| 21. |
- Stuart, Philip E., et al.
(författare)
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Genome-wide Association Analysis of Psoriatic Arthritis and Cutaneous Psoriasis Reveals Differences in Their Genetic Architecture
- 2015
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Ingår i: American Journal of Human Genetics. - : CELL PRESS. - 0002-9297 .- 1537-6605. ; 97:6, s. 816-836
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Tidskriftsartikel (refereegranskat)abstract
- Psoriasis vulgaris (PsV) is a common inflammatory and hyperproliferative skin disease. Up to 30% of people with PsV eventually develop psoriatic arthritis (PsA), an inflammatory musculoskeletal condition. To discern differences in genetic risk factors for PsA and cutaneous-only psoriasis (PsC), we carried out a genome-wide association study (GWAS) of 1,430 PsA case subjects and 1,417 unaffected control subjects. Meta-analysis of this study with three other GWASs and two targeted genotyping studies, encompassing a total of 9,293 PsV case subjects, 3,061 PsA case subjects, 3,110 PsC case subjects, and 13,670 unaffected control subjects of European descent, detected 10 regions associated with PsA and 11 with PsC at genome-wide (GW) significance. Several of these association signals (IFNLR1, IFIH1, NFKBIA for PsA; TNFRSF9, LCE3C/B, TRAF3IP2, IL23A, NFKBIA for PsC) have not previously achieved GW significance. After replication, we also identified a PsV-associated SNP near CDKAL1 (rs4712528, odds ratio [OR] = 1.16, p = 8.4 x 10(-11)). Among identified psoriasis risk variants, three were more strongly associated with PsC than PsA (rs12189871 near HLA-C, p = 5.0 x 10(-19); rs4908742 near TNFRSF9, p = 0.00020; rs10888503 near LCE3A, p = 0.0014), and two were more strongly associated with PsA than PsC (rs12044149 near IL23R, p = 0.00018; rs9321623 near TNFAIP3, p = 0.00022). The PsA-specific variants were independent of previously identified psoriasis variants near IL23R and TNFAIP3. We also found multiple independent susceptibility variants in the IL12B, NOS2, and IFIH1 regions. These results provide insights into the pathogenetic similarities and differences between PsC and PsA.
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| 22. |
- Tsoi, Lam C., et al.
(författare)
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Enhanced meta-analysis and replication studies identify five new psoriasis susceptibility loci
- 2015
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Ingår i: Nature Communications. - : Nature Publishing Group: Nature Communications. - 2041-1723. ; 6:7001
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Tidskriftsartikel (refereegranskat)abstract
- Psoriasis is a chronic autoimmune disease with complex genetic architecture. Previous genome-wide association studies (GWAS) and a recent meta-analysis using Immunochip data have uncovered 36 susceptibility loci. Here, we extend our previous meta-analysis of European ancestry by refined genotype calling and imputation and by the addition of 5,033 cases and 5,707 controls. The combined analysis, consisting of over 15,000 cases and 27,000 controls, identifies five new psoriasis susceptibility loci at genome-wide significance (Pless than5 x 10(-8)). The newly identified signals include two that reside in intergenic regions (1q31.1 and 5p13.1) and three residing near PLCL2 (3p24.3), NFKBIZ (3q12.3) and CAMK2G (10q22.2). We further demonstrate that NFKBIZ is a TRAF3IP2-dependent target of IL-17 signalling in human skin keratinocytes, thereby functionally linking two strong candidate genes. These results further integrate the genetics and immunology of psoriasis, suggesting new avenues for functional analysis and improved therapies.
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| 23. |
- Tsoi, Lam C., et al.
(författare)
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Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants
- 2017
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Psoriasis is a complex disease of skin with a prevalence of about 2%. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for psoriasis to date, including data from eight different Caucasian cohorts, with a combined effective sample size amp;gt;39,000 individuals. We identified 16 additional psoriasis susceptibility loci achieving genome-wide significance, increasing the number of identified loci to 63 for European-origin individuals. Functional analysis highlighted the roles of interferon signalling and the NFkB cascade, and we showed that the psoriasis signals are enriched in regulatory elements from different T cells (CD8(+) T-cells and CD4(+) T-cells including T(H)0, T(H)1 and T(H)17). The identified loci explain similar to 28% of the genetic heritability and generate a discriminatory genetic risk score (AUC = 0.76 in our sample) that is significantly correlated with age at onset (p = 2 x 10(-89)). This study provides a comprehensive layout for the genetic architecture of common variants for psoriasis.
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| 24. |
- 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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| 25. |
- 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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| 26. |
- Aartsen, M. G., et al.
(författare)
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Very high-energy gamma-ray follow-up program using neutrino triggers from IceCube
- 2016
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Ingår i: Journal of Instrumentation. - 1748-0221. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- We describe and report the status of a neutrino-triggered program in IceCube that generates real-time alerts for gamma-ray follow-up observations by atmospheric-Cherenkov telescopes (MAGIC and VERITAS). While IceCube is capable of monitoring the whole sky continuously, high-energy gamma-ray telescopes have restricted fields of view and in general are unlikely to be observing a potential neutrino-flaring source at the time such neutrinos are recorded. The use of neutrino-triggered alerts thus aims at increasing the availability of simultaneous multi-messenger data during potential neutrino flaring activity, which can increase the discovery potential and constrain the phenomenological interpretation of the high-energy emission of selected source classes (e. g. blazars). The requirements of a fast and stable online analysis of potential neutrino signals and its operation are presented, along with first results of the program operating between 14 March 2012 and 31 December 2015.
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| 27. |
- Becerra Garcia, Marley, 1979-, et al.
(författare)
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Spectral and electric diagnostics of low-current arc plasmas in CO2 with N2 and H2O admixtures
- 2024
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Ingår i: Journal of Physics D. - : IOP Publishing. - 0022-3727 .- 1361-6463. ; 57:1
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Tidskriftsartikel (refereegranskat)abstract
- Plasma diagnostics is a key tool to support the further development of plasma-induced chemical conversion of greenhouse gases (such as CO2) into high-value chemicals. For this reason, spectroscopic and electric measurements of low current (below 1.7 A), stationary arc plasmas in CO2 at atmospheric pressure with addition of N-2 or H2O are reported. High-speed photography, imaging emission spectroscopy and time-resolved electrical measurements are used to obtain time-space resolved gas temperatures as well as the electric-field current characteristics of the discharge. It is found that the lowest average electric field in a CO2 arc plasma at atmospheric pressure is similar to 20 kV mm(-1) at a current between 0.8 and 1 A. If the current decreases below this level, the arc remains in vibrational-translational (VT) equilibrium by increasing the electric field. However, VT equilibrium conditions can be only maintained until a threshold minimum current of 0.33 +/- 0.05 A, at which the arc transitions into a non-equilibrium condition with further increasing electric fields (reaching 68 +/- 15 V mm(-1) at 0.03 A). The addition of N-2 or H2O did not influence the electrical characteristics of the CO2 arc within to the tested mixtures. However, there is only a significant decrease in the electric field of the formed transition arcs and the threshold minimum current in the presence of N-2. The spectra of the low-current CO2 arc is found to be dominated by emission from the C-2 Swan band system and the O I 777 nm triplet peak. However, the CN band dominates the spectra even when small amounts (0.5 wt%) of N-2 is present in the plasma. The gas temperature at the axis of the CO2 arc plasma decreased slightly with decreasing current, from an estimated 7000 K at 1 A down to 6300 K at 0.4 A. The thermal radius of the arc is estimated to be larger than 1.2 mm, more than two times larger than the optical radius obtained from the emitted radiation. The addition of N-2 and H2O (up to 7 and 9 wt% respectively) lead to only to a 500 K decrease in the axial arc temperature.
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| 28. |
- Beecham, Ashley H, et al.
(författare)
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Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.
- 2013
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:11, s. 1353-60
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Tidskriftsartikel (refereegranskat)abstract
- Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.
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| 29. |
- Berndt, Sonja I., et al.
(författare)
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Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:5, s. 501-U69
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Tidskriftsartikel (refereegranskat)abstract
- Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
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| 30. |
- Bonfiglio, Ferdinando, et al.
(författare)
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GWAS of stool frequency provides insights into gastrointestinal motility and irritable bowel syndrome
- 2021
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Ingår i: Cell Genomics. - Cambridge, MA, United States : Elsevier. - 2666-979X. ; 1:3
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Tidskriftsartikel (refereegranskat)abstract
- Gut dysmotility is associated with constipation, diarrhea, and functional gastrointestinal disorders like irritable bowel syndrome (IBS), although its molecular underpinnings are poorly characterized. We studied stool frequency (defined by the number of bowel movements per day, based on questionnaire data) as a proxy for gut motility in a GWAS meta-analysis including 167,875 individuals from UK Biobank and four smaller population-based cohorts. We identify 14 loci associated with stool frequency (p ≤ 5.0 × 10-8). Gene set and pathway analyses detected enrichment for genes involved in neurotransmitter/neuropeptide signaling and preferentially expressed in enteric motor neurons controlling peristalsis. PheWAS identified pleiotropic associations with dysmotility syndromes and the response to their pharmacological treatment. The genetic architecture of stool frequency correlates with that of IBS, and UK Biobank participants from the top 1% of stool frequency polygenic score distribution were associated with 5× higher risk of IBS with diarrhea. These findings pave the way for the identification of actionable pathological mechanisms in IBS and the dysmotility syndromes.
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