| 1. |
- Butler-Laporte, G, et al.
(författare)
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Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative
- 2022
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 18:11, s. e1010367-
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Tidskriftsartikel (refereegranskat)abstract
- Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75–10.05, p = 5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.
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| 2. |
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| 4. |
- Margaritte-Jeannin, P, et al.
(författare)
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HLA-DQ relative risks for coeliac disease in European populations: a study of the European Genetics Cluster on Coeliac Disease.
- 2004
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Ingår i: Tissue antigens. - : Wiley. - 0001-2815 .- 1399-0039. ; 63:6, s. 562-7
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Tidskriftsartikel (refereegranskat)abstract
- Coeliac disease is an enteropathy due to an intolerance to gluten. The association between HLA-DQ genes and CD is well established. The majority of patients carry the HLA-DQ heterodimer encoded by DQA1*05/DQB1*02, either in cis or in trans. The remaining patients carry either part of the DQ heterodimer or DQA1*03-DQB1*0302. The aim of the study was to estimate the risks associated with different DQ genotypes in European populations. HLA information was available for 470 trio families from four countries: France (117), Italy (128), and Norway and Sweden (225). Five DQA1-DQB1 haplotypes were considered and control haplotype frequencies were estimated from the set of parental haplotypes not transmitted to the affected child. The possible genotypes were grouped into five genotype groups, based on the hierarchy of risk reported in the literature. A north-south gradient in the genotype group frequencies is observed in probands: homogeneity is strongly rejected between all country pairs. For each country, the relative risks associated with each genotype group were computed taking into account the control haplotype frequencies. Homogeneity of relative risks between countries was tested pairwise by maximum likelihood ratio statistics. The hypothesis of homogeneity of relative risks is rejected (P is approximately 10(-6)) for all country pairs. In conclusion, the gradient in the genotype group frequencies in probands is not only due to differences in haplotype frequencies but also due to differences in genotype relative risks in the studied populations; the relative risks associated with each DQ genotype group are different between northern and southern European countries; neither are they ordered in the same way.
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| 5. |
- Olson, Nathan D., et al.
(författare)
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precisionFDA Truth Challenge V2: Calling variants from short- and long-reads in difficult-to-map regions
- 2020
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The precisionFDA Truth Challenge V2 aimed to assess the state-of-the-art of variant calling in difficult-to-map regions and the Major Histocompatibility Complex (MHC). Starting with FASTQ files, 20 challenge participants applied their variant calling pipelines and submitted 64 variant callsets for one or more sequencing technologies (~35X Illumina, ~35X PacBio HiFi, and ~50X Oxford Nanopore Technologies). Submissions were evaluated following best practices for benchmarking small variants with the new GIAB benchmark sets and genome stratifications. Challenge submissions included a number of innovative methods for all three technologies, with graph-based and machine-learning methods scoring best for short-read and long-read datasets, respectively. New methods out-performed the 2016 Truth Challenge winners, and new machine-learning approaches combining multiple sequencing technologies performed particularly well. Recent developments in sequencing and variant calling have enabled benchmarking variants in challenging genomic regions, paving the way for the identification of previously unknown clinically relevant variants.
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| 6. |
- Olson, Nathan D., et al.
(författare)
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PrecisionFDA Truth Challenge V2: Calling variants from short and long reads in difficult-to-map regions
- 2022
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Ingår i: Cell Genomics. - : Elsevier BV. - 2666-979X. ; 2:5, s. 1-12
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Tidskriftsartikel (refereegranskat)abstract
- The precisionFDA Truth Challenge V2 aimed to assess the state of the art of variant calling in challenging genomic regions. Starting with FASTQs, 20 challenge participants applied their variant-calling pipelines and submitted 64 variant call sets for one or more sequencing technologies (Illumina, PacBio HiFi, and Oxford Nanopore Technologies). Submissions were evaluated following best practices for benchmarking small variants with updated Genome in a Bottle benchmark sets and genome stratifications. Challenge submissions included numerous innovative methods, with graph-based and machine learning methods scoring best for short-read and long-read datasets, respectively. With machine learning approaches, combining multiple sequencing technologies performed particularly well. Recent developments in sequencing and variant calling have enabled benchmarking variants in challenging genomic regions, paving the way for the identification of previously unknown clinically relevant variants.
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| 7. |
- Bernard, J, et al.
(författare)
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A
- 2008
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Ingår i: Rev Sci Instrum. - 0034-6748. ; 79:7, s. 075109-
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Tidskriftsartikel (refereegranskat)
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| 8. |
- Bernard, J., et al.
(författare)
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A ""tabletop"" electrostatic ion storage ring : Mini-Ring
- 2008
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Ingår i: Review of Scientific Instruments. - : AIP Publishing. - 0034-6748 .- 1089-7623. ; 79:7, s. 75109-
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Tidskriftsartikel (refereegranskat)abstract
- We report on the design, construction, and commissioning of a novel electrostatic ion storage ring of small dimensions-in the following referred to as ""Mini-Ring."" Mini-Ring consists of four horizontal parallel-plate deflectors and two conical electrostatic mirrors. Ions are injected through the two deflectors on the injection side and off axis with respect to the conical mirrors which face each other. The first injection deflector, originally at zero voltage, is switched to its set value such that the ions after one turn follow stable trajectories of lengths of roughly 30 cm. This design reduces the number of electrodes necessary to guide the ion beam through the ring in stable orbits. The six elements (deflectors and mirrors) are placed on a common grounded plate-the tabletop. Here, we present the design, ion trajectory simulations, and results of the first test experiments demonstrating the successful room-temperature operation of Mini-Ring at background pressures of 10(-6)-10(-7) mbar.
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| 9. |
- Lévy, Romain, et al.
(författare)
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Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.
- 2023
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Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 220:2
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Tidskriftsartikel (refereegranskat)abstract
- Patients with inherited CARMIL2 or CD28 deficiency have defective T cell CD28 signaling, but their immunological and clinical phenotypes remain largely unknown. We show that only one of three CARMIL2 isoforms is produced and functional across leukocyte subsets. Tested mutant CARMIL2 alleles from 89 patients and 52 families impair canonical NF-κB but not AP-1 and NFAT activation in T cells stimulated via CD28. Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant warts and low blood counts of CD4+ and CD8+ memory T cells and CD4+ TREGs. Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody responses are weak. CARMIL2 deficiency is fully penetrant by the age of 10 yr and is characterized by numerous infections, EBV+ smooth muscle tumors, and mucocutaneous inflammation, including inflammatory bowel disease. Patients with somatic reversions of a mutant allele in CD4+ T cells have milder phenotypes. Our study suggests that CARMIL2 governs immunological pathways beyond CD28.
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