Publications
189 results found
Couto Alves A, Valcarcel B, Makinen V, et al., 2017, Metabolic profiling of polycystic ovary syndrome reveals interactions with abdominal obesity, International Journal of Obesity, Vol: 41, Pages: 1331-1340, ISSN: 1476-5497
Background: Polycystic ovary syndrome (PCOS) is a common reproductive disorder associated with metabolic disturbances including obesity, insulin resistance, and diabetes mellitus. Here we investigate whether changes in the metabolic profile of PCOS women are driven by increased tendency to obesity or are specific features of PCOS related to increased testosterone levels.Design and Methods: We conducted an NMR metabolomics association study of PCOS cases (n=145) and controls (n=687) nested in a population-based birth cohort (n=3,127). Subjects were 31 years old at examination. The main analyses were adjusted for waist circumference (WC) as a proxy measure of central obesity. Subsequently, metabolite concentrations were compared between cases and controls within pre-defined WC strata. On each stratum, additional metabolomics association analyses with testosterone levels were conducted separately among cases and controls.Results: Overall, women with PCOS showed more adverse metabolite profiles than the controls. Four lipid fractions in different subclasses of very low density lipoprotein (VLDL) were associated with PCOS, after adjusting for WC and correction for multiple testing (P<0.002). In stratified analysis the PCOS women within large WC strata (≥98 cm) had significantly lower high density lipoprotein (HDL) levels, ApoA1 and albumin values compared to the controls. Testosterone levels were significantly associated with VLDL and serum lipids in PCOS cases with large WC but not in the controls. The higher testosterone levels, adjusted for WC, adversely associated with insulin levels and HOMA IR in cases but not in the controls.Conclusions: Our findings show that both abdominal obesity and hyperandrogenism contribute to the dyslipidaemia and other metabolic traits of PCOS which all may negatively contribute to the long term health of women with PCOS.
Kaforou M, Herberg JA, Wright VJ, et al., 2017, Diagnosis of bacterial infection using a 2-transcript host RNA signature in febrile infants 60 days or younger, JAMA: Journal of the American Medical Association, Vol: 317, Pages: 1577-1578, ISSN: 0098-7484
Chen W, Robertson AJ, Ganesamoorthy D, et al., 2017, sCNAphase: using haplotype resolved read depth to genotype somatic copy number alterations from low cellularity aneuploid tumors, NUCLEIC ACIDS RESEARCH, Vol: 45, ISSN: 0305-1048
- Author Web Link
- Cite
- Citations: 3
Minh DC, Son HN, Ganesamoorthy D, et al., 2017, Scaffolding and completing genome assemblies in real-time with nanopore sequencing, NATURE COMMUNICATIONS, Vol: 8
- Author Web Link
- Cite
- Citations: 69
Shimizu C, Eleftherohorinou H, Wright VJ, et al., 2016, Genetic variation in the SLC8A1 calcium signaling pathway is associated with susceptibility to Kawasaki disease and coronary artery abnormalities, Circulation. Cardiovascular Genetics, Vol: 9, Pages: 559-568, ISSN: 1942-3268
BACKGROUND: -Kawasaki disease (KD) is an acute pediatric vasculitis in which host genetics influence both susceptibility to KD and the formation of coronary artery aneurysms. Variants discovered by genome-wide association studies (GWAS) and linkage studies only partially explain the influence of genetics on KD susceptibility. METHODS AND RESULTS: -To search for additional functional genetic variation, we performed pathway and gene stability analysis on a GWAS dataset. Pathway analysis using European GWAS data identified 100 significantly associated pathways (p< 5 ×10(-4)). Gene stability selection identified 116 single nucleotide polymorphisms (SNPs) in 26 genes that were responsible for driving the pathway associations and gene ontology analysis demonstrated enrichment for calcium transport (p=1.05 ×10(-4)). Three SNPs in solute carrier family 8 member 1 (SLC8A1), a sodium/calcium exchanger encoding NCX1, were validated in an independent Japanese GWAS dataset (metaanalysis p=0.0001). Patients homozygous for the A (risk) allele of rs13017968 had higher rates of coronary artery abnormalities (p=0.029). NCX1, the protein encoded by SLC8A1, was expressed in spindle-shaped and inflammatory cells in the aneurysm wall. Increased intracellular calcium mobilization was observed in B cell lines from healthy controls carrying the risk allele. CONCLUSIONS: -Pathway-based association analysis followed by gene stability selection proved to be a valuable tool for identifying risk alleles in a rare disease with complex genetics. The role of SLC8A1 polymorphisms in altering calcium flux in cells that mediate coronary artery damage in KD suggests that this pathway may be a therapeutic target and supports the study of calcineurin inhibitors in acute KD.
Martinón-Torres F, Png E, Khor CC, et al., 2016, Natural resistance to Meningococcal Disease related to CFH loci: Meta-analysis of genome-wide association studies, Scientific Reports, Vol: 6, ISSN: 2045-2322
Meningococcal disease (MD) remains an important infectious cause of life threatening infection in both industrialized and resource poor countries. Genetic factors influence both occurrence and severity of presentation, but the genes responsible are largely unknown. We performed a genome-wide association study (GWAS) examining 5,440,063 SNPs in 422 Spanish MD patients and 910 controls. We then performed a meta-analysis of the Spanish GWAS with GWAS data from the United Kingdom (combined cohorts: 897 cases and 5,613 controls; 4,898,259 SNPs). The meta-analysis identified strong evidence of association (P-value ≤ 5 × 10(-8)) in 20 variants located at the CFH gene. SNP rs193053835 showed the most significant protective effect (Odds Ratio (OR) = 0.62, 95% confidence interval (C.I.) = 0.52-0.73; P-value = 9.62 × 10(-9)). Five other variants had been previously reported to be associated with susceptibility to MD, including the missense SNP rs1065489 (OR = 0.64, 95% C.I.) = 0.55-0.76, P-value = 3.25 × 10(-8)). Theoretical predictions point to a functional effect of rs1065489, which may be directly responsible for protection against MD. Our study confirms the association of CFH with susceptibility to MD and strengthens the importance of this link in understanding pathogenesis of the disease.
Herberg JA, Kaforou M, Wright VJ, et al., 2016, Diagnostic Test Accuracy of a 2-Transcript Host RNA Signature for Discriminating Bacterial vs Viral Infection in Febrile Children, Journal of the American Medical Association, Vol: 316, Pages: 835-845, ISSN: 0002-9955
IMPORTANCE: Because clinical features do not reliably distinguish bacterial from viral infection, many children worldwide receive unnecessary antibiotic treatment, while bacterial infection is missed in others. OBJECTIVE: To identify a blood RNA expression signature that distinguishes bacterial from viral infection in febrile children. DESIGN, SETTING, AND PARTICIPANTS: Febrile children presenting to participating hospitals in the United Kingdom, Spain, the Netherlands, and the United States between 2009-2013 were prospectively recruited, comprising a discovery group and validation group. Each group was classified after microbiological investigation as having definite bacterial infection, definite viral infection, or indeterminate infection. RNA expression signatures distinguishing definite bacterial from viral infection were identified in the discovery group and diagnostic performance assessed in the validation group. Additional validation was undertaken in separate studies of children with meningococcal disease (n = 24) and inflammatory diseases (n = 48) and on published gene expression datasets. EXPOSURES: A 2-transcript RNA expression signature distinguishing bacterial infection from viral infection was evaluated against clinical and microbiological diagnosis. MAIN OUTCOMES AND MEASURES: Definite bacterial and viral infection was confirmed by culture or molecular detection of the pathogens. Performance of the RNA signature was evaluated in the definite bacterial and viral group and in the indeterminate infection group. RESULTS: The discovery group of 240 children (median age, 19 months; 62% male) included 52 with definite bacterial infection, of whom 36 (69%) required intensive care, and 92 with definite viral infection, of whom 32 (35%) required intensive care. Ninety-six children had indeterminate infection. Analysis of RNA expression data identified a 38-transcript signature distinguishing bacterial from viral infection. A smaller
Minh DC, Ganesamoorthy D, Elliott AG, et al., 2016, Streaming algorithms for identification of pathogens and antibiotic resistance potential from real-time MinION™ sequencing, GIGASCIENCE, Vol: 5, ISSN: 2047-217X
- Author Web Link
- Cite
- Citations: 57
Elliott AG, Ganesamoorthy D, Coin L, et al., 2016, Complete Genome Sequence of Klebsiella quasipneumoniae subsp. similipneumoniae Strain ATCC 700603, Genome Announcements, Vol: 4, ISSN: 2169-8287
Klebsiella quasipneumoniae subsp. similipneumoniae strain ATCC 700603, formerly known as K. pneumoniae K6, is known for producing extended-spectrum β-lactamase (ESBL) enzymes that can hydrolyze oxyimino-β-lactams, resulting in resistance to these drugs. We herein report the complete genome of strain ATCC 700603 and show that the ESBL genes are plasmid-encoded.
Li J, Woods SL, Healey S, et al., 2016, Point mutations in exon 1B of APC reveal gastric adenocarcinoma and proximal polyposis of the stomach as a familial adenomatous polyposis variant, American Journal of Human Genetics, Vol: 98, Pages: 830-842, ISSN: 1537-6605
Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is an autosomal-dominant cancer-predisposition syndrome with a significant risk of gastric, but not colorectal, adenocarcinoma. We mapped the gene to 5q22 and found loss of the wild-type allele on 5q in fundic gland polyps from affected individuals. Whole-exome and -genome sequencing failed to find causal mutations but, through Sanger sequencing, we identified point mutations in APC promoter 1B that co-segregated with disease in all six families. The mutations reduced binding of the YY1 transcription factor and impaired activity of the APC promoter 1B in luciferase assays. Analysis of blood and saliva from carriers showed allelic imbalance of APC, suggesting that these mutations lead to decreased allele-specific expression in vivo. Similar mutations in APC promoter 1B occur in rare families with familial adenomatous polyposis (FAP). Promoter 1A is methylated in GAPPS and sporadic FGPs and in normal stomach, which suggests that 1B transcripts are more important than 1A in gastric mucosa. This might explain why all known GAPPS-affected families carry promoter 1B point mutations but only rare FAP-affected families carry similar mutations, the colonic cells usually being protected by the expression of the 1A isoform. Gastric polyposis and cancer have been previously described in some FAP-affected individuals with large deletions around promoter 1B. Our finding that GAPPS is caused by point mutations in the same promoter suggests that families with mutations affecting the promoter 1B are at risk of gastric adenocarcinoma, regardless of whether or not colorectal polyps are present.
Poznik GD, Xue Y, Mendez FL, et al., 2016, Punctuated bursts in human male demography inferred from 1,244 worldwide Y-chromosome sequences, Nature Genetics, Vol: 48, Pages: 593-599, ISSN: 1546-1718
We report the sequences of 1,244 human Y chromosomes randomly ascertained from 26 worldwide populations by the 1000 Genomes Project. We discovered more than 65,000 variants, including single-nucleotide variants, multiple-nucleotide variants, insertions and deletions, short tandem repeats, and copy number variants. Of these, copy number variants contribute the greatest predicted functional impact. We constructed a calibrated phylogenetic tree on the basis of binary single-nucleotide variants and projected the more complex variants onto it, estimating the number of mutations for each class. Our phylogeny shows bursts of extreme expansion in male numbers that have occurred independently among each of the five continental superpopulations examined, at times of known migrations and technological innovations.
Minh DC, Ganesamoorthy D, Cooper MA, et al., 2015, Realtime analysis and visualization of MinION sequencing data with npReader, Bioinformatics, Vol: 32, Pages: 764-766, ISSN: 1367-4803
Motivation: The recently released Oxford Nanopore MinION sequencing platform presents many innovative features opening up potential for a range of applications not previously possible. Among these features, the ability to sequence in real-time provides a unique opportunity for many time-critical applications. While many software packages have been developed to analyze its data, there is still a lack of toolkits that support the streaming and real-time analysis of MinION sequencing data.Results: We developed npReader, an open-source software package to facilitate real-time analysis of MinION sequencing data. npReader can simultaneously extract sequence reads and stream them to downstream analysis pipelines while the samples are being sequenced on the MinION device. It provides a command line interface for easy integration into a bioinformatics work flow, as well as a graphical user interface which concurrently displays the statistics of the run. It also provides an application programming interface for development of streaming algorithms in order to fully utilize the extent of nanopore sequencing potential.Availability and implementation: npReader is written in Java and is freely available at https://github.com/mdcao/npReader.
Altshuler DM, Durbin RM, Abecasis GR, et al., 2015, A global reference for human genetic variation, Nature, Vol: 526, Pages: 68-74, ISSN: 0028-0836
The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies.
Ramasamy A, Trabzuni D, Guelfi S, et al., 2014, Genetic variability in the regulation of gene expression in ten regions of the human brain, NATURE NEUROSCIENCE, Vol: 17, Pages: 1418-1428, ISSN: 1097-6256
- Author Web Link
- Cite
- Citations: 470
Bellos E, Kumar V, Lin C, et al., 2014, cnvCapSeq : detecting copy number variation in long-range targeted resequencing data, Nucleic Acids Research, ISSN: 0305-1048
Bellos E, Coin LJM, 2014, cnvOffSeq: detecting intergenic copy number variation using off-target exome sequencing data, BIOINFORMATICS, Vol: 30, Pages: I639-I645, ISSN: 1367-4803
- Author Web Link
- Cite
- Citations: 10
Anderson ST, Kaforou M, Brent AJ, et al., 2014, Diagnosis of Childhood Tuberculosis and Host RNA Expression in Africa, New England Journal of Medicine, Vol: 370, Pages: 1712-1723, ISSN: 1533-4406
White HD, Held C, Stewart R, et al., 2014, Darapladib for Preventing Ischemic Events in Stable Coronary Heart Disease, New England Journal of Medicine, Vol: 370, Pages: 1702-1711, ISSN: 1533-4406
Zhang F, Chen R, Liu D, et al., 2013, YHap: a population model for probabilistic assignment of Y haplogroups from re-sequencing data, BMC BIOINFORMATICS, Vol: 14, ISSN: 1471-2105
- Author Web Link
- Cite
- Citations: 3
Kaforou M, Wright VJ, Oni T, et al., 2013, Detection of Tuberculosis in HIV-Infected and -Uninfected African Adults Using Whole Blood RNA Expression Signatures: A Case-Control Study., Plos Medicine, Vol: 10
Background: A major impediment to tuberculosis control in Africa is the difficulty in diagnosing active tuberculosis (TB),particularly in the context of HIV infection. We hypothesized that a unique host blood RNA transcriptional signature woulddistinguish TB from other diseases (OD) in HIV-infected and -uninfected patients, and that this could be the basis of a simplediagnostic test.Methods and Findings: Adult case-control cohorts were established in South Africa and Malawi of HIV-infected or -uninfected individuals consisting of 584 patients with either TB (confirmed by culture of Mycobacterium tuberculosis [M.TB]from sputum or tissue sample in a patient under investigation for TB), OD (i.e., TB was considered in the differentialdiagnosis but then excluded), or healthy individuals with latent TB infection (LTBI). Individuals were randomized intotraining (80%) and test (20%) cohorts. Blood transcriptional profiles were assessed and minimal sets of significantlydifferentially expressed transcripts distinguishing TB from LTBI and OD were identified in the training cohort. A 27 transcriptsignature distinguished TB from LTBI and a 44 transcript signature distinguished TB from OD. To evaluate our signatures, weused a novel computational method to calculate a disease risk score (DRS) for each patient. The classification based on thisscore was first evaluated in the test cohort, and then validated in an independent publically available dataset(GSE19491). In our test cohort, the DRS classified TB from LTBI (sensitivity 95%, 95% CI [87–100]; specificity 90%, 95% CI[80–97]) and TB from OD (sensitivity 93%, 95% CI [83–100]; specificity 88%, 95% CI [74–97]). In the independent validationcohort, TB patients were distinguished both from LTBI individuals (sensitivity 95%, 95% CI [85–100]; specificity 94%, 95% CI[84–100]) and OD patients (sensitivity 100%, 95% CI [100–100]; specificity 96%, 95% CI [93–100]). Limitations of our studyin
Alves AC, Bruhn S, Ramasamy A, et al., 2013, Dysregulation of complement system and CD4+T cell activation pathways implicated in allergic response, PLoS One, Vol: 8, Pages: 1-15, ISSN: 1932-6203
Allergy is a complex disease that is likely to involve dysregulated CD4+ T cell activation. Here we propose a novel methodology to gain insight into how coordinated behaviour emerges between disease-dysregulated pathways in response to pathophysiological stimuli. Using peripheral blood mononuclear cells of allergic rhinitis patients and controls cultured with and without pollen allergens, we integrate CD4+ T cell gene expression from microarray data and genetic markers of allergic sensitisation from GWAS data at the pathway level using enrichment analysis; implicating the complement system in both cellular and systemic response to pollen allergens. We delineate a novel disease network linking T cell activation to the complement system that is significantly enriched for genes exhibiting correlated gene expression and protein-protein interactions, suggesting a tight biological coordination that is dysregulated in the disease state in response to pollen allergen but not to diluent. This novel disease network has high predictive power for the gene and protein expression of the Th2 cytokine profile (IL-4, IL-5, IL-10, IL-13) and of the Th2 master regulator (GATA3), suggesting its involvement in the early stages of CD4+ T cell differentiation. Dissection of the complement system gene expression identifies 7 genes specifically associated with atopic response to pollen, including C1QR1, CFD, CFP, ITGB2, ITGAX and confirms the role of C3AR1 and C5AR1. Two of these genes (ITGB2 and C3AR1) are also implicated in the network linking complement system to T cell activation, which comprises 6 differentially expressed genes. C3AR1 is also significantly associated with allergic sensitisation in GWAS data.
Levin M, Kaforou M, Herberg J, et al., 2013, METHOD FOR CALCULATING A DISEASE RISK SCORE, PCT/GB2013/050225
The present disclosure relates to a general method for converting complex gene expression data into a simple, composite disease risk score which can be used for the development of rapid diagnostic tests suitable for clinical use for the determination of the presence of an infection or disease in a host.
Munhoz RP, Teive HA, Eleftherohorinou H, et al., 2013, Demographic and motor features associated with the occurrence of neuropsychiatric and sleep complications of Parkinson's disease, JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, Vol: 84, Pages: 883-887, ISSN: 0022-3050
- Author Web Link
- Cite
- Citations: 20
Bonnelykke K, Matheson MC, Pers TH, et al., 2013, Meta-analysis of genome-wide association studies identifies ten loci influencing allergic sensitization, NATURE GENETICS, Vol: 45, Pages: 902-U290, ISSN: 1061-4036
- Author Web Link
- Cite
- Citations: 192
Ikram MA, Fornage M, Smith AV, et al., 2013, Common variants at 6q22 and 17q21 are associated with intracranial volume (vol 44, pg 539, 2012), NATURE GENETICS, Vol: 45, Pages: 713-713, ISSN: 1061-4036
Taal HR, St Pourcain B, Thiering E, et al., 2013, Common variants at 12q15 and 12q24 are associated with infant head circumference (vol 44, pg 532, 2012), NATURE GENETICS, Vol: 45, Pages: 713-713, ISSN: 1061-4036
- Author Web Link
- Cite
- Citations: 1
Walters RG, Coin LJ, Ruokonen A, et al., 2013, Rare genomic structural variants in complex disease: lessons from the replication of associations with obesity, PLoS One, Vol: 8, ISSN: 1932-6203
The limited ability of common variants to account for the genetic contribution to complex disease has prompted searches for rare variants of large effect, to partly explain the 'missing heritability'. Analyses of genome-wide genotyping data have identified genomic structural variants (GSVs) as a source of such rare causal variants. Recent studies have reported multiple GSV loci associated with risk of obesity. We attempted to replicate these associations by similar analysis of two familial-obesity case-control cohorts and a population cohort, and detected GSVs at 11 out of 18 loci, at frequencies similar to those previously reported. Based on their reported frequencies and effect sizes (OR>/=25), we had sufficient statistical power to detect the large majority (80%) of genuine associations at these loci. However, only one obesity association was replicated. Deletion of a 220 kb region on chromosome 16p11.2 has a carrier population frequency of 2x10(-4) (95% confidence interval [9.6x10(-5)-3.1x10(-4)]); accounts overall for 0.5% [0.19%-0.82%] of severe childhood obesity cases (P = 3.8x10(-10); odds ratio = 25.0 [9.9-60.6]); and results in a mean body mass index (BMI) increase of 5.8 kg.m(-2) [1.8-10.3] in adults from the general population. We also attempted replication using BMI as a quantitative trait in our population cohort; associations with BMI at or near nominal significance were detected at two further loci near KIF2B and within FOXP2, but these did not survive correction for multiple testing. These findings emphasise several issues of importance when conducting rare GSV association, including the need for careful cohort selection and replication strategy, accurate GSV identification, and appropriate correction for multiple testing and/or control of false discovery rate. Moreover, they highlight the potential difficulty in replicating rare CNV associations across different populations. Nevertheless, we show that such studies are potentially valuable for th
Shao H, Bellos E, Yin H, et al., 2013, A population model for genotyping indels from next-generation sequence data, NUCLEIC ACIDS RESEARCH, Vol: 41, ISSN: 0305-1048
- Author Web Link
- Cite
- Citations: 4
al Basatena N-KS, Hoggart CJ, Coin LJ, et al., 2013, The Effect of Genomic Inversions on Estimation of Population Genetic Parameters from SNP Data, GENETICS, Vol: 193, Pages: 243-253, ISSN: 0016-6731
- Author Web Link
- Cite
- Citations: 10
Couto-Alves A, Wright VJ, Perumal K, et al., 2013, A new scoring system derived from base excess and platelet count at presentation predicts mortality in paediatric meningococcal sepsis, CRITICAL CARE, Vol: 17, ISSN: 1466-609X
- Author Web Link
- Cite
- Citations: 19
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.