39 research outputs found
Multiple rare genetic variants co‐segregating with familial IgA nephropathy all act within a single immune‐related network
No full textBACKGROUND: IgA nephropathy (IgAN) is a common complex disease with a strong genetic involvement. We aimed to identify novel, rare, highly penetrant risk variants combining family-based linkage analysis with whole-exome sequencing (WES).METHODS: Linkage analysis of 16 kindreds of South Italian ancestry was performed using an 'affected-only' strategy. Eight most informative trios composed of two familial cases and an intrafamilial control were selected for WES. High-priority variants in linked regions were identified and validated using Sanger sequencing. Custom TaqMan assays were designed and carried out in the 16 kindreds and an independent cohort of 240 IgAN patients and 113 control subjects.RESULTS: We found suggestive linkage signals in 12 loci. After sequential filtering and validation of WES data, we identified 24 private or extremely rare (MAF <0.0003) linked variants segregating with IgAN status. These were present within coding or regulatory regions of 23 genes that merged into a common functional network. The genes were interconnected by AKT, CTNNB1, NFKB, MYC and UBC, key modulators of WNT/β-catenin and PI3K/Akt pathways, which are implicated in IgAN pathogenesis. Overlaying publicly available expression data, genes/proteins with expression notably altered in IgAN were included in this immune-related network. In particular, the network included the glucocorticoid receptor gene, NR3C1, which is the target of corticosteroid therapy routinely used in the treatment of IgAN.CONCLUSION: Our findings suggest that disease susceptibility could be influenced by multiple rare variants acting in a common network that could provide the starting point for the identification of potential drug targets for personalized therapy.</p
Insights into the genetic susceptibility to type 2 diabetes from genome-wide association studies of glycaemic traits.
No full text05/01/15 meb. Accepted version, OK to add embargo of 12 month from 25/10/1
Novel association approach for variable number tandem repeats (vntrs) identifies Dock5 as a susceptibility gene for severe obesity
No full textVariable number tandem repeats (VNTRs) constitute a relatively under-examined class of genomic variants in the context of complex disease because of their sequence complexity and the challenges in assaying them. Recent large-scale genome-wide copy number variant mapping and association efforts have highlighted the need for improved methodology for association studies using these complex polymorphisms. Here we describe the in-depth investigation of a complex region on chromosome 8p21.2 encompassing the dedicator of cytokinesis 5 (DOCK5) gene. The region includes two VNTRs of complex sequence composition which flank a common 3975 bp deletion, all three of which were genotyped by polymerase chain reaction and fragment analysis in a total of 2744 subjects. We have developed a novel VNTR association method named VNTRtest, suitable for association analysis of multi-allelic loci with binary and quantitative outcomes, and have used this approach to show significant association of the DOCK5 VNTRs with childhood and adult severe obesity (Pempirical = 8.9 × 10-8 and P = 3.1 × 10-3, respectively) which we estimate explains ~0.8% of the phenotypic variance. We also identified an independent association between the 3975 base pair (bp) deletion and obesity, explaining a further 0.46% of the variance (Pcombined = 1.6 × 10-3). Evidence for association between DOCK5 transcript levels and the 3975 bp deletion (P = 0.027) and both VNTRs (Pempirical = 0.015) was also identified in adipose tissue from a Swedish family sample, providing support for a functional effect of the DOCK5 deletion and VNTRs. These findings highlight the potential role of DOCK5 in human obesity and illustrate a novel approach for analysis of the contribution of VNTRs to disease susceptibility through association studies
Mapeo de la investigación científica sobre el síndrome de burnout
No full textIntroducción. El síndrome de agotamiento profesional o burnout es una respuesta prolongada a factores estresantes en el trabajo, con efectos devastadores sobre la salud física y mental de los trabajadores.
Objetivo. Analizar la evolución científica, las tendencias y las futuras líneas de investigación sobre el desgaste profesional.
Materiales y Métodos. Revisión de literatura con base en la guía PRISMA adaptada para análisis bibliométrico. Se analizaron 2154 documentos provenientes de la base de datos Scopus; se emplearon métodos de co-ocurrencia de términos, acoplamiento bibliográfico y análisis de redes.
Resultados. Se destacan áreas clave como las intervenciones preventivas, los factores asociados al agotamiento, la relación entre el agotamiento y la incapacidad laboral, especialmente en el sector salud y se identificaron temas emergentes como el bienestar laboral y la salud mental.
Conclusiones. Las conclusiones subrayan la necesidad de mejorar los métodos de estudio, expandir la medición de variables y promover estrategias preventivas, con el objetivo de fomentar entornos laborales más saludables y sostenibles
Polyunsaturated fatty acids in various macroalgal species from north Atlantic and tropical seas
No full textBackground - In this study the efficacy of using marine macroalgae as a source for polyunsaturated fatty acids, which are associated with the prevention of inflammation, cardiovascular diseases and mental disorders, was investigated. Methods - The fatty acid (FA) composition in lipids from seven sea weed species from the North Sea (Ulva lactuca, Chondrus crispus, Laminaria hyperborea, Fucus serratus, Undaria pinnatifida, Palmaria palmata, Ascophyllum nodosum) and two from tropical seas (Caulerpa taxifolia, Sargassum natans) was determined using GCMS. Four independent replicates were taken from each seaweed species. Results - Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs), were in the concentration range of 2-14 mg/g dry matter (DM), while total lipid content ranged from 7-45 mg/g DM. The n-9 FAs of the selected seaweeds accounted for 3%-56% of total FAs, n-6 FAs for 3%-32% and n-3 FAs for 8%-63%. Red and brown seaweeds contain arachidonic (C20:4, n-6) and/or eicosapentaenoic acids (EPA, C20:5, n-3), the latter being an important "fish" FA, as major PUFAs while in green seaweeds these values are low and mainly C16 FAs were found. A unique observation is the presence of another typical "fish" fatty acid, docosahexaenoic acid (DHA, C22:6, n-3) at ˜ 1 mg/g DM in S. natans. The n-6: n-3 ratio is in the range of 0.05-2.75 and in most cases below 1.0. Environmental effects on lipid-bound FA composition in seaweed species are discussed. Conclusion - Marine macroalgae form a good, durable and virtually inexhaustible source for polyunsaturated fatty acids with an (n-6) FA: (n-3) FA ratio of about 1.0. This ratio is recommended by the World Health Organization to be less than 10 in order to prevent inflammatory, cardiovascular and nervous system disorders. Some marine macroalgal species, like P. palmata, contain high proportions of the "fish fatty acid" eicosapentaenoic acid (EPA, C20:5, n-3), while in S. natans also docosahexaenoic acid (DHA, C22:6, n-3) was detected
Genetic effects on the skin methylome in healthy older twins.
No full textWhole-skin DNA methylation variation has been implicated in several diseases, including melanoma, but its genetic basis has not yet been fully characterized. Using bulk skin tissue samples from 414 healthy female UK twins, we performed twin-based heritability and methylation quantitative trait loci (meQTL) analyses for >400,000 DNA methylation sites. We find that the human skin DNA methylome is on average less heritable than previously estimated in blood and other tissues (mean heritability: 10.02%). meQTL analysis identified local genetic effects influencing DNA methylation at 18.8% (76,442) of tested CpG sites, as well as 1,775 CpG sites associated with at least one distal genetic variant. As a functional follow-up, we performed skin expression QTL (eQTL) analyses in a partially overlapping sample of 604 female twins. Colocalization analysis identified over 3,500 shared genetic effects affecting thousands of CpG sites (10,067) and genes (4,475). Mediation analysis of putative colocalized gene-CpG pairs identified 114 genes with evidence for eQTL effects being mediated by DNA methylation in skin, including in genes implicating skin disease such as ALOX12 and CSPG4. We further explored the relevance of skin meQTLs to skin disease and found that skin meQTLs and CpGs under genetic influence were enriched for multiple skin-related genome-wide and epigenome-wide association signals, including for melanoma and psoriasis. Our findings give insights into the regulatory landscape of epigenomic variation in skin
Erratum to: Regulatory variants at KLF14 influence type 2 diabetes risk via a female-specific effect on adipocyte size and body composition (Nature Genetics, (2018), 50, 4, (572-580), 10.1038/s41588-018-0088-x)
No full text\ua9 2018, The Author(s).In the version of this article originally published, minus signs were missing from the three β-values for BMI given in Table 1. The errors have been corrected in the HTML and PDF versions of the article
CnvHap: An integrative population and haplotype-based multiplatform model of SNPs and CNVs
No full textAlthough genome-wide association studies have uncovered single-nucleotide polymorphisms (SNPs) associated with complex disease, these variants account for a small portion of heritability. Some contribution to this 'missing heritability' may come from copy-number variants (CNVs), in particular rare CNVs; but assessment of this contribution remains challenging because of the difficulty in accurately genotyping CNVs, particularly small variants. We report a population-based approach for the identification of CNVs that integrates data from multiple samples and platforms. Our algorithm, cnvHap, jointly learns a chromosome-wide haplotype model of CNVs and cluster-based models of allele intensity at each probe. Using data for 50 French individuals assayed on four separate platforms, we found that cnvHap correctly detected at least 14% more deleted and 50% more amplified genotypes than PennCNV or QuantiSNP, with an 82% and 115% improvement for aberrations containing 10 probes. Combining data from multiple platforms additionally improved sensitivity
Current smoking and COVID-19 risk: results from a population symptom app in over 2.4 million people
No full textBackground: The association between current tobacco smoking, the risk of developing symptomatic COVID-19 and the severity of illness is an important information gap.
Methods: UK users of the Zoe COVID Symptom Study App provided baseline data including demographics, anthropometrics, smoking status and medical conditions, and were asked to log their condition daily. Participants who reported that they did not feel physically normal were then asked by the app to complete a series of questions, including 14 potential COVID-19 symptoms and about hospital attendance. The main study outcome was the development of “classic” symptoms of COVID-19 during the pandemic defined as fever, new persistent cough and breathlessness and their association with current smoking. The number of concurrent COVID-19 symptoms was used as a proxy for severity and the pattern of association between symptoms was also compared between smokers and non-smokers.
Results: Between 24th March 2020 to 23rd April 2020, data were available on 2,401,982 participants, mean(SD) age 43.6(15.1) years, 63.3% female, overall smoking prevalence 11.0%. 834,437 (35%) participants reported being unwell and entered one or more symptoms. Current smokers were more likely to report symptoms suggesting a diagnosis of COVID-19; classic symptoms adjusted OR[95%CI] 1.14[1.10 to 1.18]; >5 symptoms 1.29[1.26 to 1.31]; >10 symptoms 1.50[1.42 to 1.58]. The pattern of association between reported symptoms did not vary between smokers and non-smokers.
Interpretation: These data are consistent with people who smoke being at an increased risk of developing symptomatic COVID-19
famCNV: copy number variant association for quantitative traits in families.
No full textUNLABELLED: A program package to enable genome-wide association of copy number variants (CNVs) with quantitative phenotypes in families of arbitrary size and complexity. Intensity signals that act as proxies for the number of copies are modeled in a variance component framework and association with traits is assessed through formal likelihood testing. AVAILABILITY AND IMPLEMENTATION: The Java package is made available at www.imperial.ac.uk/medicine/people/m.falchi/. CONTACT: [email protected]
