Publications by year
Weedon MN, Jackson L, Harrison JW, Ruth KS, Tyrrell J, Hattersley AT, Wright CF
(In Press). Assessing the analytical validity of SNP-chips for detecting very rare pathogenic variants: implications for direct-to-consumer genetic testing.
Assessing the analytical validity of SNP-chips for detecting very rare pathogenic variants: implications for direct-to-consumer genetic testing
ABSTRACTObjectivesTo determine the analytical validity of SNP-chips for genotyping very rare genetic variants.DesignRetrospective study using data from two publicly available resources, the UK Biobank and the Personal Genome Project.SettingResearch biobanks and direct-to-consumer genetic testing in the UK and USA.Participants49,908 individuals recruited to UK Biobank, and 21 individuals who purchased consumer genetic tests and shared their data online via the Personal Genomes Project.Main outcome measuresWe assessed the analytical validity of genotypes from SNP-chips (index test) with sequencing data (reference standard). We evaluated the genotyping accuracy of the SNP-chips and split the results by variant frequency. We went on to select rare pathogenic variants in the BRCA1 and BRCA2 genes as an exemplar for detailed analysis of clinically-actionable variants in UK Biobank, and assessed BRCA-related cancers (breast, ovarian, prostate and pancreatic) in participants using cancer registry data.ResultsSNP-chip genotype accuracy is high overall; sensitivity, specificity and precision are all >99% for 108,574 common variants directly genotyped by the UK Biobank SNP-chips. However, the likelihood of a true positive result reduces dramatically with decreasing variant frequency; for variants with a frequency <0.001% in UK Biobank the precision is very low and only 16% of 4,711 variants from the SNP-chips confirm with sequencing data. Results are similar for SNP-chip data from the Personal Genomes Project, and 20/21 individuals have at least one rare pathogenic variant that has been incorrectly genotyped. For pathogenic variants in the BRCA1 and BRCA2 genes, the overall performance metrics of the SNP-chips in UK Biobank are sensitivity 34.6%, specificity 98.3% and precision 4.2%. Rates of BRCA-related cancers in individuals in UK Biobank with a positive SNP-chip result are similar to age-matched controls (OR 1.28, P=0.07, 95% CI: 0.98 to 1.67), while sequence-positive individuals have a significantly increased risk (OR 3.73, P=3.5×10−12, 95% CI: 2.57 to 5.40).ConclusionSNP-chips are extremely unreliable for genotyping very rare pathogenic variants and should not be used to guide health decisions without validation.SUMMARY BOXSection 1: What is already known on this topicSNP-chips are an accurate and affordable method for genotyping common genetic variants across the genome. They are often used by direct-to-consumer (DTC) genetic testing companies and research studies, but there several case reports suggesting they perform poorly for genotyping rare genetic variants when compared with sequencing.Section 2: What this study addsOur study confirms that SNP-chips are highly inaccurate for genotyping rare, clinically-actionable variants. Using large-scale SNP-chip and sequencing data from UK Biobank, we show that SNP-chips have a very low precision of <16% for detecting very rare variants (i.e. the majority of variants with population frequency of <0.001% are false positives). We observed a similar performance in a small sample of raw SNP-chip data from DTC genetic tests. Very rare variants assayed using SNP-chips should not be used to guide health decisions without validation. Abstract
Oram RA, Weedon M, Wood A, Beaumont R, Tyrrell J (In Press). Development and Standardization of an Improved Type 1 Diabetes Genetic Risk Score for Use in Newborn Screening and Incident
Diagnosis. Diabetes Care
Jones SE, van Hees VT, Mazzotti DR, Marques-Vidal P, Sabia S, van der Spek A, Dashti HS, Engmann J, Kocevska D, Tyrrell J, et al
(In Press). Genetic studies of accelerometer-based sleep measures yield new insights into human sleep behaviour. Nature Communications
Genetic studies of accelerometer-based sleep measures yield new insights into human sleep behaviour
Sleep is an essential human function but its regulation is poorly understood. Using accelerometer data from 85,670 UK Biobank participants, we perform a genome-wide association study of 8 derived sleep traits representing sleep quality, quantity and timing, and validate our findings in 5,819 individuals. We identify 47 genetic associations at P Abstract
Weedon M, Jackson L, Harrison J, Ruth K, Tyrrell J, Hattersley A, Wright C (In Press). Use of SNP chips to detect rare pathogenic variants: retrospective, population based diagnostic evaluation. BMJ: British Medical Journal
Masoli JAH, Jeffries A, Temperton B, Auckland C, Michelsen M, Warwick-Dugdale J, Manley R, Farbos A, Ellard S, Knight B, et al
(In Press). Viral genetic sequencing identifies staff transmission of COVID-19 is important in a community hospital outbreak.
Viral genetic sequencing identifies staff transmission of COVID-19 is important in a community hospital outbreak
AbstractBackgroundWe have successfully used whole-genome sequencing to provide additional information for transmission pathways in infectious spread. We report and interpret genomic sequencing results in clinical context from a large outbreak of COVID-19 with 46 cases across staff and patients in a community hospital in the UK.MethodsFollowing multiple symptomatic cases within a two-week period, all staff and patients were screened by RT-PCR and staff subsequently had serology tests.ResultsThirty staff (25%) and 16 patients (62%) tested positive for COVID-19. Genomic sequencing data showed significant overlap of viral haplotypes in staff who had overlapping shift patterns. Patient haplotypes were more distinct from each other but had overlap with staff haplotypes.ConclusionsThis study includes clinical and genomic epidemiological detail that demonstrates the value of a combined approach. Viral genetic sequencing has identified that staff transmission of COVID-19 was important in this community hospital outbreak.Key pointsDetailed analysis of a large community hospital outbreak in older adults and staff with concurrent clinical and genomic data, including working patterns.Staff transmission was important in this community hospital outbreak.We found plausible associations between staff and patient cases. Abstract
Vicente JG, McHugh J, Bryning A, Carroll S, Harrison J, Studholme D
(2023). First identification of Xanthomonas nasturtii as the cause of black rot of watercress in Hawaii. Plant Dis
First identification of Xanthomonas nasturtii as the cause of black rot of watercress in Hawaii.
Watercress (Nasturtium officinale) has been in continuous production in Hawaii for over a century and is part of the local diet. Black rot of watercress was first identified as caused by Xanthomonas nasturtii in Florida (Vicente et al. 2017), but symptoms of this disease have also been regularly observed in Hawaii production in all islands, mostly during the rainy season from December to April in areas with poor air circulation (McHugh & Constantinides, 2004). Initially, this disease was attributed to X. campestris due to similar symptoms to black rot of brassicas. Samples of watercress with symptoms that could be attributed to a bacterial disease including yellow spots and lesions on leaves and stunting and deformation of plants in more advanced stages, were collected from a farm in Aiea in the island of Oahu, Hawaii, in October 2017. Isolations were performed at the University of Warwick. Fluid from macerated leaves was streaked into plates of King's B (KB) medium and Yeast Dextrose Calcium Carbonate Agar (YDC). After 48-72 hrs incubation at 28°C, the plates showed a range of mixed colonies. Single cream-yellow mucoid colonies were sub-cultured several times and pure isolates including WHRI 8984 were stored at -76°C as previously described (Vicente et al. 2017). Colony morphology was observed in KB plates and, in contrast to the type strain from Florida (WHRI 8853 = NCPPB 4600), isolate WHRI 8984 did not cause browning of the medium. Pathogenicity was tested on four-week old watercress and Savoy cabbage cv. Wirosa F1 plants by inoculations on leaves as previously described (Vicente et al. 2017). WHRI 8984 did not produce symptoms when inoculated on cabbage but produced typical symptoms on watercress. A re-isolation from a leaf showing a V-shaped lesion, produced isolates with the same morphology, including isolate WHRI 10007A, that was also shown to be pathogenic to watercress therefore completing the Koch's postulates. Fatty acid profiling was performed on WHRI 8984 and 10007A and controls grown on trypticase soy broth agar (TSBA) plates at 28°C for 48 hrs as described by Weller et al. (2000). Profiles were compared with the RTSBA6 v6.21 library; as the database does not include X. nasturtii, the results were only interpreted at the genus level, and both isolates were shown to be Xanthomonas sp. For molecular analysis, DNA was extracted and the gyrB partial gene was amplified and sequenced as described by Parkinson et al. (2007). Comparisons with sequences available in the National Centre for Biotechnology Information (NCBI) databases using the Basic Local Alignment Search Tool (BLAST) showed that partial gyrB of WHRI 8984 and 10007A were identical to the type strain from Florida therefore confirming that they belong to X. nasturtii. For whole genome sequencing, genomic libraries for WHRI 8984 were prepared using Illumina's Nextera XT v2 kit and sequenced on a HiSeq Rapid Run flowcell. The sequences were processed as previously described (Vicente et al. 2017) and the whole genome assembly has been deposited in GenBank (accession QUZM00000000.1); the phylogenetic tree shows that WHRI 8984 is close, but not identical to the type strain. This is the first identification of X. nasturtii in watercress crops in Hawaii. Control of this disease generally involves the use of copper bactericides and minimizing moisture on leaves by reducing overhead irrigation and increasing air circulation (McHugh & Constantinides, 2004); seed testing might help to select batches that are disease free and, in longer term, breeding for disease resistance might produce cultivars that can be part of management strategies. Abstract
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Baker S, Dougan G, Hess C, Kingston N, Lehner PJ, Lyons PA, Matheson NJ, Owehand WH, Saunders C, Summers C, et al (2022). Author Correction: SARS-CoV-2 evolution during treatment of chronic infection. Nature, 608(7922), e23-e23.
Baker S, Dougan G, Hess C, Kingston N, Lehner PJ, Lyons PA, Matheson NJ, Owehand WH, Saunders C, Summers C, et al (2022). Author Correction: Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies. Nature, 608(7922), e24-e24.
Lascelles DM, Roberts MR, Cruz L, Cruz J, Studholme DJ, Harrison J, Greer SF, Grant M, Holden JM, Carter B, et al (2022). First report of black rot caused by. <i>Xanthomonas nasturtii</i>. on watercress in Spain and Portugal. New Disease Reports, 46(2).
Aggarwal D, Page AJ, Schaefer U, Savva GM, Myers R, Volz E, Ellaby N, Platt S, Groves N, Gallagher E, et al (2022). Genomic assessment of quarantine measures to prevent SARS-CoV-2 importation and transmission. Nature Communications, 13(1).
Aggarwal D, Warne B, Jahun AS, Hamilton WL, Fieldman T, du Plessis L, Hill V, Blane B, Watkins E, Wright E, et al
(2022). Genomic epidemiology of SARS-CoV-2 in a UK university identifies dynamics of transmission. Nature Communications
Genomic epidemiology of SARS-CoV-2 in a UK university identifies dynamics of transmission
AbstractUnderstanding SARS-CoV-2 transmission in higher education settings is important to limit spread between students, and into at-risk populations. In this study, we sequenced 482 SARS-CoV-2 isolates from the University of Cambridge from 5 October to 6 December 2020. We perform a detailed phylogenetic comparison with 972 isolates from the surrounding community, complemented with epidemiological and contact tracing data, to determine transmission dynamics. We observe limited viral introductions into the university; the majority of student cases were linked to a single genetic cluster, likely following social gatherings at a venue outside the university. We identify considerable onward transmission associated with student accommodation and courses; this was effectively contained using local infection control measures and following a national lockdown. Transmission clusters were largely segregated within the university or the community. Our study highlights key determinants of SARS-CoV-2 transmission and effective interventions in a higher education setting that will inform public health policy during pandemics. Abstract
Ashford F, Best A, Dunn SJ, Ahmed Z, Siddiqui H, Melville J, Wilkinson S, Mirza J, Cumley N, Stockton J, et al (2022). SARS-CoV-2 Testing in the Community: Testing Positive Samples with the TaqMan SARS-CoV-2 Mutation Panel to Find Variants in Real Time. Journal of Clinical Microbiology, 60(4), e02408-e02421.
Fasham JDR, Leslie JS, Harrison JW, Deline J, Williams KB, Kuhl A, Schwoerer JS, Cross HE, Crosby AH, Baple EL, et al
(2022). SCN9A gene variants do not cause monogenic epilepsy in humans. Author URL
Kemp SA, Collier DA, Datir RP, Ferreira IATM, Gayed S, Jahun A, Hosmillo M, Rees-Spear C, Mlcochova P, Lumb IU, et al
(2021). SARS-CoV-2 evolution during treatment of chronic infection. Nature
SARS-CoV-2 evolution during treatment of chronic infection
The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for virus infection through the engagement of the human ACE2 protein1 and is a major antibody target. Here we show that chronic infection with SARS-CoV-2 leads to viral evolution and reduced sensitivity to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma, by generating whole-genome ultra-deep sequences for 23 time points that span 101 days and using in vitro techniques to characterize the mutations revealed by sequencing. There was little change in the overall structure of the viral population after two courses of remdesivir during the first 57 days. However, after convalescent plasma therapy, we observed large, dynamic shifts in the viral population, with the emergence of a dominant viral strain that contained a substitution (D796H) in the S2 subunit and a deletion (ΔH69/ΔV70) in the S1 N-terminal domain of the spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype were reduced in frequency, before returning during a final, unsuccessful course of convalescent plasma treatment. In vitro, the spike double mutant bearing both ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, while maintaining infectivity levels that were similar to the wild-type virus.The spike substitution mutant D796H appeared to be the main contributor to the decreased susceptibility to neutralizing antibodies, but this mutation resulted in an infectivity defect. The spike deletion mutant ΔH69/ΔV70 had a twofold higher level of infectivity than wild-type SARS-CoV-2, possibly compensating for the reduced infectivity of the D796H mutation. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy, which is associated with the emergence of viral variants that show evidence of reduced susceptibility to neutralizing antibodies in immunosuppressed individuals. Abstract
Collier DA, De Marco A, Ferreira IATM, Meng B, Datir RP, Walls AC, Kemp SA, Bassi J, Pinto D, Silacci-Fregni C, et al
(2021). Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies. NATURE
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Harrison J, Nelson K, Morcrette H, Morcrette C, Preston J, Helmer L, Titball RW, Butler CS, Wagley S (2021). The increased prevalence of Vibrio species and the first reporting of Vibrio jasicida and Vibrio rotiferianus at UK shellfish sites. Water Research, 211
Sambles C, Venkatesan L, Shittu OM, Harrison J, Moore K, Tripathi L, Grant M, Warmington R, Studholme DJ
(2020). Genome sequencing data for wild and cultivated bananas, plantains and abacá. Data in Brief
Genome sequencing data for wild and cultivated bananas, plantains and abacá
We performed shotgun genome sequencing on a total of 19 different Musa genotypes including representatives of wild banana species Musa acuminata and M. balibisiana, allopolyploid bananas and plantains, Fe'i banana, pink banana (also known as hairy banana) and abacá (also known as hemp banana). We aligned sequence reads against a previously sequenced reference genome and assessed ploidy and, in the case of allopolyploids, the contributions of the a and B genomes; this provides important quality-assurance data about the taxonomic identities of the sequenced plant material. These data will be useful for phylogenetics, crop improvement, studies of the complex story of intergenomic recombination in AAB and ABB allotriploid bananas and plantains and can be integrated into resources such as the Banana Genome Hub. Abstract
Sukcharoen K, Sharp SA, Thomas NJ, Kimmitt RA, Harrison J, Bingham C, Mozere M, Weedon MN, Tyrrell J, Barratt J, et al
(2020). IgA Nephropathy Genetic Risk Score to Estimate the Prevalence of IgA Nephropathy in UK Biobank. Kidney International Reports
IgA Nephropathy Genetic Risk Score to Estimate the Prevalence of IgA Nephropathy in UK Biobank
Background: IgA nephropathy (IgAN) is the commonest glomerulonephritis worldwide. Its prevalence is difficult to estimate, as people with mild disease do not commonly receive a biopsy diagnosis. We aimed to generate an IgA nephropathy genetic risk score (IgAN-GRS) and estimate the proportion of people with hematuria who had IgAN in the UK Biobank (UKBB). Methods: We calculated an IgAN-GRS using 14 single-nucleotide polymorphisms (SNPs) drawn from the largest European Genome-Wide Association Study (GWAS) and validated the IgAN-GRS in 464 biopsy-proven IgAN European cases from the UK Glomerulonephritis DNA Bank (UKGDB) and in 379,767 Europeans in the UKBB. We used the mean of IgAN-GRS to calculate the proportion of potential IgAN in 14,181 with hematuria and other nonspecific renal phenotypes from 379,767 Europeans in the UKBB. Results: the IgAN-GRS was higher in the IgAN cohort (4.30; 95% confidence interval [95% CI: 4.23–4.38) than in controls (3.98; 3.97–3.98; P < 0.0001). The mean GRS in UKBB participants with hematuria (n = 12,858) was higher (4.04; 4.02–4.06) than UKBB controls (3.98; 3.97–3.98; P < 0.0001) and higher in those with hematuria, hypertension, and microalbuminuria (n = 1323) (4.07; 4.02–4.13) versus (3.98; 3.97–3.98; P = 0.0003). Using the difference in these means, we estimated that IgAN accounted for 19% of noncancer hematuria and 28% with hematuria, hypertension, and microalbuminuria in UKBB. Conclusions: We used an IgAN-GRS to estimate the prevalence of IgAN contributing to common phenotypes that are not always biopsied. The noninvasive use of polygenic risk in this setting may have further utility to identify likely etiology of nonspecific renal phenotypes in large population cohorts. Abstract
Fasham J, Leslie JS, Harrison JW, Deline J, Williams KB, Kuhl A, Scott Schwoerer J, Cross HE, Crosby AH, Baple EL, et al
(2020). No association between SCN9A and monogenic human epilepsy disorders. PLOS Genetics
No association between SCN9A and monogenic human epilepsy disorders
Many studies have demonstrated the clinical utility and importance of epilepsy gene panel testing to confirm the specific aetiology of disease, enable appropriate therapeutic interventions, and inform accurate family counselling. Previously, SCN9A gene variants, in particular a c.1921A>T p.(Asn641Tyr) substitution, have been identified as a likely autosomal dominant cause of febrile seizures/febrile seizures plus and other monogenic seizure phenotypes indistinguishable from those associated with SCN1A, leading to inclusion of SCN9A on epilepsy gene testing panels. Here we present serendipitous findings of genetic studies that identify the SCN9A c.1921A>T p.(Asn641Tyr) variant at high frequency in the Amish community in the absence of such seizure phenotypes. Together with findings in UK Biobank these data refute an association of SCN9A with epilepsy, which has important clinical diagnostic implications. Abstract
Harrison JW, Tallapragada DSP, Baptist A, Sharp SA, Bhaskar S, Jog KS, Patel KA, Weedon MN, Chandak GR, Yajnik CS, et al
(2020). Type 1 diabetes genetic risk score is discriminative of diabetes in non-Europeans: evidence from a study in India. Scientific Reports
Type 1 diabetes genetic risk score is discriminative of diabetes in non-Europeans: evidence from a study in India
AbstractType 1 diabetes (T1D) is a significant problem in Indians and misclassification of T1D and type 2 diabetes (T2D) is a particular problem in young adults in this population due to the high prevalence of early onset T2D at lower BMI. We have previously shown a genetic risk score (GRS) can be used to discriminate T1D from T2D in Europeans. We aimed to test the ability of a T1D GRS to discriminate T1D from T2D and controls in Indians. We studied subjects from Pune, India of Indo-European ancestry; T1D (n = 262 clinically defined, 200 autoantibody positive), T2D (n = 345) and controls (n = 324). We used the 9 SNP T1D GRS generated in Europeans and assessed its ability to discriminate T1D from T2D and controls in Indians. We compared Indians with Europeans from the Wellcome Trust Case Control Consortium study; T1D (n = 1963), T2D (n = 1924) and controls (n = 2938). The T1D GRS was discriminative of T1D from T2D in Indians but slightly less than in Europeans (ROC AUC 0.84 v 0.87, p < 0.0001). HLA SNPs contributed the majority of the discriminative power in Indians. A T1D GRS using SNPs defined in Europeans is discriminative of T1D from T2D and controls in Indians. As with Europeans, the T1D GRS may be useful for classifying diabetes in Indians. Abstract
(2020). Use of Next Generation Sequencing to Investigate the Genomics of Bacterial Pathogens.
Use of Next Generation Sequencing to Investigate the Genomics of Bacterial Pathogens.
This thesis explores the use of next generation sequencing as a tool to investigate the genomics of bacterial pathogens of plants and humans. Abstract
Firstly, second-generation sequencing was applied to the evolution of distantly related bacterial species that have converged on common host plants (Xanthomonas bacteria on sugarcane and common-bean plants). This revealed evidence of recent horizontal gene transfer between X. phaseoli pv. phaseoli and X. citri pv. fuscans and between X. axonopodis pv. vasculorum and X. vasicola. distantly related sugarcane pathogens. Furthermore, we discovered that strains isolated from lablab bean (a close relative of common bean) form a previously unknown third distinct clade (and perhaps pathovar) and whole-genome comparisons suggested horizontal gene transfer played an important role in the evolution of host specificity in xanthomonad pathogens.
Next, second-generation sequencing was used to rapidly gain insight into novel emerging bacterial pathogens, namely unusually virulent Asian strains of the human pathogen Campylobacter jejuni and a xanthomonad causing unusual symptoms on common bean in African country of Rwanda. A type six secretion system was shown to be associated with a more serious form of campylobacteriosis and a molecular marker for an intact type six secretion system was identified. This was shown to be more prevalent in strains isolated from Asia than strains isolated in the UK, a finding which has serious implications for chicken import. Further to this the genome sequence of a newly emerging Xanthomonas bean pathogen isolated from a recent outbreak in Rwanda is presented. Analysis of the Rwandan Xanthomonas genome shows it represents the first sequenced isolate in a novel species level clade, which was subsequently named as Xanthomonas cannabis and is genetically distinct from previously known bean pathogens.
Lastly, the performance of the third-generation sequencing platform Oxford Nanopore MinION was assessed which will prove to be an exciting resource to perform bacterial genomic studies in the future. In summary, this work exemplifies the value of sequencing-based approaches for rapidly and cheaply gaining insights into evolution of bacterial pathogens
Yaghootkar H, Harrison J, Frayling T, Bell J
(2019). 'Favourable adiposity' genetic factors pinpoint to the role of subcutaneous adipose tissue and ectopic liver fat in the ethnic differences in adiposity and diabetes risk. Author URL
Bewshea CM, Ahmad T, Kennedy N, Weedon M, Harrison J, Walker G, Goodhand J, Jones S (2019). Association of Genetic Variants in NUDT15 with Thiopurine-Induced
Myelosuppression in Patients with Inflammatory Bowel Disease. JAMA - Journal of the American Medical Association, 321 (8), 773-785.
Bovijn J, Jackson L, Censin J, Chen CY, Laisk T, Laber S, Ferreira T, Pulit SL, Glastonbury CA, Smoller JW, et al
(2019). GWAS Identifies Risk Locus for Erectile Dysfunction and Implicates Hypothalamic Neurobiology and Diabetes in Etiology. American Journal of Human Genetics
GWAS Identifies Risk Locus for Erectile Dysfunction and Implicates Hypothalamic Neurobiology and Diabetes in Etiology
Erectile dysfunction (ED) is a common condition affecting more than 20% of men over 60 years, yet little is known about its genetic architecture. We performed a genome-wide association study of ED in 6,175 case subjects among 223,805 European men and identified one locus at 6q16.3 (lead variant rs57989773, OR 1.20 per C-allele; p = 5.71 × 10−14), located between MCHR2 and SIM1. In silico analysis suggests SIM1 to confer ED risk through hypothalamic dysregulation. Mendelian randomization provides evidence that genetic risk of type 2 diabetes mellitus is a cause of ED (OR 1.11 per 1-log unit higher risk of type 2 diabetes). These findings provide insights into the biological underpinnings and the causes of ED and may help prioritize the development of future therapies for this common disorder. Abstract
Jones SE, Lane JM, Wood AR, van Hees VT, Tyrrell J, Beaumont RN, Jeffries AR, Dashti HS, Hillsdon M, Ruth KS, et al
(2019). Genome-wide association analyses of chronotype in 697,828 individuals provides insights into circadian rhythms. Nature Communications
Genome-wide association analyses of chronotype in 697,828 individuals provides insights into circadian rhythms
Using genome-wide data from 697,828 UK Biobank and 23andMe participants, we increase the number of identified loci associated with being a morning person, a behavioural indicator of a person’s underlying circadian rhythm, from 24 to 351. Using data from 85,760 individuals with activity-monitor derived measures of sleep timing we demonstrate that the chronotype loci influence sleep timing: the mean sleep timing of the 5% of individuals carrying the most morningness alleles is 25 minutes earlier than the 5% carrying the fewest. The loci are enriched for genes involved in circadian regulation, cAMP, glutamate and insulin signalling pathways, and those expressed in the retina, hindbrain, hypothalamus, and pituitary. Using Mendelian Randomisation, we show that being a morning person is causally associated with better mental health but does not affect BMI or risk of Type 2 diabetes. This study offers insights into circadian biology and its links to disease in humans. Abstract
Schafmayer C, Harrison JW, Buch S, Lange C, Reichert MC, Hofer P, Cossais F, Kupcinskas J, von Schönfels W, Schniewind B, et al
(2019). Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms. Gut
Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms.
OBJECTIVE: Diverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease. DESIGN: Discovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry. RESULTS: We discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p Abstract
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Tyrrell J, Mulugeta A, Wood AR, Zhou A, Beaumont RN, Tuke MA, Jones SE, Ruth KS, Yaghootkar H, Sharp S, et al
(2019). Using genetics to understand the causal influence of higher BMI on depression. Int J Epidemiol
Using genetics to understand the causal influence of higher BMI on depression.
BACKGROUND: Depression is more common in obese than non-obese individuals, especially in women, but the causal relationship between obesity and depression is complex and uncertain. Previous studies have used genetic variants associated with BMI to provide evidence that higher body mass index (BMI) causes depression, but have not tested whether this relationship is driven by the metabolic consequences of BMI nor for differences between men and women. METHODS: We performed a Mendelian randomization study using 48 791 individuals with depression and 291 995 controls in the UK Biobank, to test for causal effects of higher BMI on depression (defined using self-report and Hospital Episode data). We used two genetic instruments, both representing higher BMI, but one with and one without its adverse metabolic consequences, in an attempt to 'uncouple' the psychological component of obesity from the metabolic consequences. We further tested causal relationships in men and women separately, and using subsets of BMI variants from known physiological pathways. RESULTS: Higher BMI was strongly associated with higher odds of depression, especially in women. Mendelian randomization provided evidence that higher BMI partly causes depression. Using a 73-variant BMI genetic risk score, a genetically determined one standard deviation (1 SD) higher BMI (4.9 kg/m2) was associated with higher odds of depression in all individuals [odds ratio (OR): 1.18, 95% confidence interval (CI): 1.09, 1.28, P = 0.00007) and women only (OR: 1.24, 95% CI: 1.11, 1.39, P = 0.0001). Meta-analysis with 45 591 depression cases and 97 647 controls from the Psychiatric Genomics Consortium (PGC) strengthened the statistical confidence of the findings in all individuals. Similar effect size estimates were obtained using different Mendelian randomization methods, although not all reached P Abstract
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Frayling TM (2018). A Common Allele in FGF21 Associated with Sugar Intake is Associated with Body Shape, Lower Total Body-Fat Percentage, and Higher Blood Pressure. Cell Reports, 23(2), 327-336.
Wagley S, Borne R, Harrison J, Baker-Austin C, Ottaviani D, Leoni F, Vuddhakul V, Titball RW
(2018). Galleria mellonella as an infection model to investigate virulence of Vibrio parahaemolyticus. Virulence
Galleria mellonella as an infection model to investigate virulence of Vibrio parahaemolyticus.
Non-toxigenic V. parahaemolyticus isolates (tdh-/trh-/T3SS2-) have recently been isolated from patients with gastroenteritis. In this study we report that the larvae of the wax moth (Galleria mellonella) are susceptible to infection by toxigenic or non-toxigenic clinical isolates of V. parahaemolyticus. In comparison larvae inoculated with environmental isolates of V. parahaemolyticus did not succumb to disease. Whole genome sequencing of clinical non-toxigenic isolates revealed the presence of a gene encoding a nudix hydrolase, identified as mutT. A V. parahaemolyticus mutT mutant was unable to kill G. mellonella at 24 h post inoculation, indicating a role of this gene in virulence. Our findings show that G. mellonella is a valuable model for investigating screening of possible virulence genes of V. parahaemolyticus and can provide new insights into mechanisms of virulence of atypical non-toxigenic V. parahaemolyticus. These findings will allow improved genetic tests for the identification of pathogenic V. parahaemolyticus to be developed and will have a significant impact for the scientific community. Abstract
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Walker GJ, Harrison JW, Voskuil MD, Heap GA, Heerasing N, Hendy PJ, Koskela J, Daly MJ, Sokol H, Weersma RK, et al
(2018). NUDT15 VARIANTS CONTRIBUTE TO THIOPURINE-INDUCED MYELOSUPPRESSION IN EUROPEAN POPULATIONS. Author URL
Walker GJ, Harrison JW, Heap GA, Heerasing N, Hendy PJ, Bewshea C, Goodhand JR, Weedon MN, Kennedy NA, Ahmad T, et al
(2017). NUDT15 VARIANTS CONTRIBUTE TO THIOPURINE-INDUCED MYELOSUPPRESSION IN EUROPEAN POPULATIONS. Author URL
Harrison J, Dornbusch MR, Samac D, Studholme DJ
(2016). Draft Genome Sequence of Pseudomonas syringae pv. syringae ALF3 Isolated from Alfalfa. Genome Announc
Draft Genome Sequence of Pseudomonas syringae pv. syringae ALF3 Isolated from Alfalfa.
We report here the annotated draft genome sequence of Pseudomonas syringae pv. syringae strain ALF3, isolated in Wyoming. A comparison of this genome sequence with those of closely related strains of P. syringae adapted to other hosts will facilitate research into interactions between this pathogen and alfalfa. Abstract
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Harrison J, Grant MR, Studholme DJ
(2016). Draft Genome Sequences of Two Strains of Xanthomonas arboricola pv. celebensis Isolated from Banana Plants. Genome Announc
Draft Genome Sequences of Two Strains of Xanthomonas arboricola pv. celebensis Isolated from Banana Plants.
We report here the annotated draft genome sequences of strains Xanthomonas arboricola pv. celebensis NCPPB 1832 and NCPPB 1630 (NCPPB, National Collection of Plant Pathogenic Bacteria), both isolated from Musa species in New Zealand. This will allow the comparison of genomes between phylogenetically distant xanthomonads that have independently converged with the ability to colonize banana plants. Abstract
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McDonagh LM, West H, Harrison JW, Stevens JR
(2016). Which mitochondrial gene (if any) is best for insect phylogenetics?. INSECT SYSTEMATICS & EVOLUTION
(3), 245-266. Author URL
Laver T, Harrison J, O'Neill PA, Moore K, Farbos A, Paszkiewicz K, Studholme DJ
(2015). Assessing the performance of the Oxford Nanopore Technologies MinION. Biomolecular Detection and Quantification
Assessing the performance of the Oxford Nanopore Technologies MinION
The Oxford Nanopore Technologies (ONT) MinION is a new sequencing technology that potentially offers read lengths of tens of kilobases (kb) limited only by the length of DNA molecules presented to it. The device has a low capital cost, is by far the most portable DNA sequencer available, and can produce data in real-time. It has numerous prospective applications including improving genome sequence assemblies and resolution of repeat-rich regions. Before such a technology is widely adopted, it is important to assess its performance and limitations in respect of throughput and accuracy. In this study we assessed the performance of the MinION by re-sequencing three bacterial genomes, with very different nucleotide compositions ranging from 28.6% to 70.7%; the high G. +. C strain was underrepresented in the sequencing reads. We estimate the error rate of the MinION (after base calling) to be 38.2%. Mean and median read lengths were 2. kb and 1. kb respectively, while the longest single read was 98. kb. The whole length of a 5. kb rRNA operon was covered by a single read. As the first nanopore-based single molecule sequencer available to researchers, the MinION is an exciting prospect; however, the current error rate limits its ability to compete with existing sequencing technologies, though we do show that MinION sequence reads can enhance contiguity of de novo assembly when used in conjunction with Illumina MiSeq data. Abstract
Aritua V, Harrison J, Sapp M, Buruchara R, Smith J, Studholme DJ
(2015). Genome sequencing reveals a new lineage associated with lablab bean and genetic exchange between Xanthomonas axonopodis pv. phaseoli and Xanthomonas fuscans subsp. fuscans. Front Microbiol
Genome sequencing reveals a new lineage associated with lablab bean and genetic exchange between Xanthomonas axonopodis pv. phaseoli and Xanthomonas fuscans subsp. fuscans.
Common bacterial blight is a devastating seed-borne disease of common beans that also occurs on other legume species including lablab and Lima beans. We sequenced and analyzed the genomes of 26 strains of Xanthomonas axonopodis pv. phaseoli and X. fuscans subsp. fuscans, the causative agents of this disease, collected over four decades and six continents. This revealed considerable genetic variation within both taxa, encompassing both single-nucleotide variants and differences in gene content, that could be exploited for tracking pathogen spread. The bacterial strain from Lima bean fell within the previously described Genetic Lineage 1, along with the pathovar type strain (NCPPB 3035). The strains from lablab represent a new, previously unknown genetic lineage closely related to strains of X. axonopodis pv. glycines. Finally, we identified more than 100 genes that appear to have been recently acquired by Xanthomonas axonopodis pv. phaseoli from X. fuscans subsp. fuscans. Abstract
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Aritua V, Musoni A, Kabeja A, Butare L, Mukamuhirwa F, Gahakwa D, Kato F, Abang MM, Buruchara R, Sapp M, et al
(2015). The draft genome sequence of Xanthomonas species strain Nyagatare, isolated from diseased bean in Rwanda. FEMS Microbiol Lett
The draft genome sequence of Xanthomonas species strain Nyagatare, isolated from diseased bean in Rwanda.
We announce the genome sequence for Xanthomonas species strain Nyagatare, isolated from beans showing unusual disease symptoms in Rwanda. This strain represents the first sequenced genome belonging to an as-yet undescribed Xanthomonas species known as species-level clade 1. It has at least 100 kb of genomic sequence that shows little or no sequence similarity to other xanthomonads, including a unique lipopolysaccharide synthesis gene cluster. At least one genomic region appears to have been acquired from relatives of Agrobacterium or Rhizobium species. The genome encodes homologues of only three known type-three secretion system effectors: AvrBs2, XopF1 and AvrXv4. Availability of the genome sequence will facilitate development of molecular tools for detection and diagnostics for this newly discovered pathogen of beans and facilitate epidemiological investigations of a potential causal link between this pathogen and the disease outbreak. Abstract
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Harrison J, Moore K, Paszkiewicz K, Jones T, Grant M, Ambacheew D, Muzemil S, Studholme D
(2014). A Draft Genome Sequence for Ensete ventricosum, the Drought-Tolerant “Tree Against Hunger”. Agronomy
A Draft Genome Sequence for Ensete ventricosum, the Drought-Tolerant “Tree Against Hunger”
We present a draft genome sequence for enset (Ensete ventricosum) available via the Sequence Read Archive (accession number SRX202265) and GenBank (accession number AMZH01. Enset feeds 15 million people in Ethiopia, but is arguably the least studied African crop. Our sequence data suggest a genome size of approximately 547 megabases, similar to the 523-megabase genome of the closely related banana (Musa acuminata). At least 1.8% of the annotated M. acuminata genes are not conserved in E. ventricosum. Furthermore, enset contains genes not present in banana, including reverse transcriptases and virus-like sequences as well as a homolog of the RPP8-like resistance gene. We hope that availability of genome-wide sequence data will stimulate and accelerate research on this important but neglected crop. Abstract
Harrison J, Studholme DJ
(2014). Draft genome sequence of Xanthomonas axonopodis pathovar vasculorum NCPPB 900. FEMS Microbiology Letters
Draft genome sequence of Xanthomonas axonopodis pathovar vasculorum NCPPB 900
Xanthomonas axonopodis pathovar vasculorum strain NCPPB 900 was isolated from sugarcane on Reunion island in 1960. Consistent with its belonging to fatty-acid type D, multi-locus sequence analysis confirmed that NCPPB 900 falls within the species X. axonopodis. This genome harbours sequences similar to plasmids pXCV183 from X. campestris pv. vesicatoria 85-10 and pPHB194 from Burkholderia pseudomallei. Its repertoire of predicted effectors includes homologues of XopAA, XopAD, XopAE, XopB, XopD, XopV, XopZ, XopC and XopI and transcriptional activator-like effectors and it is predicted to encode a novel phosphonate natural product also encoded by the genome of the phylogenetically distant X. vasicola pv. vasculorum. Availability of this novel genome sequence may facilitate the study of interactions between xanthomonads and sugarcane, a host-pathogen system that appears to have evolved several times independently within the genus Xanthomonas and may also provide a source of target sequences for molecular detection and diagnostics. We present the genome sequence of a bacterial agent of gumming disease of sugarcane. Abstract
Harrison JW, Dung TTN, Siddiqui F, Korbrisate S, Bukhari H, Tra MPV, Hoang NVM, Carrique-Mas J, Bryant J, Campbell JI, et al
(2014). Identification of possible virulence marker from Campylobacter jejuni isolates. Emerg Infect Dis
Identification of possible virulence marker from Campylobacter jejuni isolates.
A novel protein translocation system, the type-6 secretion system (T6SS), may play a role in virulence of Campylobacter jejuni. We investigated 181 C. jejuni isolates from humans, chickens, and environmental sources in Vietnam, Thailand, Pakistan, and the United Kingdom for T6SS. The marker was most prevalent in human and chicken isolates from Vietnam. Abstract
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Harrison J, Studholme DJ
(2014). Recently published Streptomyces genome sequences. Microb Biotechnol
(5), 373-380. Author URL
Quinn L, O'Neill PA, Harrison J, Paskiewicz KH, Mccracken AR, Cooke LR, Grant MR, Studholme DJ
(2013). Genome-wide sequencing of Phytophthora lateralis reveals genetic variation among isolates from Lawson cypress (Chamaecyparis lawsoniana) in Northern Ireland. FEMS Microbiology Letters
Genome-wide sequencing of Phytophthora lateralis reveals genetic variation among isolates from Lawson cypress (Chamaecyparis lawsoniana) in Northern Ireland
Phytophthora lateralis is a fungus-like (oomycete) pathogen of trees in the family Cupressaceae, including Chamaecyparis lawsoniana (Lawson cypress or Port Orford cedar). Known in North America since the 1920s, presumably having been accidentally introduced from its assumed East Asian centre of origin, until recently, this pathogen has not been identified causing disease in Europe except for a few isolated outbreaks. However, since 2010, there have been several reports of infection of C. lawsoniana by P. lateralis in the United Kingdom, including Northern Ireland. We sequenced the genomes of four isolates of P. lateralis from two sites in Northern Ireland in 2011. Comparison with the closely related tree and shrub pathogen P. ramorum (cause of ramorum disease of larch and other species in the UK) shows that P. lateralis shares 91.47% nucleotide sequence identity over the core conserved compartments of the genome. The genomes of the four Northern Ireland isolates are almost identical, but we identified several single-nucleotide polymorphisms (SNPs) that distinguish between isolates, thereby presenting potential molecular markers of use for tracking routes of spread and in epidemiological studies. Our data reveal very low rates of heterozygosity (compared with P. ramorum), consistent with inbreeding within this P. lateralis population. © 2013 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. Abstract
Quinn L, O'Neill PA, Harrison J, Paskiewicz KH, McCracken AR, Cooke LR, Grant MR, Studholme DJ
(2013). Genome-wide sequencing of Phytophthora lateralis reveals genetic variation among isolates from Lawson cypress (Chamaecyparis lawsoniana) in Northern Ireland. FEMS Microbiol Lett
Genome-wide sequencing of Phytophthora lateralis reveals genetic variation among isolates from Lawson cypress (Chamaecyparis lawsoniana) in Northern Ireland.
Phytophthora lateralis is a fungus-like (oomycete) pathogen of trees in the family Cupressaceae, including Chamaecyparis lawsoniana (Lawson cypress or Port Orford cedar). Known in North America since the 1920s, presumably having been accidentally introduced from its assumed East Asian centre of origin, until recently, this pathogen has not been identified causing disease in Europe except for a few isolated outbreaks. However, since 2010, there have been several reports of infection of C. lawsoniana by P. lateralis in the United Kingdom, including Northern Ireland. We sequenced the genomes of four isolates of P. lateralis from two sites in Northern Ireland in 2011. Comparison with the closely related tree and shrub pathogen P. ramorum (cause of ramorum disease of larch and other species in the UK) shows that P. lateralis shares 91.47% nucleotide sequence identity over the core conserved compartments of the genome. The genomes of the four Northern Ireland isolates are almost identical, but we identified several single-nucleotide polymorphisms (SNPs) that distinguish between isolates, thereby presenting potential molecular markers of use for tracking routes of spread and in epidemiological studies. Our data reveal very low rates of heterozygosity (compared with P. ramorum), consistent with inbreeding within this P. lateralis population. Abstract
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Kim E, Harrison JW, Sudek S, Jones MDM, Wilcox HM, Richards TA, Worden AZ, Archibald JM
(2011). Newly identified and diverse plastid-bearing branch on the eukaryotic tree of life. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(4), 1496-1500. Author URL