansion motions. Methods. The high-mass star forming region SgrB2(M) was observed with Herschel/HIFI (HEXOS key project) in various lines of HCN and its isotopologues, complemented by APEX data. The observations are compared to spherically symmetric, centrally heated models with density power-law gradient and different velocity fields (infall or infall+expansion), using the radiative transfer code RATRAN. Results. The HCN line profiles are asymmetric, with the emission peak shifting from blue to red with increasing J and decreasing line opacity (HCN to (HCN)-C-13). This is most evident in the HCN 12-11 line at 1062 GHz. These line shapes are reproduced by a model whose velocity field changes from infall in the outer part to expansion in the inner part. Conclusions. The qualitative reproduction of the HCN lines suggests that infall dominates in the colder, outer regions, but expansion dominates in the warmer, inner regions. We are thus witnessing the onset of feedback in massive star formation, starting to reverse the infall and finally disrupting the whole molecular cloud. To obtain our result, the THz lines uniquely covered by HIFI were critically important.
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| 19. |
- Vogt, A., et al.
(författare)
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High-spin structure of Xe-134
- 2016
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Ingår i: PHYSICAL REVIEW C. - 2469-9985. ; 93:5
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Tidskriftsartikel (refereegranskat)abstract
- Detailed spectroscopic information on the N similar to 82 nuclei is necessary to benchmark shell-model calculations in the region. The nuclear structure above long-lived isomers in Xe-134 is investigated after multinucleon transfer (MNT) and actinide fission. Xenon-134 was populated as (i) a transfer product in Xe-136 + U-238 and Xe-136 + Pb-208 MNT reactions and (ii) as a fission product in the Xe-136 + U-238 reaction employing the high-resolution Advanced Gamma Tracking Array (AGATA). Trajectory reconstruction has been applied for the complete identification of beamlike transfer products with the magnetic spectrometer PRISMA. The Xe-136 + Pt-198 MNT reaction was studied with the gamma-ray spectrometer GAMMASPHERE in combination with the gas detector array Compact Heavy Ion Counter (CHICO). Several high-spin states in Xe-134 on top of the two long-lived isomers are discovered based on gamma gamma-coincidence relationships and information on the gamma-ray angular distributions as well as excitation energies from the total kinetic energy loss and fission fragments. The revised level scheme of Xe-134 is extended up to an
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| 20. |
- Vogt, A., et al.
(författare)
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Isomers and high-spin structures in the N=81 isotones Xe-135 and Ba-137
- 2017
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Ingår i: PHYSICAL REVIEW C. - : AMER PHYSICAL SOC. - 2469-9985. ; 95:2
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Tidskriftsartikel (refereegranskat)abstract
- The high-spin structures and isomers of the N = 81 isotones Xe-135 and Ba-137 are investigated after multinucleon-transfer (MNT) and fusion-evaporation reactions. Both nuclei are populated (i) in Xe-136+ U-238 and (ii) Xe-136+ Pb-208 MNT reactions employing the high-resolution Advanced Gamma Tracking Array (AGATA) coupled to the magnetic spectrometer PRISMA, (iii) in the Xe-136+ Pt-198 MNT reaction employing the gamma-ray array GAMMASPHERE in combination with the gas-detector array CHICO, and (iv) via a B-11+ Te-130 fusion-evaporation reaction with the HORUS gamma-ray array at the University of Cologne. The high-spin level schemes of Xe-135 and Ba-137 are considerably extended to higher energies. The 2058-keV (19/2(-)) state in Xe-135 is identified as an isomer, closing a gap in the systematics along the N = 81 isotones. Its half-life is measured to be 9.0(9) ns, corresponding to a reduced transition probability of B(E2,19/2(-) -> 15/2(-)) = 0.52(6) W.u. The experimentally deduced reduced transition probabilities of the isomeric states are compared to shell-model predictions. Latest shell-model calculations reproduce the experimental findings generally well and provide guidance to the interpretation of the new levels.
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| 21. |
- Wang, Haidong, et al.
(författare)
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Estimates of global, regional, and national incidence, prevalence, and mortality of HIV, 1980-2015 : the Global Burden of Disease Study 2015.
- 2016
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Ingår i: The lancet. HIV. - : Elsevier. - 2352-3018. ; 3:8, s. e361-e387
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Timely assessment of the burden of HIV/AIDS is essential for policy setting and programme evaluation. In this report from the Global Burden of Disease Study 2015 (GBD 2015), we provide national estimates of levels and trends of HIV/AIDS incidence, prevalence, coverage of antiretroviral therapy (ART), and mortality for 195 countries and territories from 1980 to 2015.METHODS: For countries without high-quality vital registration data, we estimated prevalence and incidence with data from antenatal care clinics and population-based seroprevalence surveys, and with assumptions by age and sex on initial CD4 distribution at infection, CD4 progression rates (probability of progression from higher to lower CD4 cell-count category), on and off antiretroviral therapy (ART) mortality, and mortality from all other causes. Our estimation strategy links the GBD 2015 assessment of all-cause mortality and estimation of incidence and prevalence so that for each draw from the uncertainty distribution all assumptions used in each step are internally consistent. We estimated incidence, prevalence, and death with GBD versions of the Estimation and Projection Package (EPP) and Spectrum software originally developed by the Joint United Nations Programme on HIV/AIDS (UNAIDS). We used an open-source version of EPP and recoded Spectrum for speed, and used updated assumptions from systematic reviews of the literature and GBD demographic data. For countries with high-quality vital registration data, we developed the cohort incidence bias adjustment model to estimate HIV incidence and prevalence largely from the number of deaths caused by HIV recorded in cause-of-death statistics. We corrected these statistics for garbage coding and HIV misclassification.FINDINGS: Global HIV incidence reached its peak in 1997, at 3·3 million new infections (95% uncertainty interval [UI] 3·1-3·4 million). Annual incidence has stayed relatively constant at about 2·6 million per year (range 2·5-2·8 million) since 2005, after a period of fast decline between 1997 and 2005. The number of people living with HIV/AIDS has been steadily increasing and reached 38·8 million (95% UI 37·6-40·4 million) in 2015. At the same time, HIV/AIDS mortality has been declining at a steady pace, from a peak of 1·8 million deaths (95% UI 1·7-1·9 million) in 2005, to 1·2 million deaths (1·1-1·3 million) in 2015. We recorded substantial heterogeneity in the levels and trends of HIV/AIDS across countries. Although many countries have experienced decreases in HIV/AIDS mortality and in annual new infections, other countries have had slowdowns or increases in rates of change in annual new infections.INTERPRETATION: Scale-up of ART and prevention of mother-to-child transmission has been one of the great successes of global health in the past two decades. However, in the past decade, progress in reducing new infections has been slow, development assistance for health devoted to HIV has stagnated, and resources for health in low-income countries have grown slowly. Achievement of the new ambitious goals for HIV enshrined in Sustainable Development Goal 3 and the 90-90-90 UNAIDS targets will be challenging, and will need continued efforts from governments and international agencies in the next 15 years to end AIDS by 2030.
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| 22. |
- Reinke, Beth A, et al.
(författare)
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Diverse aging rates in ectothermic tetrapods provide insights for the evolution of aging and longevity
- 2022
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Ingår i: Science. - : American Association for the Advancement of Science. - 0036-8075 .- 1095-9203. ; 376:6600, s. 1459-1466
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Tidskriftsartikel (refereegranskat)abstract
- Comparative studies of mortality in the wild are necessary to understand the evolution of aging; yet, ectothermic tetrapods are underrepresented in this comparative landscape, despite their suitability for testing evolutionary hypotheses. We present a study of aging rates and longevity across wild tetrapod ectotherms, using data from 107 populations (77 species) of nonavian reptiles and amphibians. We test hypotheses of how thermoregulatory mode, environmental temperature, protective phenotypes, and pace of life history contribute to demographic aging. Controlling for phylogeny and body size, ectotherms display a higher diversity of aging rates compared with endotherms and include phylogenetically widespread evidence of negligible aging. Protective phenotypes and life-history strategies further explain macroevolutionary patterns of aging. Analyzing ectothermic tetrapods in a comparative context enhances our understanding of the evolution of aging.
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| 23. |
- Hakkaart, C, et al.
(författare)
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Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers
- 2022
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Ingår i: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 5:1, s. 1061-
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Tidskriftsartikel (refereegranskat)abstract
- The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09–1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.
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| 24. |
- Manning, Alisa, et al.
(författare)
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A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk
- 2017
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Ingår i: Diabetes. - : AMER DIABETES ASSOC. - 0012-1797 .- 1939-327X. ; 66:7, s. 2019-2032
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Tidskriftsartikel (refereegranskat)abstract
- To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.
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| 25. |
- Newell, Felicity, et al.
(författare)
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Whole-genome landscape of mucosal melanoma reveals diverse drivers and therapeutic targets
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Knowledge of key drivers and therapeutic targets in mucosal melanoma is limited due to the paucity of comprehensive mutation data on this rare tumor type. To better understand the genomic landscape of mucosal melanoma, here we describe whole genome sequencing analysis of 67 tumors and validation of driver gene mutations by exome sequencing of 45 tumors. Tumors have a low point mutation burden and high numbers of structural variants, including recurrent structural rearrangements targeting TERT, CDK4 and MDM2. Significantly mutated genes are NRAS, BRAF, NF1, KIT, SF3B1, TP53, SPRED1, ATRX, HLA-A and CHD8. SF3B1 mutations occur more commonly in female genital and anorectal melanomas and CTNNB1 mutations implicate a role for WNT signaling defects in the genesis of some mucosal melanomas. TERT aberrations and ATRX mutations are associated with alterations in telomere length. Mutation profiles of the majority of mucosal melanomas suggest potential susceptibility to CDK4/6 and/or MEK inhibitors.
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