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Whole genome sequencing approach to identifying genetic risk factors underlying anterior cruciate ligament injuries in a twin family study
Get PDFBackground: Predisposition to ACL rupture is multifactorial, resulting from a complex interplay of intrinsic and extrinsic risk factors. Variation in the genome is now considered a key intrinsic risk factor, but the majority of currently implicated loci have been identified through case-control genetic association studies, which are limited by a candidate gene approach and insufficient statistical power. The primary aim of this thesis was to use a whole genome sequencing (WGS) approach within the context of a twin family study to identify novel or previously implicated genetic loci contributing to ACL rupture predisposition (Chapter 2). Additionally, this research aimed to explore prioritised genetic polymorphisms previously associated with ACL rupture and functioning in key biological pathways implicated through the WGS analyses, independently and as a collective, with ACL rupture predisposition in a large combined ACL rupture dataset (Chapter 3 and 4). Methods: The complete genomes of all family members in two unrelated families, each with affected twins were sequenced. Variants with potential loss of function effect were prioritised, and explored for probable biological function in the ACL rupture risk pathway. Furthermore, identity by descent analysis (IBD) was performed to identify potential disease causing mutations, on chromosomal regions shared between family members, and across families. Enriched biological pathway analyses were further explored to prioritise potential candidate genes. Two biological networks were prioritised which highlighted the angiogenesis and proteoglycan family of proteins. Specific polymorphisms within previously investigated candidate genes were further explored in case-control genetic association studies conducted in a large collective data set, including participants from three independent (Sweden, Poland and Australia) cohorts, combined with previously published South African and Polish data. The anterior cruciate ligament (ACL) rupture group included individuals diagnosed with a clinical diagnosis of an ACL rupture based on physical examination, and confirmed by either magnetic resonance imaging or arthroscopy. Only ACL ruptures resulting from a non-contact mechanism of injury were included. The control group comprised individuals of similar age to cases with no prior history of ACL injury or other ligament and tendon injuries, and participating in regular sporting activity, which was similar to cases. Participant samples were genotyped for single nucleotide polymorphisms in the VEGFA (rs699947 C/A rs1570360 G/A, rs2010963 G/C) and KDR (rs2071559 A/G, rs1870377 T/A) genes (Sweden CON: 116 ACL: 95; Poland CON: 149 ACL: 127 and Australia CON: 83 ACL: 342). Additionally, in the ACAN (rs2351491 C/T, rs1042631 T/C, rs1516797 T/G), DCN (rs516115 T/C) and BGN (rs1126499 C/T, rs1042103 G/A) genes (Sweden and Poland). Haplotype analyses were explored (VEGFA, KDR, ACAN and BGN) using the individual genotype data. In addition, inferred allele interactions were presented for VEGFA-KDR, ACAN-BGN ACAN-DCN, BGN-DCN, and VEGFA-DCN as a proxy for gene-gene interactions within the discrete angiogenesis and proteoglycan gene families, and between genes as a proxy for pathway interactions. For association studies, frequencies were calculated for the genotype, allele, inferred haplotypes and allele interactions, and the distributions compared between the control and ACL rupture participants. The statistical programs in R were used for all the analyses, and a p value < 0.05 was accepted to be significant. Results: The WGS analyses highlighted six candidate genetic loci in three genes (COL12A1, CATSPER2, and KCNJ12) with predicted loss of function effects in all affected and unaffected family members within the two studied families. Of the three genes, polymorphisms within COL12A1 were previously associated with ACL rupture predisposition, while CATSPER2 and KCNJ12 are two novel genetic loci with no known previous association with predisposition to ACL rupture. The IBD analyses identified several regions shared in each independent family, of which a segment including a long intergenic non-protein coding RNA (lincRNA) LINC01250 gene in the telomeric region of chromosome 2p25.3 was shared between affected twins in both families, and an affected brother. Furthermore, several functional partners were highlighted. Genetic association analyses of the prioritised polymorphisms in a combined cohort identified an independent association of the VEGFA rs2010963 CC genotype and C allele with increased risk (genotype p = 0.0001, FDR p = 0.001, OR 2.16, 95% CI: 1.47-3.19; allele p = 0.0006, FDR p = 0.003, OR 1.29, 95% CI: 1.11-1.49). Furthermore, the association of the VEGFA A-A-G and A-G-G inferred haplotypes (rs699947 A/C-rs1570360 G/Ars2010963 G/C) with reduced risk (p = 0.010, haplo.score: -2.58, OR: 0.85, 95% CI: 0.69-1.05; A-G-G: p = 0.036, haplo.score: -2.09, OR: 0.81, 95% CI: 0.64-1.02) of ACL rupture. Moreover, a reduced interval (rs1570360 G/A-rs2010963 G/C) revealed an association of the VEGFA -GG and -A-G inferred haplotypes with reduced risk (-G-G: p = 0.031, haplo.score: -2.15, OR: 1.00 and -A-G: p = 0.024, haplo.score: -2.25, OR: 0.98, 95% CI: 0.82-1.18) and the -G-C inferred haplotype with increased risk p = 0.012, haplo.score: 2.50, OR: 1.18, 95% CI: 0.99- 1.40). The KDR genotype and haplotype analyses illustrated that it is highly unlikely that the investigated KDR polymorphisms are associated with modulating ACL rupture risk. Inferred allele interactions noted a significant association of the VEGFA (rs699947 A/C, rs2010963 G/C) - KDR (rs2071559 A/G, rs1870377 T/A) A-G-A-A (p = 0.005, OR: 0.51, 95% CI: 0.30- 0.87) and A-G-G-A (p = 0.018, OR: 0.93, 95% CI: 0.54-1.60) combinations with reduced ACL rupture risk. Further, a significant association of the VEGFA (rs699947 C/A, rs1570360 G/A, rs20109630 G/C) - DCN (rs516115 T/C) A-G-G-T (p = 0.010, OR: 0.53, 95% CI: 0.30-0.91), A-A-G-C (p = 0.010, OR: 0.42, 95% CI: 0.21-0.81) and A-A-G-T (p = 0.046, OR: 0.77, CI: 0.49-1.2) allele combinations with reduced risk was noted for male participants in the collective cohort. No independent or haplotype associations with ACL rupture risk were noted for any of the investigated proteoglycan polymorphisms, in the collective cohort. Conclusion: Collectively, this work has expanded current knowledge on the genetic regions contributing to ACL rupture predisposition, and further highlights the polygenic nature of multifactorial phenotypes. Employing whole genome sequencing in a twin family context, together with a pathway based approach, novel and previously implicated genetic loci were identified towards the aims of the thesis. The catalogue of candidate in silico mutations and modifier genes that clustered in pathophysiological pathways important in ACL rupture, and with implications for therapeutic intervention were identified, and need to be interrogated. Of particular interest are the novel CATSPER2, KCNJ12 and LINC01250 genetic loci. Furthermore, additional evidence to support the implication of the VEGFA gene in modulating ACL rupture risk is provided, and highlighted is the potential collaboration of members within the angiogenesis and proteoglycan gene family in modulating risk. The studies in Chapter 3 and 4 suggest genetic association studies in single populations are less informative, and instead larger collective cohorts with increased statistical power should be employed. Further to that, rather than investigating single polymorphisms, larger regions of the genome should be explored to determine the potential interacting components contributing to musculoskeletal injury risk. Going forward, characterisation of the functional biological effect of implicated loci may assist in unravelling the underlying mechanisms altering tissue homeostasis, and subsequently an individual's capacity for healing and adaptive response
Inactivity and overfeeding related changes in skeletal muscle composition and metabolism in captive felids - are they at risk of developing metabolic syndrome?
Get PDFObesity and physical inactivity are established key risk factors in the development of skeletal muscle insulin-resistance and type II diabetes in human and domestic animal populations. Wild animals are similarly exposed to these risk factors as a result of captivity. This study aimed at describing the skeletal muscle properties of captive lions (Panthera leo) who present with obesity and are physically inactive, with a group of free roaming wild lions. Skeletal muscle biopsies were collected from the Triceps brachii and analysed for fibre type composition, fibre size, and maximum oxidative (citrate synthase (CS), 3-hydroxyacyl CoA dehydrogenase (3HAD) and glycolytic (phosphofructokinase (PFK) and lactate dehydrogenase (LDH) enzyme capacities. The type IIA fibres were the predominant fibre type in both the wild (48%) and captive (44%) lions. No significant differences were evident in the overall fibre type composition between groups, although a trend towards less type I (28% vs 36%) and more type IIX (28% vs 16%) fibres in the captive group were observed. The captive lions displayed significantly larger cross-sectional areas (CSA) of the type I (5847μm² vs 3318 μm²) and IIA fibres (8344μm² vs 4360μm²) with no difference evident in the CSA of the IIX fibres. Relationships were observed between body mass and the CSAs of type I (r = 0.68, P = 0.0002) and IIA (r = 0.44; P = 0.03) fibres. Metabolically, the captive lions displayed higher flux through the glycolytic pathway as represented by their higher PFK activities (551 ± 287 vs. 338 ± 123 μmol/min/g protein, P < 0.05). In contrast, their CS activities (11 ± 3 vs. 14 ± 2 μmol/min/g protein) were lower than free roaming lions, suggesting lower oxidative capacity. No differences in LDH and 3HAD activities were observed between the two groups. Relationships were observed between 3HAD activity and MHC IIx fibre content (r = -0.43, P = 0.001), 3HAD activity and MHC I content (r = 0.55, P = 0.001). A positive correlation was observed between CS activity and MHC I content (r = 0.35, P = 0.009). In light of previous research, the data collected from this project follows that observed in exercise training models, where a sedentary lifestyle decreases oxidative capacity of muscle and increases type II fibre content. However, due to the low sample size in the free roaming wild lion group, interpretation of the data is difficult. Therefore, future research must strive to increase the sample number of the free roaming group
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
Get PDF“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
Get PDFWe 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
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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