| 1. |
- Lange, Leslie A, et al.
(författare)
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Whole-Exome Sequencing Identifies Rare and Low-Frequency Coding Variants Associated with LDL Cholesterol.
- 2014
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 94:2, s. 233-245
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Tidskriftsartikel (refereegranskat)abstract
- Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or <2(nd) percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.
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| 2. |
- Bentley, Michael J., et al.
(författare)
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A community-based geological reconstruction of Antarctic Ice Sheet deglaciation since the Last Glacial Maximum
- 2014
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Ingår i: Quaternary Science Reviews. - : Elsevier BV. - 0277-3791 .- 1873-457X. ; 100, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- A robust understanding of Antarctic Ice Sheet deglacial history since the Last Glacial Maximum is important in order to constrain ice sheet and glacial-isostatic adjustment models, and to explore the forcing mechanisms responsible for ice sheet retreat. Such understanding can be derived from a broad range of geological and glaciological datasets and recent decades have seen an upsurge in such data gathering around the continent and Sub-Antarctic islands. Here, we report a new synthesis of those datasets, based on an accompanying series of reviews of the geological data, organised by sector. We present a series of timeslice maps for 20 ka, 15 ka, 10 ka and 5 ka, including grounding line position and ice sheet thickness changes, along with a clear assessment of levels of confidence. The reconstruction shows that the Antarctic Ice sheet did not everywhere reach the continental shelf edge at its maximum, that initial retreat was asynchronous, and that the spatial pattern of deglaciation was highly variable, particularly on the inner shelf. The deglacial reconstruction is consistent with a moderate overall excess ice volume and with a relatively small Antarctic contribution to meltwater pulse la. We discuss key areas of uncertainty both around the continent and by time interval, and we highlight potential priorities for future work. The synthesis is intended to be a resource for the modelling and glacial geological community.
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| 3. |
- Estrada, Karol, et al.
(författare)
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Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.
- 2012
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:5, s. 491-501
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Tidskriftsartikel (refereegranskat)abstract
- Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
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| 4. |
- Fouhy, Fiona, et al.
(författare)
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High-throughput sequencing reveals the incomplete, short-term recovery of infant gut microbiota following parenteral antibiotic treatment with ampicillin and gentamicin
- 2012
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Ingår i: Antimicrobial Agents and Chemotherapy. - Washington, USA : American Society for Microbiology. - 0066-4804 .- 1098-6596. ; 56:11, s. 5811-5820
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Tidskriftsartikel (refereegranskat)abstract
- The infant gut microbiota undergoes dramatic changes during the first 2 years of life. The acquisition and development of this population can be influenced by numerous factors, and antibiotic treatment has been suggested as one of the most significant. Despite this, however, there have been relatively few studies which have investigated the short-term recovery of the infant gut microbiota following antibiotic treatment. The aim of this study was to use high-throughput sequencing (employing both 16S rRNA and rpoB-specific primers) and quantitative PCR to compare the gut microbiota of nine infants who underwent parenteral antibiotic treatment with ampicillin and gentamicin (within 48 h of birth), 4 and 8 weeks after the conclusion of treatment, relative to that of nine matched healthy controls. The investigation revealed that the gut microbiota of the antibiotic-treated infants had significantly higher proportions of Proteobacteria (P = 0.0049) and significantly lower proportions of Actinobacteria (P = 0.00001) (and the associated genus Bifidobacterium [P = 0.0132]) as well as the genus Lactobacillus (P = 0.0182) than the untreated controls 4 weeks after the cessation of treatment. By week 8, the Proteobacteria levels remained significantly higher in the treated infants (P = 0.0049), but the Actinobacteria, Bifidobacterium, and Lactobacillus levels had recovered and were similar to those in the control samples. Despite this recovery of total Bifidobacterium numbers, rpoB-targeted pyrosequencing revealed that the number of different Bifidobacterium species present in the antibiotic-treated infants was reduced. It is thus apparent that the combined use of ampicillin and gentamicin in early life can have significant effects on the evolution of the infant gut microbiota, the long-term health implications of which remain unknown.
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| 5. |
- Kiemeney, Lambertus A, et al.
(författare)
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A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer.
- 2010
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 42:5, s. 415-9
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Tidskriftsartikel (refereegranskat)abstract
- Previously, we reported germline DNA variants associated with risk of urinary bladder cancer (UBC) in Dutch and Icelandic subjects. Here we expanded the Icelandic sample set and tested the top 20 markers from the combined analysis in several European case-control sample sets, with a total of 4,739 cases and 45,549 controls. The T allele of rs798766 on 4p16.3 was found to associate with UBC (odds ratio = 1.24, P = 9.9 x 10(-12)). rs798766 is located in an intron of TACC3, 70 kb from FGFR3, which often harbors activating somatic mutations in low-grade, noninvasive UBC. Notably, rs798766[T] shows stronger association with low-grade and low-stage UBC than with more aggressive forms of the disease and is associated with higher risk of recurrence in low-grade stage Ta tumors. The frequency of rs798766[T] is higher in Ta tumors that carry an activating mutation in FGFR3 than in Ta tumors with wild-type FGFR3. Our results show a link between germline variants, somatic mutations of FGFR3 and risk of UBC.
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| 6. |
- Makarova, Kira S, et al.
(författare)
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Evolution and classification of the CRISPR-Cas systems
- 2011
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Ingår i: Nature Reviews Microbiology. - : Nature Publishing Group. - 1740-1526 .- 1740-1534. ; 9:6, s. 467-477
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Tidskriftsartikel (refereegranskat)abstract
- The CRISPR-Cas (clustered regularly interspaced short palindromic repeats-CRISPR-associated proteins) modules are adaptive immunity systems that are present in many archaea and bacteria. These defence systems are encoded by operons that have an extraordinarily diverse architecture and a high rate of evolution for both the cas genes and the unique spacer content. Here, we provide an updated analysis of the evolutionary relationships between CRISPR-Cas systems and Cas proteins. Three major types of CRISPR-Cas system are delineated, with a further division into several subtypes and a few chimeric variants. Given the complexity of the genomic architectures and the extremely dynamic evolution of the CRISPR-Cas systems, a unified classification of these systems should be based on multiple criteria. Accordingly, we propose a 'polythetic' classification that integrates the phylogenies of the most common cas genes, the sequence and organization of the CRISPR repeats and the architecture of the CRISPR-cas loci.
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| 7. |
- Quax, Tessa E. F., et al.
(författare)
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Differential Translation Tunes Uneven Production of Operon-Encoded Proteins
- 2013
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 4:5, s. 938-944
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Tidskriftsartikel (refereegranskat)abstract
- Clustering of functionally related genes in operons allows for coregulated gene expression in prokaryotes. This is advantageous when equal amounts of gene products are required. Production of protein complexes with an uneven stoichiometry, however, requires tuning mechanisms to generate subunits in appropriate relative quantities. Using comparative genomic analysis, we show that differential translation is a key determinant of modulated expression of genes clustered in operons and that codon bias generally is the best in silico indicator of unequal protein production. Variable ribosome density profiles of polycistronic transcripts correlate strongly with differential translation patterns. In addition, we provide experimental evidence that de novo initiation of translation can occur at intercistronic sites, allowing for differential translation of any gene irrespective of its position on a polycistronic messenger. Thus, modulation of translation efficiency appears to be a universal mode of control in bacteria and archaea that allows for differential production of operon-encoded proteins.
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| 8. |
- Roy, Sushmita, et al.
(författare)
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Identification of functional elements and regulatory circuits by Drosophila modENCODE.
- 2010
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Ingår i: Science (New York, N.Y.). - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 330:6012, s. 1787-1797
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Tidskriftsartikel (refereegranskat)abstract
- To gain insight into how genomic information is translated into cellular and developmental programs, the Drosophila model organism Encyclopedia of DNA Elements (modENCODE) project is comprehensively mapping transcripts, histone modifications, chromosomal proteins, transcription factors, replication proteins and intermediates, and nucleosome properties across a developmental time course and in multiple cell lines. We have generated more than 700 data sets and discovered protein-coding, noncoding, RNA regulatory, replication, and chromatin elements, more than tripling the annotated portion of the Drosophila genome. Correlated activity patterns of these elements reveal a functional regulatory network, which predicts putative new functions for genes, reveals stage- and tissue-specific regulators, and enables gene-expression prediction. Our results provide a foundation for directed experimental and computational studies in Drosophila and related species and also a model for systematic data integration toward comprehensive genomic and functional annotation.
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| 9. |
- Stacey, Simon N, et al.
(författare)
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A germline variant in the TP53 polyadenylation signal confers cancer susceptibility.
- 2011
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 43:11, s. 1098-103
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Tidskriftsartikel (refereegranskat)abstract
- To identify new risk variants for cutaneous basal cell carcinoma, we performed a genome-wide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders. We imputed genotypes for 41,675 Illumina SNP chip-typed Icelanders and their relatives. In the discovery phase, the strongest signal came from rs78378222[C] (odds ratio (OR) = 2.36, P = 5.2 × 10(-17)), which has a frequency of 0.0192 in the Icelandic population. We then confirmed this association in non-Icelandic samples (OR = 1.75, P = 0.0060; overall OR = 2.16, P = 2.2 × 10(-20)). rs78378222 is in the 3' untranslated region of TP53 and changes the AATAAA polyadenylation signal to AATACA, resulting in impaired 3'-end processing of TP53 mRNA. Investigation of other tumor types identified associations of this SNP with prostate cancer (OR = 1.44, P = 2.4 × 10(-6)), glioma (OR = 2.35, P = 1.0 × 10(-5)) and colorectal adenoma (OR = 1.39, P = 1.6 × 10(-4)). However, we observed no effect for breast cancer, a common Li-Fraumeni syndrome tumor (OR = 1.06, P = 0.57, 95% confidence interval 0.88-1.27).
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| 10. |
- Wang, Thomas J., et al.
(författare)
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Metabolite profiles and the risk of developing diabetes
- 2011
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 17:4, s. 83-448
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Tidskriftsartikel (refereegranskat)abstract
- Emerging technologies allow the high-throughput profiling of metabolic status from a blood specimen (metabolomics). We investigated whether metabolite profiles could predict the development of diabetes. Among 2,422 normoglycemic individuals followed for 12 years, 201 developed diabetes. Amino acids, amines and other polar metabolites were profiled in baseline specimens by liquid chromatography-tandem mass spectrometry (LC-MS). Cases and controls were matched for age, body mass index and fasting glucose. Five branched-chain and aromatic amino acids had highly significant associations with future diabetes: isoleucine, leucine, valine, tyrosine and phenylalanine. A combination of three amino acids predicted future diabetes (with a more than fivefold higher risk for individuals in top quartile). The results were replicated in an independent, prospective cohort. These findings underscore the potential key role of amino acid metabolism early in the pathogenesis of diabetes and suggest that amino acid profiles could aid in diabetes risk assessment.
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