| 1. |
- Turcot, Valerie, et al.
(författare)
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Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
- 2018
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:1, s. 26-41
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are similar to 10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed similar to 7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
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| 2. |
- Lawrenson, Kate, et al.
(författare)
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Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
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| 3. |
- Marouli, Eirini, et al.
(författare)
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Rare and low-frequency coding variants alter human adult height
- 2017
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 542:7640, s. 186-190
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Tidskriftsartikel (refereegranskat)abstract
- Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
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| 4. |
- 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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| 5. |
- Hollestelle, Antoinette, et al.
(författare)
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No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer
- 2016
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Ingår i: Gynecologic Oncology. - : Elsevier BV. - 0090-8258 .- 1095-6859. ; 141:2, s. 386-401
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Tidskriftsartikel (refereegranskat)abstract
- Objective Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3′ UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. Methods Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). Results We found no association with risk of ovarian cancer (OR = 0.99, 95% CI 0.94-1.04, p = 0.74) or breast cancer (OR = 0.98, 95% CI 0.94-1.01, p = 0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR = 1.09, 95% CI 0.97-1.23, p = 0.14, breast cancer HR = 1.04, 95% CI 0.97-1.12, p = 0.27; BRCA2, ovarian cancer HR = 0.89, 95% CI 0.71-1.13, p = 0.34, breast cancer HR = 1.06, 95% CI 0.94-1.19, p = 0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR = 0.94, 95% CI 0.83-1.07, p = 0.38), breast cancer (HR = 0.96, 95% CI 0.87-1.06, p = 0.38), and all other previously-reported associations. Conclusions rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.
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| 6. |
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| 7. |
- Wuttke, Matthias, et al.
(författare)
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A catalog of genetic loci associated with kidney function from analyses of a million individuals
- 2019
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Ingår i: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 51:6, s. 957-972
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Tidskriftsartikel (refereegranskat)abstract
- Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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| 8. |
- Lu, Yingchang, et al.
(författare)
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A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk.
- 2018
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 78:18, s. 5419-5430
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Tidskriftsartikel (refereegranskat)abstract
- .AbstractLarge-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 × 10−6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10−7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 × 10−3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419–30. ©2018 AACR.
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| 9. |
- Battarbee, Richard W., et al.
(författare)
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John Birks: Pioneer in quantitative palaeoecology
- 2015
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Ingår i: The Holocene. - : SAGE Publications. - 0959-6836 .- 1477-0911. ; 25:1, s. 3-16
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Forskningsöversikt (refereegranskat)abstract
- We describe the career of John Birks as a pioneering scientist who has, over a career spanning five decades, transformed palaeoecology from a largely descriptive to a rigorous quantitative science relevant to contemporary questions in ecology and environmental change. We review his influence on students and colleagues not only at Cambridge and Bergen Universities, his places of primary employment, but also on individuals and research groups in Europe and North America. We also introduce the collection of papers that we have assembled in his honour. The papers are written by his former students and close colleagues and span many of the areas of palaeoecology to which John himself has made major contributions. These include the relationship between ecology and palaeoecology, late-glacial and Holocene palaeoecology, ecological succession, climate change and vegetation history, the role of palaeoecological techniques in reconstructing and understanding the impact of human activity on terrestrial and freshwater ecosystems and numerical analysis of multivariate palaeoecological data.
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| 10. |
- Ercan, Ayse Bahar, et al.
(författare)
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Clinical and biological landscape of constitutional mismatch-repair deficiency syndrome: an International Replication Repair Deficiency Consortium cohort study.
- 2024
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Ingår i: The Lancet. Oncology. - 1474-5488. ; 25:5, s. 668-682
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Tidskriftsartikel (refereegranskat)abstract
- Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD.In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions.We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8·9 years (IQR 5·9-12·6), and median follow-up from diagnosis was 7·2 years (3·6-14·8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80-99). Median time between cancer diagnoses for patients with more than one cancer was 1·9 years (IQR 0·8-3·9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30-52] at 10 years from diagnosis; log-rank p<0·0001 across four cancer types), followed by those with haematological cancers (67% [55-82]), gastrointestinal cancers (89% [81-97]), and other solid tumours (96% [88-100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55-73] for PMS2, 49% [35-68] for MSH6, 19% [6-66] for MLH1, and 0% for MSH2; p<0·0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0·0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions.The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD.The Canadian Institutes for Health Research, Stand Up to Cancer, Children's Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan's Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold'em for Life, and Garron Family Cancer Center.
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| 11. |
- Pichora-Fuller, Kathleen M., et al.
(författare)
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Hearing Impairment and Cognitive Energy: The Framework for Understanding Effortful Listening (FUEL)
- 2016
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Ingår i: Ear and Hearing. - : LIPPINCOTT WILLIAMS & WILKINS. - 0196-0202 .- 1538-4667. ; 37, s. 5S-27S
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Tidskriftsartikel (refereegranskat)abstract
- The Fifth Eriksholm Workshop on "Hearing Impairment and Cognitive Energy" was convened to develop a consensus among interdisciplinary experts about what is known on the topic, gaps in knowledge, the use of terminology, priorities for future research, and implications for practice. The general term cognitive energy was chosen to facilitate the broadest possible discussion of the topic. It goes back to Titchener (1908) who described the effects of attention on perception; he used the term psychic energy for the notion that limited mental resources can be flexibly allocated among perceptual and mental activities. The workshop focused on three main areas: (1) theories, models, concepts, definitions, and frameworks; (2) methods and measures; and (3) knowledge translation. We defined effort as the deliberate allocation of mental resources to overcome obstacles in goal pursuit when carrying out a task, with listening effort applying more specifically when tasks involve listening. We adapted Kahnemans seminal (1973) Capacity Model of Attention to listening and proposed a heuristically useful Framework for Understanding Effortful Listening (FUEL). Our FUEL incorporates the well-known relationship between cognitive demand and the supply of cognitive capacity that is the foundation of cognitive theories of attention. Our FUEL also incorporates a motivation dimension based on complementary theories of motivational intensity, adaptive gain control, and optimal performance, fatigue, and pleasure. Using a three-dimensional illustration, we highlight how listening effort depends not only on hearing difficulties and task demands but also on the listeners motivation to expend mental effort in the challenging situations of everyday life.
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| 12. |
- Rijal, Dilli P., et al.
(författare)
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Sedimentary ancient DNA shows terrestrial plant richness continuously increased over the Holocene in northern Fennoscandia
- 2021
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 7:31
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Tidskriftsartikel (refereegranskat)abstract
- The effects of climate change on species richness are debated but can be informed by the past. Here, we generated a sedimentary ancient DNA dataset covering 10 lakes and applied novel methods for data harmonization. We assessed the impact of Holocene climate changes and nutrients on terrestrial plant richness in northern Fennoscandia. We find that richness increased steeply during the rapidly warming Early Holocene. In contrast to findings from most pollen studies, we show that richness continued to increase thereafter, although the climate was stable, with richness and the regional species pool only stabilizing during the past three millennia. Furthermore, overall increases in richness were greater in catchments with higher soil nutrient availability. We suggest that richness will increase with ongoing warming, especially at localities with high nutrient availability and assuming that human activity remains low in the region, although lags of millennia may be expected.
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| 13. |
- Wang, Yucheng, et al.
(författare)
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Late Quaternary Dynamics of Arctic Biota from Ancient Environmental Genomics
- 2021
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 600:7887, s. 86-92
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Tidskriftsartikel (refereegranskat)abstract
- During the last glacial–interglacial cycle, Arctic biotas experienced substantial climatic changes, yet the nature, extent and rate of their responses are not fully understood1–8. Here we report a large-scale environmental DNA metagenomic study of ancient plant and mammal communities, analysing 535 permafrost and lake sediment samples from across the Arctic spanning the past 50,000 years. Furthermore, we present 1,541 contemporary plant genome assemblies that were generated as reference sequences. Our study provides several insights into the long-term dynamics of the Arctic biota at the circumpolar and regional scales. Our key fndings include: (1) a relatively homogeneous steppe–tundra fora dominated the Arctic during the Last Glacial Maximum, followed by regional divergence of vegetation during the Holocene epoch; (2) certain grazing animals consistently co-occurred in space and time; (3) humans appear to have been a minor factor in driving animal distributions; (4) higher efective precipitation, as well as an increase in the proportion of wetland plants, show negative efects on animal diversity; (5) the persistence of the steppe–tundra vegetation in northern Siberia enabled the late survival of several now-extinct megafauna species, including the woolly mammoth until 3.9 ± 0.2 thousand years ago (ka) and the woolly rhinoceros until 9.8 ± 0.2 ka; and (6) phylogenetic analysis of mammoth environmental DNA reveals a previously unsampled mitochondrial lineage. Our fndings highlight the power of ancient environmental metagenomics analyses to advance understanding of population histories and long-term ecological dynamics
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| 14. |
- Wang, Yucheng, et al.
(författare)
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Reply to: When did mammoths go extinct?
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 612:7938, s. 4-6
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Tidskriftsartikel (refereegranskat)
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| 15. |
- Anné, Jennifer, et al.
(författare)
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Independent Evidence for the Preservation of Endogenous Bone Biochemistry in a Specimen of Tyrannosaurus rex
- 2023
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Ingår i: Biology. - : MDPI AG. - 2079-7737. ; 12:2
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Tidskriftsartikel (refereegranskat)abstract
- Biomolecules preserved in deep time have potential to shed light on major evolutionary questions, driving the search for new and more rigorous methods to detect them. Despite the increasing body of evidence from a wide variety of new, high resolution/high sensitivity analytical techniques, this research is commonly met with skepticism, as the long standing dogma persists that such preservation in very deep time (>1 Ma) is unlikely. The Late Cretaceous dinosaur Tyrannosaurus rex (MOR 1125) has been shown, through multiple biochemical studies, to preserve original bone chemistry. Here, we provide additional, independent support that deep time bimolecular preservation is possible. We use synchrotron X-ray fluorescence imaging (XRF) and X-ray absorption spectroscopy (XAS) to investigate a section from the femur of this dinosaur, and demonstrate preservation of elements (S, Ca, and Zn) associated with bone remodeling and redeposition. We then compare these data to the bone of an extant dinosaur (bird), as well as a second non-avian dinosaur, Tenontosaurus tilletti (OMNH 34784) that did not preserve any sign of original biochemistry. Our data indicate that MOR 1125 bone cortices have similar bone elemental distributions to that of an extant bird, which supports preservation of original endogenous chemistry in this specimen.
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| 16. |
- Brehony, Carina, et al.
(författare)
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Implications of Differential Age Distribution of Disease-Associated Meningococcal Lineages for Vaccine Development
- 2014
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Ingår i: Clinical and Vaccine Immunology. - : American Society for Microbiology. - 1556-6811 .- 1556-679X. ; 21:6, s. 847-853
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Tidskriftsartikel (refereegranskat)abstract
- New vaccines targeting meningococci expressing serogroup B polysaccharide have been developed, with some being licensed in Europe. Coverage depends on the distribution of disease-associated genotypes, which may vary by age. It is well established that a small number of hyperinvasive lineages account for most disease, and these lineages are associated with particular antigens, including vaccine candidates. A collection of 4,048 representative meningococcal disease isolates from 18 European countries, collected over a 3-year period, were characterized by multilocus sequence typing (MLST). Age data were available for 3,147 isolates. The proportions of hyperinvasive lineages, identified as particular clonal complexes (ccs) by MLST, differed among age groups. Subjects <1 year of age experienced lower risk of sequence type 11 (ST-11) cc, ST-32 cc, and ST-269 cc disease and higher risk of disease due to unassigned STs, 1- to 4-year-olds experienced lower risk of ST-11 cc and ST-32 cc disease, 5- to 14-year-olds were less likely to experience ST-11 cc and ST-269 cc disease, and >= 25-year-olds were more likely to experience disease due to less common ccs and unassigned STs. Younger and older subjects were vulnerable to a more diverse set of genotypes, indicating the more clonal nature of genotypes affecting adolescents and young adults. Knowledge of temporal and spatial diversity and the dynamics of meningococcal populations is essential for disease control by vaccines, as coverage is lineage specific. The nonrandom age distribution of hyperinvasive lineages has consequences for the design and implementation of vaccines, as different variants, or perhaps targets, may be required for different age groups.
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| 17. |
- Dar, Pe'er, et al.
(författare)
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Cell-free DNA screening for prenatal detection of 22q11.2 deletion syndrome.
- 2022
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Ingår i: American journal of obstetrics and gynecology. - : Elsevier BV. - 1097-6868 .- 0002-9378. ; 227:1
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Tidskriftsartikel (refereegranskat)abstract
- Prenatal screening has historically focused primarily on detection of fetal aneuploidies. Cell-free DNA (cfDNA) now enables noninvasive screening for subchromosomal copy number variants, including 22q11.2 deletion syndrome (22q11.2DS or DiGeorge syndrome), which is the most common microdeletion and a leading cause of congenital heart defects and neurodevelopmental delay. Although smaller studies have demonstrated the feasibility of screening for 22q11.2DS, large cohort studies with postnatal confirmatory testing to assess test performance have not been reported.To assess the performance of SNP-based cfDNA prenatal screening for detection of 22q11.2DS.Patients who had SNP-based cfDNA prenatal screening for 22q11.2DS were prospectively enrolled at 21 centers in 6 countries. Prenatal or newborn DNA samples were requested in all cases for genetic confirmation with chromosomal microarray. The primary outcome was sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of cfDNA for detection of all deletions, including the classical deletion and nested deletions that are ≥500kb, in the 22q11.2 low copy repeat A-D region. Secondary outcomes included the prevalence of 22q11.2DS and performance of an updated cfDNA algorithm that was evaluated blinded to pregnancy outcome.Of 20,887 women enrolled, genetic outcome was available in 18,289 (87.6%). Twelve 22q11.2DS cases were confirmed in the cohort, including five (41.7%) nested deletions, yielding a prevalence of 1:1524. In the total cohort, cfDNA reported 17,976 (98.3%) as low risk for 22q11.2DS and 38 (0.2%) as high-risk; 275 (1.5%) were non-reportable. Overall, 9 of 12 cases of 22q11.2 were detected, yielding a sensitivity of 75.0% (95% CI: 42.8, 94.5); specificity of 99.84% (95% CI: 99.77, 99.89); PPV of 23.7% (95% CI: 11.44, 40.24) and NPV of 99.98% (95% CI: 99.95, 100). None of the cases with a non-reportable result was diagnosed with 22q11.2DS. The updated algorithm detected 10/12 cases (83.3%; 95% CI: 51.6-97.9) with a lower false positive rate (0.05% vs. 0.16%, p<0.001) and a PPV of 52.6% (10/19; 95% CI 28.9-75.6).Noninvasive cfDNA prenatal screening for 22q11.2DS can detect most affected cases, including smaller nested deletions, with a low false positive rate.
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| 18. |
- Dar, Pe'er, et al.
(författare)
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Cell-free DNA screening for trisomies 21, 18 and 13 in pregnancies at low and high risk for aneuploidy with genetic confirmation
- 2022
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Ingår i: American journal of obstetrics and gynecology. - : Elsevier BV. - 1097-6868 .- 0002-9378. ; 227:2
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Tidskriftsartikel (refereegranskat)abstract
- Cell-free DNA (cfDNA) non-invasive prenatal screening for trisomy (T) 21, 18, and 13 has been rapidly adopted into clinical practice. However, prior studies are limited by lack of follow up genetic testing to confirm outcomes and accurately assess test performance, particularly in women at low-risk for aneuploidy.To compare the performance of cfDNA screening for T21, T18 and T13 between women at low and high-risk for aneuploidy in a large, prospective cohort with genetic confirmation of results.A multicenter prospective observational study at 21 centers in 6 countries. Women who had SNP-based cfDNA screening for T21, T18 and T13 were enrolled. Genetic confirmation was obtained from prenatal or newborn DNA samples. Test performance and test failure (no-call) rates were assessed for the cohort and women with low and high prior risk for aneuploidy were compared. An updated cfDNA algorithm, blinded to pregnancy outcome, was also assessed.20,194 were enrolled at median gestational age of 12.6 weeks (IQR:11.6, 13.9). Genetic outcomes were confirmed in 17,851 (88.4%): 13,043 (73.1%) low-risk and 4,808 (26.9%) high-risk for aneuploidy. Overall, 133 trisomies were diagnosed (100 T21; 18 T18; 15 T13). cfDNA screen positive rate was lower in low- vs. high-risk (0.27% vs. 2.2%, p<0.0001). Sensitivity and specificity were similar between groups. The positive predictive value (PPV) for the low and high-risk groups was 85.7% vs. 97.5%, p=0.058 for T21; 50.0% vs. 81.3%, p=0.283 for T18; and 62.5% vs. 83.3, p=0.58 for T13, respectively. Overall, 602 (3.4%) patients had no-call result after the first draw and 287 (1.61%) after including cases with a second draw. Trisomy rate was higher in the 287 with no-call results than patients with a result on a first draw (2.8% vs. 0.7%, p=0.001). The updated algorithm showed similar sensitivity and specificity to the study algorhitm with a lower no-call rate.In women at low-risk for aneuploidy, SNP-based cfDNA has high sensitivity and specificity, PPV of 85.7% for T21 and 74.3% for the three common trisomies. Patients who receive a no-call result are at increased risk of aneuploidy and require additional investigation.
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| 19. |
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| 20. |
- Li, Furong, 1986-
(författare)
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Pollen productivity estimates and pollen-based reconstructions of Holocene vegetation cover in Northern and temperate China for climate modelling
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Model projections of future climate change require that coupled climate-vegetation models are developed and validated, i.e. these models should be able to reproduce past climate and vegetation change. Records of pollen deposited in lake bottoms and peat bogs can provide the information needed to validate these models. The aim of this thesis was i) to explore the modern relationships between pollen and vegetation in northern and temperate China and estimate pollen productivity of major plant taxa, and ii) to use the results of i) to produce the first reconstruction of plant cover in China over the last 10 000 years for the purpose of climate modelling. A study of the modern pollen-vegetation-climate relationships was performed in northwestern China (Paper I). Pollen productivity for 18 major plants of cultural landscapes in central-eastern China was estimated (Paper II). Based on a synthesis and evaluation of all existing estimates of pollen productivity in the study region, a standard dataset of pollen productivity for 31 plant taxa is proposed (Paper III). This dataset was used to achieve pollen-based REVEALS reconstructions of plant cover over the last 10 000 years in 35 regions of northern and temperate China (Paper IV). The major findings can be summarized as follows. Paper I: Annual precipitation (Pann) is the major climatic factor influencing pollen assemblages, followed by July precipitation (PJul). The shared effect of combinations of two climatic factors explains a larger portion of the variation in pollen data than individual variables. Paper II: Of the 16 reliable pollen productivities estimated, the estimates for 8 taxa are new, Castanea, Cupressaceae, Robinia/Sophora, Anthemis type/Aster type, Cannabis/Humulus, Caryophyllaceae, Cruciferae, and Galium type. Trees have in general larger pollen productivity than herbs. Paper III: Of the total 31 taxa for which estimates of pollen productivity are available in China, 13 taxa have more than 1 value. All or most of these values are similar for Artemisia, Cyperaceae, Larix, Quercus and Pinus. Eight taxa have very variable estimates. Paper IV: The REVEALS plant percentage-cover strongly differs from the pollen percentages, and they provide new important insights on past changes in plant composition and vegetation dynamics.
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| 21. |
- Parducci, Laura, et al.
(författare)
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Glacial Survival of Boreal Trees in Northern Scandinavia
- 2012
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 335:6072, s. 1083-1086
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Tidskriftsartikel (refereegranskat)abstract
- It is commonly believed that trees were absent in Scandinavia during the last glaciation and first recolonized the Scandinavian Peninsula with the retreat of its ice sheet some 9000 years ago. Here, we show the presence of a rare mitochondrial DNA haplotype of spruce that appears unique to Scandinavia and with its highest frequency to the west-an area believed to sustain ice-free refugia during most of the last ice age. We further show the survival of DNA from this haplotype in lake sediments and pollen of Trondelag in central Norway dating back similar to 10,300 years and chloroplast DNA of pine and spruce in lake sediments adjacent to the ice-free Andoya refugium in northwestern Norway as early as similar to 22,000 and 17,700 years ago, respectively. Our findings imply that conifer trees survived in ice-free refugia of Scandinavia during the last glaciation, challenging current views on survival and spread of trees as a response to climate changes.
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| 22. |
- Parducci, Laura, et al.
(författare)
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Response to Comment on "Glacial Survival of Boreal Trees in Northern Scandinavia"
- 2012
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 338:6108, s. 742-
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Birks et al. question our proposition that trees survived the Last Glacial Maximum (LGM) in Northern Scandinavia. We dispute their interpretation of our modern genetic data but agree that more work is required. Our field and laboratory procedures were robust; contamination is an unlikely explanation of our results. Their description of Endletvatn as ice-covered and inundated during the LGM is inconsistent with recent geological literature.
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| 23. |
- Walentowitz, Anna, et al.
(författare)
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Long-term trajectories of non-native vegetation on islands globally
- 2023
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Ingår i: Ecology Letters. - : Wiley. - 1461-023X .- 1461-0248. ; 26:5, s. 729-741
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Tidskriftsartikel (refereegranskat)abstract
- Human-mediated changes in island vegetation are, among others, largely caused by the introduction and establishment of non-native species. However, data on past changes in non-native plant species abundance that predate historical documentation and censuses are scarce. Islands are among the few places where we can track human arrival in natural systems allowing us to reveal changes in vegetation dynamics with the arrival of non-native species. We matched fossil pollen data with botanical status information (native, non-native), and quantified the timing, trajectories and magnitude of non-native plant vegetational change on 29 islands over the past 5000 years. We recorded a proportional increase in pollen of non-native plant taxa within the last 1000 years. Individual island trajectories are context-dependent and linked to island settlement histories. Our data show that non-native plant introductions have a longer and more dynamic history than is generally recognized, with critical implications for biodiversity baselines and invasion biology.
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