1,721,002 research outputs found
Characterising the genetic architecture of common elastic tissue disorders using UK Biobank
Full text linkBackground
Elastic fibres are key extracellular matrix (ECM) components that provide elasticity to tissues throughout the body, allowing them to recover after deformation. Derangement of elastic fibres lead to cutaneous and systemic disorders that show elastic tissue pathology. To distinguish between rarer disorders of elastic tissue, and common disease, I have coined the term ‘elastopathies.’ Common elastopathies such as hiatus hernia, diverticular disease, haemorrhoids, inguinal hernia, varicose veins, female genital prolapse, umbilical hernia, aneurysmal disease, emphysema, pneumothorax, rectal prolapse, and femoral hernia, have a complex aetiology where genetic predisposition and environmental factors interplay to influence overall phenotypic expression. These elastopathies are highly prevalent and exert a significant healthcare and socioeconomic burden. However, their genetic basis remains poorly defined, with limited putative genes identified.
Method
To unravel the genetic architecture of the 12 elastopathies identified in the UK Biobank resource (hiatus hernia, diverticular disease, haemorrhoids, inguinal hernia, varicose veins, female genital prolapse, umbilical hernia, aneurysmal disease, emphysema, pneumothorax, rectal prolapse, and femoral hernia), genome-wide association study (GWAS) testing was performed across ~400,000 genotyped participants from the UK Biobank resource, with replication from ~410,000 participants from 23andMe, Inc. (California) for the varicose veins analysis. All 12 elastopathies were studied independently, and then combined in a final pan-elastopathy GWA study to identify the shared genetic architecture of common elastopathies in UK Biobank. A disparate analysis was performed combining all four types of hernia in a pan-hernia analysis to identify shared genetics. Genes and pathways were prioritised using a suite of bioinformatic approaches, and pharmacological targets identified using the Open Targets Platform. A genetic risk score was constructed to examine the genetic burden among participants with severe disease. For the pan-hernia analysis, multi-trait and multivariate meta-analysis approaches were deployed to uncover the shared genetic susceptibility to multiple hernia phenotypes. For the pan-elastopathy analysis, an individual patient data (IPD) meta-analysis was performed and the latent elastopathy phenotype was analysed using genomic structural equation modelling (SEM) to uncover shared genetic biology.
Results
Performing the largest two-stage GWAS of varicose veins in 810,625 participants, forty-nine signals at 46 susceptibility loci were discovered, including 29 previously unreported associations. Next, through (at the time) the first-ever GWA study of haemorrhoids in over 400,000 participants, 13 signals at 12 novel loci were discovered to associate with haemorrhoids. Association analysis of inguinal, femoral, umbilical, and hiatus hernia individually yielded 58 signals at 38 loci (34 new) associated with the four hernia phenotypes. When combined in a multi-trait meta-analysis, 12 biologically relevant putative loci were discovered to associate with multiple hernia phenotypes, demonstrating novel and robust evidence of shared susceptibility to hernia. Of significance, the genetic risk scoring correlated with disease severity across the varicose veins, haemorrhoids, and pan-hernia analyses, with patients undergoing surgery having a higher genetic burden than those managed non-surgically. Lastly, studying the 12 elastopathies in a pan-elastopathy IPD meta-analysis, 18 susceptibility loci were discovered to associate with the pan-elastopathy phenotype which were not discovered when the 12 elastopathies were studied individually. Moreover, employing common factor analysis to unveil the latent elastopathy phenotype, a further four loci were discovered to be integral to a shared genetic risk towards elastopathies. Collectively, over 250 independent susceptibility loci were discovered to associate with the 12 elastopathies, which were mapped to over 500 putative genes, many of which demonstrated profound evidence of a shared genetic biology, therapeutic tractability and clustered in pathways pertaining to core matrisomal components and ECM homeostasis.
Conclusion
Prioritised genes and pathways demonstrate significant biological plausibility, and represent promising candidates for further investigation of elastic tissue biology and potential pharmacological targeting. The genetic risk score correlated with disease across varicose veins, haemorrhoids and hernia disorders, representing an important proof-of-principle for the future use of genetic risk scoring in personalised medicine approaches to surgical disorders. Lastly, studying the 12 elastic tissue disorders together, a novel category of pathologically linked disorders defined by elastic tissue dysfunction were discovered— the elastopathies. To this end, this thesis advances the field of study around elastopathies and complex trait genetics
A Cost-Effectiveness Review of Mohs Micrographic Surgery Versus Surgical Excision for Treating Primary Non-Melanoma Skin Cancers
Full text link
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Tackling mental health barriers at medical school – insights from fellow medical students
Full text link
Varicose veins GWAS summary statistics
No full textSummary statistics for discovery GWAS of 22,473 varicose veins cases and 379,183 non-varicose veins controls in UK Biobank. Related publication: Ahmed W. et al., Nature Communications, 2022.
SNP = SNP name
CHR = Chromosome number
BP = Genomic position (GRCh37)
ALLELE1 = effect allele
ALLELE0 = non-effect allele
A1FREQ = frequency of allele A
INFO = INFO score for imputed SNPs
BETA = beta coefficient
SE = standard error
PVAL = p-valu
- …
