The influence of adult hip shape genetic variants on adolescent hip shape : Findings from a population-based DXA study

Acknowledgments: We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. The UK Medical Research Council and the Wellcome Trust (ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents /grant-acknowledgements.pdf). GWAS data was generated at Laboratory Corporation of America (LabCorp Holdings, Burlington, NC, USA) by 23andMe and small subset was also performed at Wellcome Sanger Institute to check data quality. MF was supported by a Wellcome Trust PhD studentship (ref: 105504/Z/14/Z). LP works in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol which is supported by the Medical Research Council and the University of Bristol (MC_UU_00011/1). This publication is the work of the authors and MF will serve as guarantor for the contents of this paper. None of the funders had any influence on data collection, analysis, interpretation of the results, or writing of the paper.Peer reviewedPublisher PD

Investigation of the Relationship Between Susceptibility Loci for Hip Osteoarthritis and Dual X-Ray Absorptiometry–Derived Hip Shape in a Population-Based Cohort of Perimenopausal Women

This publication is the work of the authors and does not necessarily reflect the views of any funders. Supported by the UK Medical Research Council (grant G1001357 for collection of hip shape), and the Wellcome Trust (grants WT092830M for collection of hip shape and WT088806 for genotyping). Core support for the Avon Longitudinal Study of Parents and Children is provided by the UK Medical Research Council, the Wellcome Trust (102215/2/13/2), and the University of Bristol. Dr. Baird's work was supported by Arthritis Research UK (grant 20244). Mr. Faber's work was supported by an Elizabeth Blackwell Institute Clinical Research Primer Scheme.Peer reviewedPostprin

Recent developments in mendelian randomization studies

Mendelian randomization (MR) is a strategy for evaluating causality in observational epidemiological studies. MR exploits the fact that genotypes are not generally susceptible to reverse causation and confounding, due to their fixed nature and Mendel's First and Second Laws of Inheritance. MR has the potential to provide information on causality in many situations where randomized controlled trials are not possible, but the results of MR studies must be interpreted carefully to avoid drawing erroneous conclusions.In this review, we outline the principles behind MR, as well as assumptions and limitations of the method. Extensions to the basic approach are discussed, including two-sample MR, bidirectional MR, two-step MR, multivariable MR, and factorial MR. We also consider some new applications and recent developments in the methodology, including its ability to inform drug development, automation of the method using tools such as MR-Base, and phenome-wide and hypothesis-free MR.In conjunction with the growing availability of large-scale genomic databases, higher level of automation and increased robustness of the methods, MR promises to be a valuable strategy to examine causality in complex biological/omics networks, inform drug development and prioritize intervention targets for disease prevention in the future

Inflammatory Properties and Adjuvant Potential of Synthetic Glycolipids Homologous to Mycolate Esters of the Cell Wall of Mycobacterium tuberculosis

&lt;p&gt;The cell wall of mycobacteria is characterised by glycolipids composed of different classes of mycolic acids (MAs; alpha-, keto-, and methoxy-) and sugars (trehalose, glucose, and arabinose). Studies using mutant Mtb strains have shown that the structure of MAs influences the inflammatory potential of these glycolipids. As mutant Mtb strains possess a complex mixture of glycolipids, we analysed the inflammatory potential of single classes of mycolate esters of the Mtb cell wall using 38 different synthetic analogues. Our results show that synthetic trehalose dimycolate (TDM) and trehalose, glucose, and arabinose monomycolates (TMM, GMM, and AraMM) activate bone marrow-derived dendritic cells in terms of the production of pro-inflammatory cytokines (IL-6 and TNF-&amp;alpha;) and reactive oxygen species, upregulation of costimulatory molecules, and activation of NLRP3 inflammasome by a mechanism dependent on Mincle. These findings demonstrate that Mincle receptor can also recognise pentose esters and seem to contradict the hypothesis that production of GMM is an escape mechanism used by pathogenic mycobacteria to avoid recognition by the innate immune system. Finally, our experiments indicate that TMM and GMM, as well as TDM, can promote Th1 and Th17 responses in mice in an OVA immunisation model, and that further analysis of their potential as novel adjuvants for subunit vaccines is warranted.&lt;/p&gt;</p

Multi-ancestry Mendelian randomization of omics traits revealing drug targets of COVID-19 severity

BACKGROUND: Recent omic studies prioritised several drug targets associated with coronavirus disease 2019 (COVID-19) severity. However, little evidence was provided to systematically estimate the effect of drug targets on COVID-19 severity in multiple ancestries. METHODS: In this study, we applied Mendelian randomization (MR) and colocalization approaches to understand the putative causal effects of 16,059 transcripts and 1608 proteins on COVID-19 severity in European and effects of 610 proteins on COVID-19 severity in African ancestry. We further integrated genetics, clinical and literature evidence to prioritise drug targets. Additional sensitivity analyses including multi-trait colocalization and phenome-wide MR were conducted to test for MR assumptions. FINDINGS: MR and colocalization prioritized four protein targets, FCRL3, ICAM5, ENTPD5 and OAS1 that showed effect on COVID-19 severity in European ancestry. One protein target, SERPINA1 showed a stronger effect in African ancestry but much weaker effect in European ancestry (odds ratio [OR] in Africans=0.369, 95%CI=0.203 to 0.668, P = 9.96 × 10(−4); OR in Europeans=1.021, 95%CI=0.901 to 1.157, P = 0.745), which suggested that increased level of SERPINA1 will reduce COVID-19 risk in African ancestry. One protein, ICAM1 showed suggestive effect on COVID-19 severity in both ancestries (OR in Europeans=1.152, 95%CI=1.063 to 1.249, P = 5.94 × 10(−4); OR in Africans=1.481, 95%CI=1.008 to 2.176; P = 0.045). The OAS1, SERPINA1 and ICAM1 effects were replicated using updated COVID-19 severity data in the two ancestries respectively, where alternative splicing events in OAS1 and ICAM1 also showed marginal effects on COVID-19 severity in Europeans. The phenome-wide MR of the prioritised targets on 622 complex traits provided information on potential beneficial effects on other diseases and suggested little evidence of adverse effects on major complications. INTERPRETATION: Our study identified six proteins as showing putative causal effects on COVID-19 severity. OAS1 and SERPINA1 were targets of existing drugs in trials as potential COVID-19 treatments. ICAM1, ICAM5 and FCRL3 are related to the immune system. Across the six targets, OAS1 has no reliable instrument in African ancestry; SERPINA1, FCRL3, ICAM5 and ENTPD5 showed a different level of putative causal evidence in European and African ancestries, which highlights the importance of more powerful ancestry-specific GWAS and value of multi-ancestry MR in informing the effects of drug targets on COVID-19 across different populations. This study provides a first step towards clinical investigation of beneficial and adverse effects of COVID-19 drug targets. FUNDING: No

Identifying Highly Penetrant Disease Causal Mutations Using Next Generation Sequencing: Guide to Whole Process

Recent technological advances have created challenges for geneticists and a need to adapt to a wide range of new bioinformatics tools and an expanding wealth of publicly available data (e.g., mutation databases, and software). This wide range of methods and a diversity of file formats used in sequence analysis is a significant issue, with a considerable amount of time spent before anyone can even attempt to analyse the genetic basis of human disorders. Another point to consider that is although many possess “just enough” knowledge to analyse their data, they do not make full use of the tools and databases that are available and also do not fully understand how their data was created. The primary aim of this review is to document some of the key approaches and provide an analysis schema to make the analysis process more efficient and reliable in the context of discovering highly penetrant causal mutations/genes. This review will also compare the methods used to identify highly penetrant variants when data is obtained from consanguineous individuals as opposed to nonconsanguineous; and when Mendelian disorders are analysed as opposed to common-complex disorders

HAPRAP: a haplotype-based iterative method for statistical fine mapping using GWAS summary statistics

Motivation Fine mapping is a widely used approach for identifying the causal variant(s) at disease-associated loci. Standard methods (e.g. multiple regression) require individual level genotypes. Recent fine mapping methods using summary-level data require the pairwise correlation coefficients (r2 ) of the variants. However, haplotypes rather than pairwise r2 , are the true biological representation of linkage disequilibrium (LD) among multiple loci. In this article, we present an empirical iterative method, HAPlotype Regional Association analysis Program (HAPRAP), that enables fine mapping using summary statistics and haplotype information from an individual-level reference panel. Results Simulations with individual-level genotypes show that the results of HAPRAP and multiple regression are highly consistent. In simulation with summary-level data, we demonstrate that HAPRAP is less sensitive to poor LD estimates. In a parametric simulation using Genetic Investigation of ANthropometric Traits height data, HAPRAP performs well with a small training sample size (N < 2000) while other methods become suboptimal. Moreover, HAPRAP’s performance is not affected substantially by single nucleotide polymorphisms (SNPs) with low minor allele frequencies. We applied the method to existing quantitative trait and binary outcome meta-analyses (human height, QTc interval and gallbladder disease); all previous reported association signals were replicated and two additional variants were independently associated with human height. Due to the growing availability of summary level data, the value of HAPRAP is likely to increase markedly for future analyses (e.g. functional prediction and identification of instruments for Mendelian randomization)

How Can the EU Beating Cancer Plan Help in Tackling Lung Cancer, Colorectal Cancer, Breast Cancer and Melanoma?

Cancer is the second leading cause of mortality in EU countries, and the needs to tackle cancer are obvious. New scientific understanding, techniques and methodologies are opening up horizons for significant improvements in diagnosis and care. However, take-up is uneven, research needs and potential outstrip currently available resources, manifestly beneficial practices—such as population-level screening for lung cancer—are still not generalised, and the quality of life of patients and survivors is only beginning to be given attention it merits. This paper, mainly based on a series of multistakeholder expert workshops organised by the European Alliance for Personalised Medicine (EAPM), looks at some of those specifics in the interest of planning a way forward. Part of this exercise also involves taking account of the specific nature of Europe and its constituent countries, where the complexities of planning a way forward are redoubled by the wide variations in national and regional approaches to cancer, local epidemiology and the wide disparities in health systems. Despite all the differences between cancers and national and regional resources and approaches to cancer care, there is a common objective in pursuing broader and more equal access to the best available care for all European citizens

How Can the EU Beating Cancer Plan Help in Tackling Lung Cancer, Colorectal Cancer, Breast Cancer and Melanoma?

Cancer is the second leading cause of mortality in EU countries, and the needs to tackle cancer are obvious. New scientific understanding, techniques and methodologies are opening up horizons for significant improvements in diagnosis and care. However, take-up is uneven, research needs and potential outstrip currently available resources, manifestly beneficial practices—such as population-level screening for lung cancer—are still not generalised, and the quality of life of patients and survivors is only beginning to be given attention it merits. This paper, mainly based on a series of multistakeholder expert workshops organised by the European Alliance for Personalised Medicine (EAPM), looks at some of those specifics in the interest of planning a way forward. Part of this exercise also involves taking account of the specific nature of Europe and its constituent countries, where the complexities of planning a way forward are redoubled by the wide variations in national and regional approaches to cancer, local epidemiology and the wide disparities in health systems. Despite all the differences between cancers and national and regional resources and approaches to cancer care, there is a common objective in pursuing broader and more equal access to the best available care for all European citizens

Oscillatory activity in the infant brain and the representation of small numbers

Gamma-band oscillatory activity (GBA) is an established neural signature of sustained occluded object representation in infants and adults. However, it is not yet known whether the magnitude of GBA in the infant brain reflects the quantity of occluded items held in memory. To examine this, we compared GBA of 6–8 month-old infants during occlusion periods after the representation of two objects vs. that of one object. We found that maintaining a representation of two objects during occlusion resulted in significantly greater GBA relative to maintaining a single object. Further, this enhancement was located in the right occipital region, which is consistent with previous object representation research in adults and infants. We conclude that enhanced GBA reflects neural processes underlying infants’ representation of small numbers