| 1. |
- Fresard, Laure, et al.
(författare)
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Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts
- 2019
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Ingår i: Nature Medicine. - : NATURE PUBLISHING GROUP. - 1078-8956 .- 1546-170X. ; 25:6, s. 911-919
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Tidskriftsartikel (refereegranskat)abstract
- It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene(1). The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches(2-5). For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases(6-8). This includes muscle biopsies from patients with undiagnosed rare muscle disorders(6,9), and cultured fibroblasts from patients with mitochondrial disorders(7). However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution.
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| 2. |
- Wang, Zhaoming, et al.
(författare)
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Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:24, s. 6616-6633
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
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| 3. |
- Ahrens, Lutz, et al.
(författare)
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Analysis of per- and polyfluoroalkyl substances (PFASs) and phenolic compounds in Swedish rivers over four different seasons
- 2018
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Syftet med denna studie var att undersöka miljökoncentrationer, sammansättning, säsongsvariationoch flöden av 28 PFAS-substanser och 10 fenolära ämnen i 10 svenska vattendrag över fyra olikaårstider (oktober 2016, januari 2017, april 2017 och juli 2017). Totalt detekterades 7 av 28 PFASämneni relativt låga nivåer (i genomsnitt 3,2 ng per liter för Σ28PFAS) i flodvatten (n = 40).Koncentrationerna av de fenolära föreningarna var generellt högre (genomsnittshalt 230 ng per literför summan av alla fenoler som mättes; n = 38). Detektionsfrekvensen var dock låg (i genomsnitt50%), vilket resulterade i låga mediankoncentrationer för summahalten (0 ng per liter). Dedominerande PFAS-substanserna var perfluorbutansulfonsyra (PFBS, 38% av Σ28PFAS),perfluoroktansyra (PFOA, 21%) och perfluoroktansulfonsyra (PFOS (grenad), 8,9%) medan dedominerande fenolära föreningarna var 4-nonylfenol (4-NP, 67%), 4-tert-nonylfenol-dietoxilat (4-NP-EO2, 20%) och 2,4,6-tribromfenol (TBP, 10%). Koncentrationerna av PFAS och fenolföreningaruppvisade ingen säsongsvariation under de fyra undersökta årstiderna, vilket indikerar ett relativtstabilt flöde av dessa två ämnesklasser till vattendragen. De uppmätta PFAS-koncentrationerna varinte relaterade till koncentrationerna av fenolära föreningarna, vilket indikerar olika källor för de tvåämnesklasserna. Flödena för totalhalterna uppskattades till 220 g per dag (81 kg per år) för Σ28PFAS,och >70 gånger högre för de fenolära ämnena med totalflöden på 16000 g per dag (5700 kg per år).Miljökvalitetsstandarden för ett årligt genomsnitt (AA-EQS) som anges i EU: s ramdirektiv förvatten (WFD) överskreds för 33% (n = 13) av vattenproverna för summan av linjära och grenadePFOS och för 13% (n = 5) av för 4-NP. Detta indikerar att halterna av PFOS och 4-NP utgör enpotentiell risk för vattenmiljön. AA-EQS för 4-oktylfenol (4-OP) och pentaklorfenol (PCP)överskreds inte i något fall.vatten (WFD) överskreds för 33% (n = 13) av vattenproverna för summan av linjära och grenadePFOS och för 13% (n = 5) av för 4-NP. Detta indikerar att halterna av PFOS och 4-NP utgör enpotentiell risk för vattenmiljön. AA-EQS för 4-oktylfenol (4-OP) och pentaklorfenol (PCP)överskreds inte i något fall.
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| 4. |
- Ahrens, Lutz, et al.
(författare)
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Analysis of per- and polyfluoroalkyl substances (PFASs) and phenolic compounds in Swedish rivers over four different seasons
- 2018
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Per- and polyfluoroalkyl substances (PFASs) and phenolic compounds are emerging organic pollutants characterized by their persistency, bioaccumulation and toxicity potential. In this study, 28 PFASs and 10 phenolic compounds were investigated in 10 Swedish rivers over four different seasons (October 2016, January 2017, April 2017 and July 2017). The objective was to investigate the levels, composition profiles, sesonal trends and fluxes for both compound classes. In total, 7 out of 28 PFASs and 9 out of 10 phenolic compounds were detected in surface water from the 10 rivers. The average concentration in all samples was 3.2 ng L-1 for ∑28PFASs (median 2.4 ng L-1, n = 40), while 230 ng L-1 for the sum of the phenolic compounds (median 0 ng L-1, n = 38). Highest average ∑28PFAS concentrations were found in Rönneån with 10 ng L-1 (median 11 ng L-1), followed by Norrström with 9.0 ng L-1 (median 9.1 ng L-1), whereas no PFASs were detected in Umeå älv and Ångermanälven. On the other hand, highest average of the sum of the phenolic compound concentrations were found in Nyköpingsån with 1500 ng L-1 (median 57 ng L-1), while for the other rivers the average ranged between 50 ng L-1 and 140 ng L-1, except for Emån where TBP was only detected in one sample with 0.33 ng L-1. This indicates that PFASs and phenolic compounds origin from different sources. The dominant PFASs were perfluorobutane sulfonic acid (PFBS, 38 % of the ∑28PFASs), perfluorooctanoic acid (PFOA, 21 %), and perfluorooctane sulfonic acid (PFOS (branched), 8.9 %), while the dominant phenolic compounds were 4nonylphenol (4-NP, 67 %), 4-tert-nonylphenol-diethoxylate (4-NP-EO2, 20 %), and 2,4,6tribromophenol (TBP, 10 %). The concentrations of PFASs and phenolic compounds were relatively constant during the four investigated seasons which indicates a relatively steady input of these two compound classes into the river systems. The daily fluxes of Σ28PFAS was estimated to be in total 220 g d-1 (81 kg year-1), whereas the daily fluxes of phenolic compounds was estimated to be 16000 g d-1 (5700 kg year-1) for all 10 investigated rivers. The Annual Average Environmental Quality Standard (AA-EQS) of the EU Water Framework Directive (WFD) was exceeded in 33% (n = 13) of the surface water samples for the sum of linear and branched PFOS and in 13% (n = 5) of the surface water samples for 4NP. This indicates that there is a potential risk for the aquatic environment. The AA-EQS of 4-octylphenol (4-OP) and pentachlorophenol (PCP) was not exceeded in any surface water sample.
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| 5. |
- Buchanan, James, et al.
(författare)
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Factor's that impact on women's decision-making around prenatal genomic tests : An international discrete choice survey
- 2022
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Ingår i: Prenatal Diagnosis. - : John Wiley & Sons. - 0197-3851 .- 1097-0223. ; 42:7, s. 934-946
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Tidskriftsartikel (refereegranskat)abstract
- Objective We conducted a survey-based discrete-choice experiment (DCE) to understand the test features that drive women's preferences for prenatal genomic testing, and explore variation across countries. Methods Five test attributes were identified as being important for decision-making through a literature review, qualitative interviews and quantitative scoring exercise. Twelve scenarios were constructed in which respondents choose between two invasive tests or no test. Women from eight countries who delivered a baby in the previous 24 months completed a DCE presenting these scenarios. Choices were modeled using conditional logit regression analysis. Results Surveys from 1239 women (Australia: n = 178; China: n = 179; Denmark: n = 88; Netherlands: n = 177; Singapore: n = 90; Sweden: n = 178; UK: n = 174; USA: n = 175) were analyzed. The key attribute affecting preferences was a test with the highest diagnostic yield (p < 0.01). Women preferred tests with short turnaround times (p < 0.01), and tests reporting variants of uncertain significance (VUS; p < 0.01) and secondary findings (SFs; p < 0.01). Several country-specific differences were identified, including time to get a result, who explains the result, and the return of VUS and SFs. Conclusion Most women want maximum information from prenatal genomic tests, but our findings highlight country-based differences. Global consensus on how to return uncertain results is not necessarily realistic or desirable.
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| 6. |
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| 7. |
- Dahlberg, Anna-Karin, 1982-, et al.
(författare)
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Persistent organic pollutants in wood fiber–contaminated sediments from the Baltic Sea
- 2020
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Ingår i: Journal of Soils and Sediments. - : Springer Science and Business Media LLC. - 1439-0108 .- 1614-7480. ; 20:5, s. 2471-2483
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Tidskriftsartikel (refereegranskat)abstract
- Many coastal areas in the Baltic Sea are contaminated with wood fiber and pollutants from pulp and paper industries. These anthropogenic, organic-rich, sediments (fiberbanks) have not been characterized and knowledge about their role as secondary sources for dispersal of persistent organic pollutants (POPs) is limited. Hence, the aim of this study was to elucidate the fate of POPs and the relationships between sorption (KD and KTOC), sediment type, and compound hydrophobicity (KOW) in fiber-contaminated sediments.
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| 8. |
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| 9. |
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| 10. |
- Hau, Stephan, 1960-, et al.
(författare)
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Die Frankfurter Präventionsstudie. Zur psychischen und psychosozialen Integration von verhaltensauffälligen Kindern (insbesondere von ADHS) im Kindergartenalter - ein Arbeitsbericht.
- 2006
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Ingår i: ADHS - Frühprävention statt Medikalisierung. Theorie, Forschung, Kontroversen.. - Göttingen : Vandenhoeck & Ruprecht. - 9783525451786 - 3525451784 ; , s. 238-269
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Wie soll ADHS behandelt werden? Dieses Buch setzt sich auf fachlich-wissenschaftlicher Ebene sowohl mit der Diagnose als auch mit der Behandlung von ADHS auseinander. Die einen plädieren für einen verstehenden und therapeutischen Umgang mit dem betroffenen Kind, während andere in einer medikamentösen Behandlung das Mittel der Wahl sehen.Das Aufmerksamkeits-Defizit-Hyperaktivitäts-Syndrom (ADHS) ist heutzutage eine weitverbreitete Diagnose, mancherorts für fast alle kindlichen Schwierigkeiten im Vorschul- und Grundschulalter. Die Erklärungen reichen von Störungen des Hirnstoffwechsels, Frühverwahrlosungen, psychischen oder psychosozialen Regulationsstörungen bis hin zu Hochbegabungen. Bei den Präventions- und Therapieangeboten gehen die Empfehlungen weit auseinander. Für die einen ist ein verstehender Zugang zum einzelnen Kind und seiner Lebenssituation der richtige Weg, während andere in einer medikamentösen Behandlung die Lösung des Problems sehen. Diese Sichtweise hat in den letzten zehn Jahren enormen Auftrieb erhalten. Die Autoren dieses Bandes problematisieren und diskutieren eine drohende Medikalisierung sozialer Probleme. Sie greifen aktuelle Kontroversen auf und plädieren für eine sorgfältige Diagnostik sowie für eine professionelle Zusammenarbeit aller beteiligten Experten bei der Therapie der betroffenen Kinder.
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