Imperial College London

DrCliveHoggart

Faculty of MedicineDepartment of Infectious Disease

Honorary Research Officer
 
 
 
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Contact

 

+44 (0)20 7594 3915c.hoggart

 
 
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Location

 

231Norfolk PlaceSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
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54 results found

Hoggart C, Shimizu C, Galassini R, Wright VJ, Shailes H, Bellos E, Herberg JA, Pollard AJ, O'Connor D, Choi SW, Seaby EG, Menikou S, Hibberd M, Sallah N, Burgner D, Brogan P, Patel H, Kim J, Tremoulet AH, Salo E, van Stijn D, Kuijpers T, Burns JC, Levin Met al., 2021, Identification of novel locus associated with coronary artery aneurysms and validation of loci for susceptibility to Kawasaki disease, European Journal of Human Genetics, ISSN: 1018-4813

Kawasaki disease (KD) is a paediatric vasculitis associated with coronary artery aneurysms (CAA). Genetic variants influencing susceptibility to KD have been previously identified, but no risk alleles have been validated that influence CAA formation. We conducted a genome-wide association study (GWAS) for CAA in KD patients of European descent with 200 cases and 276 controls. A second GWAS for susceptibility pooled KD cases with healthy paediatric controls from vaccine trials in the UK (n = 1609). Logistic regression mixed models were used for both GWASs. The susceptibility GWAS was meta-analysed with 400 KD cases and 6101 controls from a previous European GWAS, these results were further meta-analysed with Japanese GWASs at two putative loci. The CAA GWAS identified an intergenic region of chromosome 20q13 with multiple SNVs showing genome-wide significance. The risk allele of the most associated SNV (rs6017006) was present in 13% of cases and 4% of controls; in East Asian 1000 Genomes data, the allele was absent or rare. Susceptibility GWAS with meta-analysis with previously published European data identified two previously associated loci (ITPKC and FCGR2A). Further meta-analysis with Japanese GWAS summary data from the CASP3 and FAM167A genomic regions validated these loci in Europeans showing consistent effects of the top SNVs in both populations. We identified a novel locus for CAA in KD patients of European descent. The results suggest that different genes determine susceptibility to KD and development of CAA and future work should focus on the function of the intergenic region on chromosome 20q13.

Journal article

Morris TC, Hoggart CJ, Chegou NN, Kidd M, Oni T, Goliath R, Wilkinson KA, Dockrell HM, Sichali L, Banda L, Crampin AC, French N, Walzl G, Levin M, Wilkinson RJ, Hamilton MSet al., 2021, Evaluation of host serum protein biomarkers of tuberculosis in sub-Saharan Africa, Frontiers in Immunology, Vol: 12, Pages: 1-12, ISSN: 1664-3224

Accurate and affordable point-of-care diagnostics for tuberculosis (TB) are needed. Host serum protein signatures have been derived for use in primary care settings, however validation of these in secondary care settings is lacking. We evaluated serum protein biomarkers discovered in primary care cohorts from Africa reapplied to patients from secondary care. In this nested case-control study, concentrations of 22 proteins were quantified in sera from 292 patients from Malawi and South Africa who presented predominantly to secondary care. Recruitment was based upon intention of local clinicians to test for TB. The case definition for TB was culture positivity for Mycobacterium tuberculosis; and for other diseases (OD) a confirmed alternative diagnosis. Equal numbers of TB and OD patients were selected. Within each group, there were equal numbers with and without HIV and from each site. Patients were split into training and test sets for biosignature discovery. A nine-protein signature to distinguish TB from OD was discovered comprising fibrinogen, alpha-2-macroglobulin, CRP, MMP-9, transthyretin, complement factor H, IFN-gamma, IP-10, and TNF-alpha. This signature had an area under the receiver operating characteristic curve in the training set of 90% (95% CI 86–95%), and, after adjusting the cut-off for increased sensitivity, a sensitivity and specificity in the test set of 92% (95% CI 80–98%) and 71% (95% CI 56–84%), respectively. The best single biomarker was complement factor H [area under the receiver operating characteristic curve 70% (95% CI 64–76%)]. Biosignatures consisting of host serum proteins may function as point-of-care screening tests for TB in African hospitals. Complement factor H is identified as a new biomarker for such signatures.

Journal article

David A, 2020, A polygenic biomarker to identify patients with severe hypercholesterolemia of polygenic origin, Molecular Genetics and Genomic Medicine, Vol: 8, Pages: 1-9, ISSN: 2324-9269

BackgroundSevere hypercholesterolemia (HC, LDL‐C > 4.9 mmol/L) affects over 30 million people worldwide. In this study, we validated a new polygenic risk score (PRS) for LDL‐C.MethodsSummary statistics from the Global Lipid Genome Consortium and genotype data from two large populations were used.ResultsA 36‐SNP PRS was generated using data for 2,197 white Americans. In a replication cohort of 4,787 Finns, the PRS was strongly associated with the LDL‐C trait and explained 8% of its variability (p = 10–41). After risk categorization, the risk of having HC was higher in the high‐ versus low‐risk group (RR = 4.17, p < 1 × 10−7). Compared to a 12‐SNP LDL‐C raising score (currently used in the United Kingdom), the PRS explained more LDL‐C variability (8% vs. 6%). Among Finns with severe HC, 53% (66/124) versus 44% (55/124) were classified as high risk by the PRS and LDL‐C raising score, respectively. Moreover, 54% of individuals with severe HC defined as low risk by the LDL‐C raising score were reclassified to intermediate or high risk by the new PRS.ConclusionThe new PRS has a better predictive role in identifying HC of polygenic origin compared to the currently available method and can better stratify patients into diagnostic and therapeutic algorithms.

Journal article

Cust AE, Drummond M, Kanetsky PA, Goldstein AM, Barrett JH, MacGregor S, Law MH, Iles MM, Bui M, Hopper JL, Brossard M, Demenais F, Taylor JC, Hoggart C, Brown KM, Landi MT, Newton-Bishop JA, Mann GJ, Bishop DTet al., 2018, Assessing the incremental contribution of common genomic variants to melanoma risk prediction in two population-based studies, Journal of Investigative Dermatology, Vol: 138, Pages: 2617-2624, ISSN: 0022-202X

It is unclear to what degree genomic and traditional (phenotypic and environmental) risk factors overlap in their prediction of melanoma risk. We evaluated the incremental contribution of common genomic variants (in pigmentation, nevus, and other pathways) and their overlap with traditional risk factors, using data from two population-based case-control studies from Australia (n = 1,035) and the United Kingdom (n = 1,460) that used the same questionnaires. Polygenic risk scores were derived from 21 gene regions associated with melanoma and odds ratios from published meta-analyses. Logistic regression models were adjusted for age, sex, center, and ancestry. Adding the polygenic risk score to a model with traditional risk factors increased the area under the receiver operating characteristic curve (AUC) by 2.3% (P = 0.003) for Australia and by 2.8% (P = 0.002) for Leeds. Gene variants in the pigmentation pathway, particularly MC1R, were responsible for most of the incremental improvement. In a cross-tabulation of polygenic by traditional tertile risk scores, 59% (Australia) and 49% (Leeds) of participants were categorized in the same (concordant) tertile. Of participants with low traditional risk, 9% (Australia) and 21% (Leeds) had high polygenic risk. Testing of genomic variants can identify people who are susceptible to melanoma despite not having a traditional phenotypic risk profile.

Journal article

Wright V, Herberg J, Kaforou M, Shimizu C, Eleftherohorinou H, Shailes H, Barendregt A, Menikou S, Gormley S, Berk M, Hoang L, Tremoulet A, Kanegaye J, Coin L, Glode M, Hibberd M, Kuijpers T, Hoggart C, Burns J, Levin Met al., 2018, Diagnosis of Kawasaki disease using a minimal whole blood gene expression signature, JAMA Pediatrics, Vol: 172, Pages: 1-10, ISSN: 2168-6203

Importance There is no diagnostic test for Kawasaki disease (KD). Diagnosis is based on clinical features shared with other febrile conditions, frequently resulting in delayed or missed treatment and an increased risk of coronary artery aneurysms. Objective To identify a whole blood gene expression signature that distinguishes children with KD in the first week of illness from other febrile conditions.Design Case-control discovery study groups comprising training, test, and validation groups of children with KD or comparator febrile illness. Setting Hospitals in the UK, Spain, Netherlands and USA.Participants The training and test discovery group comprised 404 children with infectious and inflammatory conditions (78 KD, 84 other inflammatory diseases, 242 bacterial or viral infections) and 55 healthy controls. The independent validation group included 130 febrile children and 102 KD patients, including 72 in the first 7 days of illness.Exposures Whole blood gene expression was evaluated using microarrays, and minimal transcript sets distinguishing KD were identified using a novel variable selection method (Parallel Deterministic Model Search).Main outcomes and measures The ability of transcript signatures - implemented as Disease Risk Scores - to discriminate KD cases from controls, was assessed by Area Under the Curve (AUC), sensitivity, and specificity at the optimal cut-point according to Youden’s index. Results A 13-transcript signature identified in the discovery training set distinguished KD from other infectious and inflammatory conditions in the discovery test set with AUC, sensitivity, and specificity (95% confidence intervals (CI)) of 96.2% (92.5-99.9), 81.7% (60.0-94.8), and 92.1% (84.0-97.0), respectively. In the validation set, the signature distinguished KD from febrile controls with AUC, sensitivity, and specificity (95% CI) of 94.6% (91.3-98.0), 85.9% (76.8-92.6), and 89.1% (83.0-93.7) respectively. The signature was applied to clinically defin

Journal article

Shao H, Ganesamoorthy D, Duarte T, Minh DC, Hoggart CJ, Coin LJMet al., 2018, nplnv: accurate detection and genotyping of inversions using long read sub-alignment, BMC Bioinformatics, Vol: 19, ISSN: 1471-2105

BackgroundDetection of genomic inversions remains challenging. Many existing methods primarily target inzversions with a non repetitive breakpoint, leaving inverted repeat (IR) mediated non-allelic homologous recombination (NAHR) inversions largely unexplored.ResultWe present npInv, a novel tool specifically for detecting and genotyping NAHR inversion using long read sub-alignment of long read sequencing data. We benchmark npInv with other tools in both simulation and real data. We use npInv to generate a whole-genome inversion map for NA12878 consisting of 30 NAHR inversions (of which 15 are novel), including all previously known NAHR mediated inversions in NA12878 with flanking IR less than 7kb. Our genotyping accuracy on this dataset was 94%. We used PCR to confirm the presence of two of these novel inversions. We show that there is a near linear relationship between the length of flanking IR and the minimum inversion size, without inverted repeats.ConclusionThe application of npInv shows high accuracy in both simulation and real data. The results give deeper insight into understanding inversion.

Journal article

Martinón-Torres F, Salas A, Rivero-Calle I, Cebey-López M, Pardo-Seco J, Herberg JA, Boeddha NP, Klobassa DS, Secka F, Paulus S, de Groot R, Schlapbach LJ, Driessen GJ, Anderson ST, Emonts M, Zenz W, Carrol ED, Van der Flier M, Levin M, Levin M, Coin L, Gormley S, Hamilton S, Herberg J, Hourmat B, Hoggart C, Kaforou M, Sancho-Shimizu V, Wright V, Abdulla A, Agapow P, Bartlett M, Bellos E, Eleftherohorinou H, Galassini R, Inwald D, Mashbat M, Menikou S, Mustafa S, Nadel S, Rahman R, Thakker C, Bokhandi S, Power S, Barham H, Pathan N, Ridout J, White D, Thurston S, Faust S, Patel S, McCorkell J, Davies P, Crate L, Navarra H, Carter S, Ramaiah R, Patel R, Tuffrey C, Gribbin A, McCready S, Peters M, Hardy K, Standing F, O'Neill L, Abelake E, Deep A, Nsirim E, Pollard A, Willis L, Young Z, Royad C, White S, Fortune PM, Hudnott P, Martinón-Torres F, Salas Ellacuriaga A, Álvez González F, Barral-Arca R, Cebey-López M, Curras-Tuala MJ, García N, García Vicente L, Gómez-Carballa A, Gómez Rial J, Grela Beiroa A, Justicia Grande A, Leboráns Iglesias P, Martínez Santos AE, Martinón-Torres N, Martinón Sánchez JM, Morillo Gutiérrez Bet al., 2018, Life-threatening infections in children in Europe (the EUCLIDS Project): a prospective cohort study, Lancet Child and Adolescent Health, Vol: 2, Pages: 404-414, ISSN: 2352-4642

Background: Sepsis and severe focal infections represent a substantial disease burden in children admitted to hospital. We aimed to understand the burden of disease and outcomes in children with life-threatening bacterial infections in Europe. Methods: The European Union Childhood Life-threatening Infectious Disease Study (EUCLIDS) was a prospective, multicentre, cohort study done in six countries in Europe. Patients aged 1 month to 18 years with sepsis (or suspected sepsis) or severe focal infections, admitted to 98 participating hospitals in the UK, Austria, Germany, Lithuania, Spain, and the Netherlands were prospectively recruited between July 1, 2012, and Dec 31, 2015. To assess disease burden and outcomes, we collected demographic and clinical data using a secured web-based platform and obtained microbiological data using locally available clinical diagnostic procedures. Findings: 2844 patients were recruited and included in the analysis. 1512 (53·2%) of 2841 patients were male and median age was 39·1 months (IQR 12·4–93·9). 1229 (43·2%) patients had sepsis and 1615 (56·8%) had severe focal infections. Patients diagnosed with sepsis had a median age of 27·6 months (IQR 9·0–80·2), whereas those diagnosed with severe focal infections had a median age of 46·5 months (15·8–100·4; p < 0·0001). Of 2844 patients in the entire cohort, the main clinical syndromes were pneumonia (511 [18·0%] patients), CNS infection (469 [16·5%] ), and skin and soft tissue infection (247 [8·7%]). The causal microorganism was identified in 1359 (47·8%) children, with the most prevalent ones being Neisseria meningitidis (in 259 [9·1%] patients), followed by Staphylococcus aureus (in 222 [7·8%]), Streptococcus pneumoniae (in 219 [7·7%] ), and group A streptococcus (in 162 [5·7%]). 1070 (37·6%) patients required admis

Journal article

Mobula LM, MacDermott NE, Hoggart C, Brantly K, Plyler L, Brown J, Kauffeldt B, Eisenhut D, Cooper LA, Fankhauser Jet al., 2018, Clinical manifestations and modes of death among Ebola Virus disease patients, Monrovia, Liberia, 2014, American Journal of Tropical Medicine and Hygiene, Vol: 98, Pages: 1186-1193, ISSN: 0002-9637

Although the high case fatality rate (CFR) associated with Ebola virus disease (EVD) is well documented, there are limited data on the actual modes of death. We conducted a retrospective, observational cohort study among patients with laboratory-confirmed EVD. The patients were all seen at the Eternal Love Winning Africa Ebola Treatment Unit in Monrovia, Liberia, from June to August 2014. Our primary objective was to describe the modes of death of our patients and to determine predictors of mortality. Data were available for 53 patients with laboratory-confirmed EVD, with a median age of 35 years. The most frequent presenting symptoms were weakness (91%), fever (81%), and diarrhea (78%). Visible hemorrhage was noted in 25% of the cases. The CFR was 79%. Odds of death were higher in patients with diarrhea (odds ratio = 26.1, P < 0.01). All patients with hemorrhagic signs died (P < 0.01). Among the 18 fatal cases for which clinical information was available, three distinct modes of death were observed: sudden death after a moderate disease process (44%), profuse hemorrhage (33%), and encephalopathy (22%). We found that these modes of death varied by age (P = 0.04), maximum temperature (P = 0.43), heart rate on admission (P = 0.04), time to death from symptom onset (P = 0.13), and duration of hospitalization (P = 0.04). Although further study is required, our findings provide a foundation for developing treatment strategies that factor in patients with specific disease phenotypes (which often require the use of aggressive hydration). These findings provide insights into underlying pathogenic mechanisms resulting in severe EVD and suggest direction for future research and development of effective treatment options.

Journal article

Martinón-Torres F, Png E, Khor CC, Davila S, Wright VJ, Sim KS, Vega A, Fachal L, Inwald D, Nadel S, Carrol ED, Martinón-Torres N, Alonso SM, Carracedo A, Morteruel E, López-Bayón J, Torre AC, Monge CC, de Aguilar PA, Torné EE, Martínez-Padilla MD, Martinón-Sánchez JM, Levin M, Hibberd ML, Salas A, ESIGEM network, ESPID meningococcal consortium UK, EUCLIDS consortium members - Imperial College London wwweuclids-projecteuet 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.

Journal article

Herberg JA, Kaforou M, Wright VJ, Shailes H, Eleftherohorinou H, Hoggart CJ, Cebey-López M, Carter MJ, Janes VA, Gormley S, Shimizu C, Tremoulet AH, Barendregt AM, Salas A, Kanegaye J, Pollard AJ, Faust SN, Patel S, Kuijpers T, Martinón-Torres F, Burns JC, Coin LJ, Levin Met 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

Journal article

McArdle AJ, Webbe J, Sim K, Parrish G, Hoggart C, Wang Y, Kroll JS, Godambe S, Cunnington Aet al., 2016, Determinants of Carboxyhemoglobin Levels and Relationship with Sepsis in a Retrospective Cohort of Preterm Neonates, PLOS One, Vol: 11, ISSN: 1932-6203

Carboxyhemoglobin levels in blood reflect endogenous carbon monoxide production and are often measured during routine blood gas analysis. Endogenous carbon monoxide production has been reported to be increased during sepsis, but carboxyhemoglobin levels have not been thoroughly evaluated as a biomarker of sepsis. We sought to determine whether carboxyhemoglobin levels were elevated during sepsis in a high risk population of premature neonates. We conducted a retrospective cohort study of 30 infants in two neonatal intensive care units using electronic medical and laboratory records. The majority of infants were extremely premature and extremely low birth weight, and 25 had at least one episode of sepsis. We collected all carboxyhemoglobin measurements during their in-patient stay and examined the relationship between carboxyhemoglobin and a variety of clinical and laboratory parameters, in addition to the presence or absence of sepsis, using linear mixed-effect models. We found that postnatal age had the most significant effect on carboxyhemoglobin levels, and other significant associations were identified with gestational age, hemoglobin concentration, oxyhemoglobin saturation, and blood pH. Accounting for these covariates, there was no significant relationship between the onset of sepsis and carboxyhemoglobin levels. Our results show that carboxyhemoglobin is unlikely to be a clinically useful biomarker of sepsis in premature infants, and raise a note of caution about factors which may confound the use of carbon monoxide as a clinical biomarker for other disease processes such as hemolysis.

Journal article

Davies S, Sutton N, Blackstock S, Gormley S, Hoggart CJ, Levin M, Herberg JAet al., 2015, Predicting IVIG resistance in UK Kawasaki disease, ARCHIVES OF DISEASE IN CHILDHOOD, Vol: 100, Pages: 366-368, ISSN: 0003-9888

Journal article

Hoggart CJ, Venturini G, Mangino M, Gomez F, Ascari G, Zhao JH, Teumer A, Winkler TW, Tsernikova N, Luan J, Mihailov E, Ehret GB, Zhang W, Lamparter D, Esko T, Mace A, Rueeger S, Bochud P-Y, Barcella M, Dauvilliers Y, Benyamin B, Evans DM, Hayward C, Lopez MF, Franke L, Russo A, Heid IM, Salvi E, Vendantam S, Arking DE, Boerwinkle E, Chambers JC, Fiorito G, Grallert H, Guarrera S, Homuth G, Huffman JE, Porteous D, Moradpour D, Iranzo A, Hebebrand J, Kemp JP, Lammers GJ, Aubert V, Heim MH, Martin NG, Montgomery GW, Peraita-Adrados R, Santamaria J, Negro F, Schmidt CO, Scott RA, Spector TD, Strauch K, Voelzke H, Wareham NJ, Yuan W, Bell JT, Chakravarti A, Kooner JS, Peters A, Matullo G, Wallaschofski H, Whitfield JB, Paccaud F, Vollenweider P, Bergmann S, Beckmann JS, Tafti M, Hastie ND, Cusi D, Bochud M, Frayling TM, Metspalu A, Jarvelin M-R, Scherag A, Smith GD, Borecki IB, Rousson V, Hirschhorn JN, Rivolta C, Loos RJF, Kutalik Zet al., 2014, Novel Approach Identifies SNPs in SLC2A10 and KCNK9 with Evidence for Parent-of-Origin Effect on Body Mass Index, PLOS Genetics, Vol: 10, ISSN: 1553-7390

The phenotypic effect of some single nucleotide polymorphisms (SNPs) depends on their parental origin. We present anovel approach to detect parent-of-origin effects (POEs) in genome-wide genotype data of unrelated individuals. Themethod exploits increased phenotypic variance in the heterozygous genotype group relative to the homozygous groups.We applied the method to .56,000 unrelated individuals to search for POEs influencing body mass index (BMI). Six leadSNPs were carried forward for replication in five family-based studies (of ,4,000 trios). Two SNPs replicated: the paternalrs2471083-C allele (located near the imprinted KCNK9 gene) and the paternal rs3091869-T allele (located near the SLC2A10gene) increased BMI equally (beta = 0.11 (SD), P,0.0027) compared to the respective maternal alleles. Real-time PCRexperiments of lymphoblastoid cell lines from the CEPH families showed that expression of both genes was dependent onparental origin of the SNPs alleles (P,0.01). Our scheme opens new opportunities to exploit GWAS data of unrelatedindividuals to identify POEs and demonstrates that they play an important role in adult obesity.

Journal article

Speed D, Hoggart C, Petrovski S, Tachmazidou I, Coffey A, Jorgensen A, Eleftherohorinou H, De Iorio M, Todaro M, De T, Smith D, Smith PE, Jackson M, Cooper P, Kellett M, Howell S, Newton M, Yerra R, Tan M, French C, Reuber M, Sills GE, Chadwick D, Pirmohamed M, Bentley D, Scheffer I, Berkovic S, Balding D, Palotie A, Marson A, OBrien TJ, Johnson MRet al., 2014, Genome-wide association study and biological pathway analysis of epilepsy prognosis in a prospective cohort of newly treated epilepsy, Human Molecular Genetics

Journal article

Fatemifar G, Hoggart CJ, Paternoster L, Kemp JP, Prokopenko I, Horikoshi M, Wright VJ, Tobias JH, Richmond S, Zhurov AI, Toma AM, Pouta A, Taanila A, Sipila K, Lahdesmaki R, Pillas D, Geller F, Feenstra B, Melbye M, Nohr EA, Ring SM, St Pourcain B, Timpson NJ, Smith GD, Jarvelin M-R, Evans DMet al., 2013, Genome-wide association study of primary tooth eruption identifies pleiotropic loci associated with height and craniofacial distances, HUMAN MOLECULAR GENETICS, Vol: 22, Pages: 3807-3817, ISSN: 0964-6906

Journal article

al Basatena N-KS, Hoggart CJ, Coin LJ, O'Reilly PFet 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

Journal article

O'Reilly P, Hoggart C, 2013, A Novel Method to Prioritise Genetic Loci Identified in GWAS for Sequencing, 42nd European Mathematical Genetics Meeting (EMGM), Publisher: KARGER, Pages: 111-111, ISSN: 0001-5652

Conference paper

Ehret GB, Lamparter D, Hoggart CJ, Whittaker JC, Beckmann JS, Kutalik Zet al., 2012, A Multi-SNP Locus-Association Method Reveals a Substantial Fraction of the Missing Heritability, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 91, Pages: 863-871, ISSN: 0002-9297

Journal article

Papathomas M, Molitor J, Hoggart C, Hastie D, Richardson Set al., 2012, Exploring Data From Genetic Association Studies Using Bayesian Variable Selection and the Dirichlet Process: Application to Searching for Gene Gene Patterns, GENETIC EPIDEMIOLOGY, Vol: 36, Pages: 663-674, ISSN: 0741-0395

Journal article

Fatemifar G, Hoggart C, Prokopenko I, Horikoshi M, Tobias J, Jarvelin M-R, Evans Det al., 2012, GENOME-WIDE ASSOCIATION STUDY OF PRIMARY TOOTH ERUPTION, Osteoporosis and Bone Conference, Publisher: SPRINGER LONDON LTD, Pages: S562-S562, ISSN: 0937-941X

Conference paper

Hoggart C, Brennan P, Tjonneland A, Vogel U, Overvad K, Ostergaard JN, Kaaks R, Canzian F, Boeing H, Steffen A, Trichopoulou A, Bamia C, Trichopoulos D, Johansson M, Palli D, Krogh V, Tumino R, Sacerdote C, Panico S, Boshuizen H, Bueno-de-Mesquita HB, Peeters PHM, Lund E, Gram IT, Braaten T, Rodriguez L, Agudo A, Sanchez-Cantalejo E, Arriola L, Chirlaque M-D, Barricarte A, Rasmuson T, Khaw K-T, Wareham N, Allen NE, Riboli E, Vineis Pet al., 2012, A Risk Model for Lung Cancer Incidence, CANCER PREVENTION RESEARCH, Vol: 5, Pages: 834-846, ISSN: 1940-6207

Journal article

O'Reilly PF, Hoggart CJ, Pomyen Y, Calboli FCF, Elliott P, Jarvelin M-R, Coin LJMet al., 2012, MultiPhen: Joint Model of Multiple Phenotypes Can Increase Discovery in GWAS, PLOS One, Vol: 7, ISSN: 1932-6203

The genome-wide association study (GWAS) approach has discovered hundreds of genetic variants associated with diseasesand quantitative traits. However, despite clinical overlap and statistical correlation between many phenotypes, GWAS aregenerally performed one-phenotype-at-a-time. Here we compare the performance of modelling multiple phenotypes jointlywith that of the standard univariate approach. We introduce a new method and software, MultiPhen, that models multiplephenotypes simultaneously in a fast and interpretable way. By performing ordinal regression, MultiPhen tests the linearcombination of phenotypes most associated with the genotypes at each SNP, and thus potentially captures effects hiddento single phenotype GWAS. We demonstrate via simulation that this approach provides a dramatic increase in power inmany scenarios. There is a boost in power for variants that affect multiple phenotypes and for those that affect only onephenotype. While other multivariate methods have similar power gains, we describe several benefits of MultiPhen overthese. In particular, we demonstrate that other multivariate methods that assume the genotypes are normally distributed,such as canonical correlation analysis (CCA) and MANOVA, can have highly inflated type-1 error rates when testing casecontrolor non-normal continuous phenotypes, while MultiPhen produces no such inflation. To test the performance ofMultiPhen on real data we applied it to lipid traits in the Northern Finland Birth Cohort 1966 (NFBC1966). In these dataMultiPhen discovers 21% more independent SNPs with known associations than the standard univariate GWAS approach,while applying MultiPhen in addition to the standard approach provides 37% increased discovery. The most associatedlinear combinations of the lipids estimated by MultiPhen at the leading SNPs accurately reflect the Friedewald Formula,suggesting that MultiPhen could be used to refine the definition of existing phenotypes or uncover novel heritablepheno

Journal article

Fatemifar G, Hoggart C, Prokopenko I, Horikoshi M, Tobias J, Jarvelin M-R, Evans DMet al., 2012, Genome-wide association study of primary tooth eruption, 39th Annual Congress of the European-Calcified-Tissue-Society (ECTS), Publisher: ELSEVIER SCIENCE INC, Pages: S107-S107, ISSN: 8756-3282

Conference paper

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