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Article ; Online: Sharing GWAS summary statistics results in more citations

Guillermo Reales / Chris Wallace

Communications Biology, Vol 6, Iss 1, Pp 1-

2023 Volume 6

Abstract: A review of citation rates from genomic studies in the GWAS Catalog suggests that sharing summary statistics results, on average, in ~81.8% more citations, highlighting a benefit of publicly sharing GWAS summary statistics. ...

Abstract	A review of citation rates from genomic studies in the GWAS Catalog suggests that sharing summary statistics results, on average, in ~81.8% more citations, highlighting a benefit of publicly sharing GWAS summary statistics.
Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: fcfdr

Anna Hutchinson / James Liley / Chris Wallace

BMC Bioinformatics, Vol 23, Iss 1, Pp 1-

an R package to leverage continuous and binary functional genomic data in GWAS

2022 Volume 15

Abstract: Abstract Background Genome-wide association studies (GWAS) are limited in power to detect associations that exceed the stringent genome-wide significance threshold. This limitation can be alleviated by leveraging relevant auxiliary data, such as ... ...

Abstract	Abstract Background Genome-wide association studies (GWAS) are limited in power to detect associations that exceed the stringent genome-wide significance threshold. This limitation can be alleviated by leveraging relevant auxiliary data, such as functional genomic data. Frameworks utilising the conditional false discovery rate have been developed for this purpose, and have been shown to increase power for GWAS discovery whilst controlling the false discovery rate. However, the methods are currently only applicable for continuous auxiliary data and cannot be used to leverage auxiliary data with a binary representation, such as whether SNPs are synonymous or non-synonymous, or whether they reside in regions of the genome with specific activity states. Results We describe an extension to the cFDR framework for binary auxiliary data, called “Binary cFDR”. We demonstrate FDR control of our method using detailed simulations, and show that Binary cFDR performs better than a comparator method in terms of sensitivity and FDR control. We introduce an all-encompassing user-oriented CRAN R package ( https://annahutch.github.io/fcfdr/ https://cran.r-project.org/web/packages/fcfdr/index.html ) and demonstrate its utility in an application to type 1 diabetes, where we identify additional genetic associations. Conclusions Our all-encompassing R package, fcfdr, serves as a comprehensive toolkit to unite GWAS and functional genomic data in order to increase statistical power to detect genetic associations.
Keywords	GWAS ; Functional genomics ; Power ; FDR ; Multiple testing ; Computer applications to medicine. Medical informatics ; R858-859.7 ; Biology (General) ; QH301-705.5
Subject code	006
Language	English
Publishing date	2022-07-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Improving the coverage of credible sets in Bayesian genetic fine-mapping.

Anna Hutchinson / Hope Watson / Chris Wallace

PLoS Computational Biology, Vol 16, Iss 4, p e

2020 Volume 1007829

Abstract: Genome Wide Association Studies (GWAS) have successfully identified thousands of loci associated with human diseases. Bayesian genetic fine-mapping studies aim to identify the specific causal variants within GWAS loci responsible for each association, ... ...

Abstract	Genome Wide Association Studies (GWAS) have successfully identified thousands of loci associated with human diseases. Bayesian genetic fine-mapping studies aim to identify the specific causal variants within GWAS loci responsible for each association, reporting credible sets of plausible causal variants, which are interpreted as containing the causal variant with some "coverage probability". Here, we use simulations to demonstrate that the coverage probabilities are over-conservative in most fine-mapping situations. We show that this is because fine-mapping data sets are not randomly selected from amongst all causal variants, but from amongst causal variants with larger effect sizes. We present a method to re-estimate the coverage of credible sets using rapid simulations based on the observed, or estimated, SNP correlation structure, we call this the "adjusted coverage estimate". This is extended to find "adjusted credible sets", which are the smallest set of variants such that their adjusted coverage estimate meets the target coverage. We use our method to improve the resolution of a fine-mapping study of type 1 diabetes. We found that in 27 out of 39 associated genomic regions our method could reduce the number of potentially causal variants to consider for follow-up, and found that none of the 95% or 99% credible sets required the inclusion of more variants-a pattern matched in simulations of well powered GWAS. Crucially, our method requires only GWAS summary statistics and remains accurate when SNP correlations are estimated from a large reference panel. Using our method to improve the resolution of fine-mapping studies will enable more efficient expenditure of resources in the follow-up process of annotating the variants in the credible set to determine the implicated genes and pathways in human diseases.
Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2020-04-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: 7-Ketocholesterol Promotes Retinal Pigment Epithelium Senescence and Fibrosis of Choroidal Neovascularization via IQGAP1 Phosphorylation-Dependent Signaling

Haibo Wang / Aniket Ramshekar / Thaonhi Cung / Chris Wallace-Carrete / Chandler Zaugg / Jasmine Nguyen / Gregory J. Stoddard / M. Elizabeth Hartnett

International Journal of Molecular Sciences, Vol 24, Iss 10276, p

2023 Volume 10276

Abstract: Accumulation of 7-ketocholesterol (7KC) occurs in age-related macular degeneration (AMD) and was found previously to promote fibrosis, an untreatable cause of vision loss, partly through induction of endothelial-mesenchymal transition. To address the ... ...

Abstract	Accumulation of 7-ketocholesterol (7KC) occurs in age-related macular degeneration (AMD) and was found previously to promote fibrosis, an untreatable cause of vision loss, partly through induction of endothelial-mesenchymal transition. To address the hypothesis that 7KC causes mesenchymal transition of retinal pigment epithelial cells (RPE), we exposed human primary RPE (hRPE) to 7KC or a control. 7KC-treated hRPE did not manifest increased mesenchymal markers, but instead maintained RPE-specific proteins and exhibited signs of senescence with increased serine phosphorylation of histone H3, serine/threonine phosphorylation of mammalian target of rapamycin (p-mTOR), p16 and p21, β-galactosidase labeling, and reduced LaminB1, suggesting senescence. The cells also developed senescence-associated secretory phenotype (SASP) determined by increased IL-1β, IL-6, and VEGF through mTOR-mediated NF-κB signaling, and reduced barrier integrity that was restored by the mTOR inhibitor, rapamycin. 7KC-induced p21, VEGF, and IL-1β were inhibited by an inhibitor of protein kinase C. The kinase regulates IQGAP1 serine phosphorylation. Furthermore, after 7KC injection and laser-induced injury, mice with an IQGAP1 serine 1441-point mutation had significantly reduced fibrosis compared to littermate control mice. Our results provide evidence that age-related accumulation of 7KC in drusen mediates senescence and SASP in RPE, and IQGAP1 serine phosphorylation is important in causing fibrosis in AMD.
Keywords	retinal pigment epithelium ; cellular senescence ; mammalian target of rapamycin (mTOR) ; macular degeneration ; IQ motif containing GTPase activating protein (IQGAP1) ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	571
Language	English
Publishing date	2023-06-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Recent Trends in Neurosurgery Career Outcomes in Canada.

Tso, Michael K / Max Findlay, J / Lownie, Stephen P / Chris Wallace, M / Toyota, Brian D / Fleetwood, Ian G

The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques

2019 Volume 46, Issue 4, Page(s) 436–442

Abstract: Background: As with other specialties, Royal College of Physicians and Surgeons of Canada (RCPSC) trainees in Neurosurgery have anecdotally had challenges securing full-time employment. This study presents the employment status, research pursuits, and ... ...

Abstract	Background: As with other specialties, Royal College of Physicians and Surgeons of Canada (RCPSC) trainees in Neurosurgery have anecdotally had challenges securing full-time employment. This study presents the employment status, research pursuits, and fellowship choices of neurosurgery trainees in Canadian programs. Methods: RCPSC neurosurgery trainees (n = 143) who began their residency training between 1998 and 2008 were included in this study. Associations between year of residency completion, research pursuits, and fellowship choice with career outcomes were determined by Fisher's exact test (p < 0.05, statistical significance). Results: In 2015, 60% and 26% of neurosurgery trainees had permanent positions in Canada and the USA, respectively. Underemployment, defined as locum and clinical associate positions, pursuit of multiple unrelated fellowships, unemployment, and career change to non-surgical career, was 12% in 2015. The proportion of neurosurgery trainees who had been underemployed at some point within 5 years since residency completion was 20%. Pursuit of in-folded research (MSc, PhD, or non-degree research greater than 1 year) was significantly associated with obtaining full employment (94% vs. 73%, p = 0.011). However, fellowship training was not significantly associated with obtaining full employment (78% vs. 75%, p = 1.000). Conclusions: Underemployment in neurosurgery has become a significant issue in Canada for various reasons. Pursuit of in-folded research, but not fellowship training, was associated with obtaining full employment.
MeSH term(s)	Canada ; Career Choice ; Employment ; Fellowships and Scholarships ; Humans ; Internship and Residency ; Neurosurgery ; Physicians
Language	English
Publishing date	2019-04-23
Publishing country	England
Document type	Journal Article
ZDB-ID	197622-9
ISSN	0317-1671
ISSN	0317-1671
DOI	10.1017/cjn.2019.22
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Stochastic search and joint fine-mapping increases accuracy and identifies previously unreported associations in immune-mediated diseases

Jennifer L. Asimit / Daniel B. Rainbow / Mary D. Fortune / Nastasiya F. Grinberg / Linda S. Wicker / Chris Wallace

Nature Communications, Vol 10, Iss 1, Pp 1-

2019 Volume 15

Abstract: Statistical fine-mapping to pinpoint likely causal variants in a genomic region is complicated by linkage disequilibrium (LD). Here, Asimit et al. compare stepwise and stochastic approaches to fine-mapping and propose a Bayesian multinomial stochastic ... ...

Abstract	Statistical fine-mapping to pinpoint likely causal variants in a genomic region is complicated by linkage disequilibrium (LD). Here, Asimit et al. compare stepwise and stochastic approaches to fine-mapping and propose a Bayesian multinomial stochastic search method which they apply to six immune-mediated diseases.
Keywords	Science ; Q
Language	English
Publishing date	2019-07-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Stochastic search and joint fine-mapping increases accuracy and identifies previously unreported associations in immune-mediated diseases

Jennifer L. Asimit / Daniel B. Rainbow / Mary D. Fortune / Nastasiya F. Grinberg / Linda S. Wicker / Chris Wallace

Nature Communications, Vol 10, Iss 1, Pp 1-

2019 Volume 15

Abstract	Statistical fine-mapping to pinpoint likely causal variants in a genomic region is complicated by linkage disequilibrium (LD). Here, Asimit et al. compare stepwise and stochastic approaches to fine-mapping and propose a Bayesian multinomial stochastic search method which they apply to six immune-mediated diseases.
Keywords	Science ; Q
Language	English
Publishing date	2019-07-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Resolving mechanisms of immune‐mediated disease in primary CD4 T cells

Christophe Bourges / Abigail F Groff / Oliver S Burren / Chiara Gerhardinger / Kaia Mattioli / Anna Hutchinson / Theodore Hu / Tanmay Anand / Madeline W Epping / Chris Wallace / Kenneth GC Smith / John L Rinn / James C Lee

EMBO Molecular Medicine, Vol 12, Iss 5, Pp n/a-n/a (2020)

2020

Abstract: Abstract Deriving mechanisms of immune‐mediated disease from GWAS data remains a formidable challenge, with attempts to identify causal variants being frequently hampered by strong linkage disequilibrium. To determine whether causal variants could be ... ...

Abstract	Abstract Deriving mechanisms of immune‐mediated disease from GWAS data remains a formidable challenge, with attempts to identify causal variants being frequently hampered by strong linkage disequilibrium. To determine whether causal variants could be identified from their functional effects, we adapted a massively parallel reporter assay for use in primary CD4 T cells, the cell type whose regulatory DNA is most enriched for immune‐mediated disease SNPs. This enabled the effects of candidate SNPs to be examined in a relevant cellular context and generated testable hypotheses into disease mechanisms. To illustrate the power of this approach, we investigated a locus that has been linked to six immune‐mediated diseases but cannot be fine‐mapped. By studying the lead expression‐modulating SNP, we uncovered an NF‐κB‐driven regulatory circuit which constrains T‐cell activation through the dynamic formation of a super‐enhancer that upregulates TNFAIP3 (A20), a key NF‐κB inhibitor. In activated T cells, this feedback circuit is disrupted—and super‐enhancer formation prevented—by the risk variant at the lead SNP, leading to unrestrained T‐cell activation via a molecular mechanism that appears to broadly predispose to human autoimmunity.
Keywords	CD4 T cells ; GWAS ; MPRA ; super‐enhancer ; TNFAIP3 ; Medicine (General) ; R5-920 ; Genetics ; QH426-470
Subject code	570
Language	English
Publishing date	2020-05-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Towards stratified treatment of JIA

Stephanie J.W. Shoop-Worrall / Saskia Lawson-Tovey / Lucy R. Wedderburn / Kimme L. Hyrich / Nophar Geifman / Aline Kimonyo / Alyssia McNeece / Andrew Dick / Andrew Morris / Annie Yarwood / Athimalaipet Ramanan / Bethany R. Jebson / Chris Wallace / Daniela Dastros-Pitei / Damian Tarasek / Elizabeth Ralph / Emil Carlsson / Emily Robinson / Emma Sumner /

Fatema Merali / Fatjon Dekaj / Helen Neale / Hussein Al-Mossawi / Jacqui Roberts / Jenna F. Gritzfeld / Joanna Fairlie / John Bowes / John Ioannou / Melissa Kartawinata / Melissa Tordoff / Michael Barnes / Michael W. Beresford / Michael Stadler / Paul Martin / Rami Kallala / Sandra Ng / Samantha Smith / Sarah Clarke / Soumya Raychaudhuri / Stephen Eyre / Sumanta Mukherjee / Teresa Duerr / Thierry Sornasse / Vasiliki Alexiou / Victoria J. Burton / Wei-Yu Lin / Wendy Thomson / Zoe Wanstall

EBioMedicine, Vol 100, Iss , Pp 104946- (2024)

machine learning identifies subtypes in response to methotrexate from four UK cohortsResearch in context

2024

Abstract: Summary: Background: Methotrexate (MTX) is the gold-standard first-line disease-modifying anti-rheumatic drug for juvenile idiopathic arthritis (JIA), despite only being either effective or tolerated in half of children and young people (CYP). To ... ...

Abstract	Summary: Background: Methotrexate (MTX) is the gold-standard first-line disease-modifying anti-rheumatic drug for juvenile idiopathic arthritis (JIA), despite only being either effective or tolerated in half of children and young people (CYP). To facilitate stratified treatment of early JIA, novel methods in machine learning were used to i) identify clusters with distinct disease patterns following MTX initiation; ii) predict cluster membership; and iii) compare clusters to existing treatment response measures. Methods: Discovery and verification cohorts included CYP who first initiated MTX before January 2018 in one of four UK multicentre prospective cohorts of JIA within the CLUSTER consortium. JADAS components (active joint count, physician (PGA) and parental (PGE) global assessments, ESR) were recorded at MTX start and over the following year.Clusters of MTX ‘response’ were uncovered using multivariate group-based trajectory modelling separately in discovery and verification cohorts. Clusters were compared descriptively to ACR Pedi 30/90 scores, and multivariate logistic regression models predicted cluster-group assignment. Findings: The discovery cohorts included 657 CYP and verification cohorts 1241 CYP. Six clusters were identified: Fast improvers (11%), Slow Improvers (16%), Improve-Relapse (7%), Persistent Disease (44%), Persistent PGA (8%) and Persistent PGE (13%), the latter two characterised by improvement in all features except one. Factors associated with clusters included ethnicity, ILAR category, age, PGE, and ESR scores at MTX start, with predictive model area under the curve values of 0.65–0.71. Singular ACR Pedi 30/90 scores at 6 and 12 months could not capture speeds of improvement, relapsing courses or diverging disease patterns. Interpretation: Six distinct patterns following initiation of MTX have been identified using methods in artificial intelligence. These clusters demonstrate the limitations in traditional yes/no treatment response assessment (e.g., ACRPedi30) and can form the basis ...
Keywords	Juvenile idiopathic arthritis ; Machine learning ; Treatment outcome ; Epidemiology ; Methotrexate ; Medicine ; R ; Medicine (General) ; R5-920
Subject code	310
Language	English
Publishing date	2024-02-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Author Correction

Mun-Kit Choy / Biola M. Javierre / Simon G. Williams / Stephanie L. Baross / Yingjuan Liu / Steven W. Wingett / Artur Akbarov / Chris Wallace / Paula Freire-Pritchett / Peter J. Rugg-Gunn / Mikhail Spivakov / Peter Fraser / Bernard D. Keavney

Nature Communications, Vol 9, Iss 1, Pp 1-

Promoter interactome of human embryonic stem cell-derived cardiomyocytes connects GWAS regions to cardiac gene networks

2018 Volume 1

Abstract: In the original version of the Article, the gene symbol for tissue factor pathway inhibitor was inadvertently given as ‘TFP1’ instead of ‘TFPI’. This has now been corrected in both the PDF and HTML versions of the Article. ...

Abstract	In the original version of the Article, the gene symbol for tissue factor pathway inhibitor was inadvertently given as ‘TFP1’ instead of ‘TFPI’. This has now been corrected in both the PDF and HTML versions of the Article.
Keywords	Science ; Q
Language	English
Publishing date	2018-11-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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