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1. Plasma Protein Biomarkers Distinguish Multisystem Inflammatory Syndrome in Children from Other Pediatric Infectious and Inflammatory Diseases

Author: Infectieziekten patientenzorg, Child Health, Infection & Immunity, Yeoh, Sophya, Estrada-Rivadeneyra, Diego, Jackson, Heather, Keren, Ilana, Galassini, Rachel, Cooray, Samantha, Shah, Priyen, Agyeman, Philipp, Basmaci, Romain, Carrol, Enitan, Emonts, Marieke, Fink, Colin, Kuijpers, Taco, Martinon-Torres, Federico, Mommert-Tripon, Marine, Paulus, Stephane, Pokorn, Marko, Rojo, Pablo, Romani, Lorenza, Schlapbach, Luregn, Schweintzger, Nina, Shen, Ching Fen, Tsolia, Maria, Usuf, Effua, Van Der Flier, Michiel, Vermont, Clementien, Von Both, Ulrich, Yeung, Shunmay, Zavadska, Dace, Coin, Lachlan, Cunnington, Aubrey, Herberg, Jethro, Levin, Michael, Kaforou, Myrsini, Hamilton, Shea, Infectieziekten patientenzorg, Child Health, Infection & Immunity, Yeoh, Sophya, Estrada-Rivadeneyra, Diego, Jackson, Heather, Keren, Ilana, Galassini, Rachel, Cooray, Samantha, Shah, Priyen, Agyeman, Philipp, Basmaci, Romain, Carrol, Enitan, Emonts, Marieke, Fink, Colin, Kuijpers, Taco, Martinon-Torres, Federico, Mommert-Tripon, Marine, Paulus, Stephane, Pokorn, Marko, Rojo, Pablo, Romani, Lorenza, Schlapbach, Luregn, Schweintzger, Nina, Shen, Ching Fen, Tsolia, Maria, Usuf, Effua, Van Der Flier, Michiel, Vermont, Clementien, Von Both, Ulrich, Yeung, Shunmay, Zavadska, Dace, Coin, Lachlan, Cunnington, Aubrey, Herberg, Jethro, Levin, Michael, Kaforou, Myrsini, and Hamilton, Shea
Published: 2024

2. Plasma Protein Biomarkers Distinguish Multisystem Inflammatory Syndrome in Children From Other Pediatric Infectious and Inflammatory Diseases

Author: Yeoh, Sophya, Estrada-Rivadeneyra, Diego; https://orcid.org/0000-0003-2512-7131, Jackson, Heather; https://orcid.org/0000-0002-1054-9983, Keren, Ilana, Galassini, Rachel; https://orcid.org/0000-0002-1025-0367, Cooray, Samantha; https://orcid.org/0000-0001-6103-8895, Shah, Priyen; https://orcid.org/0000-0001-9164-8862, Agyeman, Philipp; https://orcid.org/0000-0002-8339-5444, Basmaci, Romain; https://orcid.org/0000-0002-5277-0002, Carrol, Enitan; https://orcid.org/0000-0001-8357-7726, Emonts, Marieke; https://orcid.org/0000-0002-2822-3527, Fink, Colin; https://orcid.org/0000-0002-8008-5870, Kuijpers, Taco; https://orcid.org/0000-0002-7421-3370, Martinon-Torres, Federico; https://orcid.org/0000-0002-9023-581X, Mommert-Tripon, Marine; https://orcid.org/0000-0001-5624-7756, Paulus, Stephane; https://orcid.org/0000-0002-0703-9114, Pokorn, Marko; https://orcid.org/0000-0002-2341-2791, Rojo, Pablo, Romani, Lorenza; https://orcid.org/0000-0003-4195-6626, Schlapbach, Luregn; https://orcid.org/0000-0003-2281-2598, Schweintzger, Nina; https://orcid.org/0000-0003-2549-5911, Shen, Ching-Fen, Tsolia, Maria; https://orcid.org/0000-0003-2485-4409, Usuf, Effua, van der Flier, Michiel; https://orcid.org/0000-0003-1296-0159, Vermont, Clementien, von Both, Ulrich; https://orcid.org/0000-0001-8411-1071, Yeung, Shunmay; https://orcid.org/0000-0002-0997-0850, Zavadska, Dace; https://orcid.org/0000-0003-4892-3763, Coin, Lachlan; https://orcid.org/0000-0002-4300-455X, et al, Yeoh, Sophya, Estrada-Rivadeneyra, Diego; https://orcid.org/0000-0003-2512-7131, Jackson, Heather; https://orcid.org/0000-0002-1054-9983, Keren, Ilana, Galassini, Rachel; https://orcid.org/0000-0002-1025-0367, Cooray, Samantha; https://orcid.org/0000-0001-6103-8895, Shah, Priyen; https://orcid.org/0000-0001-9164-8862, Agyeman, Philipp; https://orcid.org/0000-0002-8339-5444, Basmaci, Romain; https://orcid.org/0000-0002-5277-0002, Carrol, Enitan; https://orcid.org/0000-0001-8357-7726, Emonts, Marieke; https://orcid.org/0000-0002-2822-3527, Fink, Colin; https://orcid.org/0000-0002-8008-5870, Kuijpers, Taco; https://orcid.org/0000-0002-7421-3370, Martinon-Torres, Federico; https://orcid.org/0000-0002-9023-581X, Mommert-Tripon, Marine; https://orcid.org/0000-0001-5624-7756, Paulus, Stephane; https://orcid.org/0000-0002-0703-9114, Pokorn, Marko; https://orcid.org/0000-0002-2341-2791, Rojo, Pablo, Romani, Lorenza; https://orcid.org/0000-0003-4195-6626, Schlapbach, Luregn; https://orcid.org/0000-0003-2281-2598, Schweintzger, Nina; https://orcid.org/0000-0003-2549-5911, Shen, Ching-Fen, Tsolia, Maria; https://orcid.org/0000-0003-2485-4409, Usuf, Effua, van der Flier, Michiel; https://orcid.org/0000-0003-1296-0159, Vermont, Clementien, von Both, Ulrich; https://orcid.org/0000-0001-8411-1071, Yeung, Shunmay; https://orcid.org/0000-0002-0997-0850, Zavadska, Dace; https://orcid.org/0000-0003-4892-3763, Coin, Lachlan; https://orcid.org/0000-0002-4300-455X, and et al
Abstract: Background: Multisystem inflammatory syndrome in children (MIS-C) is a rare but serious hyperinflammatory complication following infection with severe acute respiratory syndrome coronavirus 2. The mechanisms underpinning the pathophysiology of MIS-C are poorly understood. Moreover, clinically distinguishing MIS-C from other childhood infectious and inflammatory conditions, such as Kawasaki disease or severe bacterial and viral infections, is challenging due to overlapping clinical and laboratory features. We aimed to determine a set of plasma protein biomarkers that could discriminate MIS-C from those other diseases. Methods: Seven candidate protein biomarkers for MIS-C were selected based on literature and from whole blood RNA sequencing data from patients with MIS-C and other diseases. Plasma concentrations of ARG1, CCL20, CD163, CORIN, CXCL9, PCSK9 and ADAMTS2 were quantified in MIS-C (n = 22), Kawasaki disease (n = 23), definite bacterial (n = 28) and viral (n = 27) disease and healthy controls (n = 8). Logistic regression models were used to determine the discriminatory ability of individual proteins and protein combinations to identify MIS-C and association with severity of illness. Results: Plasma levels of CD163, CXCL9 and PCSK9 were significantly elevated in MIS-C with a combined area under the receiver operating characteristic curve of 85.7% (95% confidence interval: 76.6%–94.8%) for discriminating MIS-C from other childhood diseases. Lower ARG1 and CORIN plasma levels were significantly associated with severe MIS-C cases requiring inotropes, pediatric intensive care unit admission or with shock. Conclusion: Our findings demonstrate the feasibility of a host protein biomarker signature for MIS-C and may provide new insight into its pathophysiology.
Published: 2024

3. Achievement of therapeutic antibiotic exposures using Bayesian dosing software in critically unwell children and adults with sepsis

Author: Chai, Ming G, Tu, Quyen, Cotta, Menino O, Bauer, Michelle J, Balch, Ross, Okafor, Charles, Comans, Tracy, Kruger, Peter, Meyer, Jason, Shekar, Kiran, Brady, Kara, Fourie, Cheryl, Sharp, Natalie, Vlad, Luminita, Whiley, David, Ungerer, Jacobus P J, Mcwhinney, Brett C, Farkas, Andras, Paterson, David L, Clark, Julia E, Hajkowicz, Krispin, Raman, Sainath; https://orcid.org/0000-0002-0152-9980, Bialasiewicz, Seweryn; https://orcid.org/0000-0001-9474-6943, Lipman, Jeffrey, Forde, Brian M; https://orcid.org/0000-0002-2264-4785, Harris, Patrick N A; https://orcid.org/0000-0002-2895-0345, Schlapbach, Luregn J; https://orcid.org/0000-0003-2281-2598, Coin, Lachlan, Roberts, Jason A; https://orcid.org/0000-0001-6218-435X, Irwin, Adam D; https://orcid.org/0000-0001-8974-6789, Chai, Ming G, Tu, Quyen, Cotta, Menino O, Bauer, Michelle J, Balch, Ross, Okafor, Charles, Comans, Tracy, Kruger, Peter, Meyer, Jason, Shekar, Kiran, Brady, Kara, Fourie, Cheryl, Sharp, Natalie, Vlad, Luminita, Whiley, David, Ungerer, Jacobus P J, Mcwhinney, Brett C, Farkas, Andras, Paterson, David L, Clark, Julia E, Hajkowicz, Krispin, Raman, Sainath; https://orcid.org/0000-0002-0152-9980, Bialasiewicz, Seweryn; https://orcid.org/0000-0001-9474-6943, Lipman, Jeffrey, Forde, Brian M; https://orcid.org/0000-0002-2264-4785, Harris, Patrick N A; https://orcid.org/0000-0002-2895-0345, Schlapbach, Luregn J; https://orcid.org/0000-0003-2281-2598, Coin, Lachlan, Roberts, Jason A; https://orcid.org/0000-0001-6218-435X, and Irwin, Adam D; https://orcid.org/0000-0001-8974-6789
Abstract: PURPOSE: Early recognition and effective treatment of sepsis improves outcomes in critically ill patients. However, antibiotic exposures are frequently suboptimal in the intensive care unit (ICU) setting. We describe the feasibility of the Bayesian dosing software Individually Designed Optimum Dosing Strategies (ID-ODS™), to reduce time to effective antibiotic exposure in children and adults with sepsis in ICU. METHODS: A multi-centre prospective, non-randomised interventional trial in three adult ICUs and one paediatric ICU. In a pre-intervention Phase 1, we measured the time to target antibiotic exposure in participants. In Phase 2, antibiotic dosing recommendations were made using ID-ODS™, and time to target antibiotic concentrations were compared to patients in Phase 1 (a pre-post-design). RESULTS: 175 antibiotic courses (Phase 1 = 123, Phase 2 = 52) were analysed from 156 participants. Across all patients, there was no difference in the time to achieve target exposures (8.7 h vs 14.3 h in Phase 1 and Phase 2, respectively, p = 0.45). Sixty-one courses in 54 participants failed to achieve target exposures within 24 h of antibiotic commencement (n = 36 in Phase 1, n = 18 in Phase 2). In these participants, ID-ODS™ was associated with a reduction in time to target antibiotic exposure (96 vs 36.4 h in Phase 1 and Phase 2, respectively, p < 0.01). These patients were less likely to exhibit subtherapeutic antibiotic exposures at 96 h (hazard ratio (HR) 0.02, 95% confidence interval (CI) 0.01-0.05, p < 0.01). There was no difference observed in in-hospital mortality. CONCLUSIONS: Dosing software may reduce the time to achieve target antibiotic exposures. It should be evaluated further in trials to establish its impact on clinical outcomes.
Published: 2024

4. Rapid nanopore sequencing and predictive susceptibility testing of positive blood cultures from intensive care patients with sepsis

Author: Papp-Wallace, Krisztina M, Papp-Wallace, K M ( Krisztina M ), Harris, Patrick N A; https://orcid.org/0000-0002-2895-0345, Bauer, Michelle J, Lüftinger, Lukas, Beisken, Stephan, Forde, Brian M; https://orcid.org/0000-0002-2264-4785, Balch, Ross, Cotta, Menino; https://orcid.org/0000-0002-2058-2314, Schlapbach, Luregn J; https://orcid.org/0000-0003-2281-2598, Raman, Sainath; https://orcid.org/0000-0002-0152-9980, Shekar, Kiran, Krüger, Peter; https://orcid.org/0000-0002-1247-9886, Lipman, Jeff, Bialasiewicz, Seweryn; https://orcid.org/0000-0001-9474-6943, Coin, Lachlan, Roberts, Jason A; https://orcid.org/0000-0001-6218-435X, Paterson, David L, Irwin, Adam D, Papp-Wallace, Krisztina M, Papp-Wallace, K M ( Krisztina M ), Harris, Patrick N A; https://orcid.org/0000-0002-2895-0345, Bauer, Michelle J, Lüftinger, Lukas, Beisken, Stephan, Forde, Brian M; https://orcid.org/0000-0002-2264-4785, Balch, Ross, Cotta, Menino; https://orcid.org/0000-0002-2058-2314, Schlapbach, Luregn J; https://orcid.org/0000-0003-2281-2598, Raman, Sainath; https://orcid.org/0000-0002-0152-9980, Shekar, Kiran, Krüger, Peter; https://orcid.org/0000-0002-1247-9886, Lipman, Jeff, Bialasiewicz, Seweryn; https://orcid.org/0000-0001-9474-6943, Coin, Lachlan, Roberts, Jason A; https://orcid.org/0000-0001-6218-435X, Paterson, David L, and Irwin, Adam D
Abstract: We aimed to evaluate the performance of Oxford Nanopore Technologies (ONT) sequencing from positive blood culture (BC) broths for bacterial identification and antimicrobial susceptibility prediction. Patients with suspected sepsis in four intensive care units were prospectively enrolled. Human-depleted DNA was extracted from positive BC broths and sequenced using ONT (MinION). Species abundance was estimated using Kraken2, and a cloud-based system (AREScloud) provided in silico predictive antimicrobial susceptibility testing (AST) from assembled contigs. Results were compared to conventional identification and phenotypic AST. Species-level agreement between conventional methods and AST predicted from sequencing was 94.2% (49/52), increasing to 100% in monomicrobial infections. In 262 high-quality AREScloud AST predictions across 24 samples, categorical agreement (CA) was 89.3%, with major error (ME) and very major error (VME) rates of 10.5% and 12.1%, respectively. Over 90% CA was achieved for some taxa (e.g.,Staphylococcus aureus) but was suboptimal for Pseudomonas aeruginosa. In 470 AST predictions across 42 samples, with both high quality and exploratory-only predictions, overall CA, ME, and VME rates were 87.7%, 8.3%, and 28.4%. VME rates were inflated by false susceptibility calls in a small number of species/antibiotic combinations with few representative resistant isolates. Time to reporting from sequencing could be achieved within 8–16 h from BC positivity. Direct sequencing from positive BC broths is feasible and can provide accurate predictive AST for some species. ONT-based approaches may be faster but significant improvements in accuracy are required before it can be considered for clinical use. IMPORTANCE Sepsis and bloodstream infections carry a high risk of morbidity and mortality. Rapid identification and susceptibility prediction of causative pathogens, using Nanopore sequencing direct from blood cultures, may offer clinical benefit. We ass
Published: 2024

5. Plasma Protein Biomarkers Distinguish Multisystem Inflammatory Syndrome in Children from Other Pediatric Infectious and Inflammatory Diseases

Author: Yeoh, Sophya, Estrada-Rivadeneyra, Diego, Jackson, Heather, Keren, Ilana, Galassini, Rachel, Cooray, Samantha, Shah, Priyen, Agyeman, Philipp, Basmaci, Romain, Carrol, Enitan, Emonts, Marieke, Fink, Colin, Kuijpers, Taco, Martinon-Torres, Federico, Mommert-Tripon, Marine, Paulus, Stephane, Pokorn, Marko, Rojo, Pablo, Romani, Lorenza, Schlapbach, Luregn, Schweintzger, Nina, Shen, Ching Fen, Tsolia, Maria, Usuf, Effua, Van Der Flier, Michiel, Vermont, Clementien, Von Both, Ulrich, Yeung, Shunmay, Zavadska, Dace, Coin, Lachlan, Cunnington, Aubrey, Herberg, Jethro, Levin, Michael, Kaforou, Myrsini, Hamilton, Shea, Yeoh, Sophya, Estrada-Rivadeneyra, Diego, Jackson, Heather, Keren, Ilana, Galassini, Rachel, Cooray, Samantha, Shah, Priyen, Agyeman, Philipp, Basmaci, Romain, Carrol, Enitan, Emonts, Marieke, Fink, Colin, Kuijpers, Taco, Martinon-Torres, Federico, Mommert-Tripon, Marine, Paulus, Stephane, Pokorn, Marko, Rojo, Pablo, Romani, Lorenza, Schlapbach, Luregn, Schweintzger, Nina, Shen, Ching Fen, Tsolia, Maria, Usuf, Effua, Van Der Flier, Michiel, Vermont, Clementien, Von Both, Ulrich, Yeung, Shunmay, Zavadska, Dace, Coin, Lachlan, Cunnington, Aubrey, Herberg, Jethro, Levin, Michael, Kaforou, Myrsini, and Hamilton, Shea
Abstract: Background: Multisystem inflammatory syndrome in children (MIS-C) is a rare but serious hyperinflammatory complication following infection with severe acute respiratory syndrome coronavirus 2. The mechanisms underpinning the pathophysiology of MIS-C are poorly understood. Moreover, clinically distinguishing MIS-C from other childhood infectious and inflammatory conditions, such as Kawasaki disease or severe bacterial and viral infections, is challenging due to overlapping clinical and laboratory features. We aimed to determine a set of plasma protein biomarkers that could discriminate MIS-C from those other diseases. Methods: Seven candidate protein biomarkers for MIS-C were selected based on literature and from whole blood RNA sequencing data from patients with MIS-C and other diseases. Plasma concentrations of ARG1, CCL20, CD163, CORIN, CXCL9, PCSK9 and ADAMTS2 were quantified in MIS-C (n = 22), Kawasaki disease (n = 23), definite bacterial (n = 28) and viral (n = 27) disease and healthy controls (n = 8). Logistic regression models were used to determine the discriminatory ability of individual proteins and protein combinations to identify MIS-C and association with severity of illness. Results: Plasma levels of CD163, CXCL9 and PCSK9 were significantly elevated in MIS-C with a combined area under the receiver operating characteristic curve of 85.7% (95% confidence interval: 76.6%-94.8%) for discriminating MIS-C from other childhood diseases. Lower ARG1 and CORIN plasma levels were significantly associated with severe MIS-C cases requiring inotropes, pediatric intensive care unit admission or with shock. Conclusion: Our findings demonstrate the feasibility of a host protein biomarker signature for MIS-C and may provide new insight into its pathophysiology.
Published: 2024

6. Identification of a Major QTL-Controlling Resistance to the Subtropical Race 4 of Fusarium oxysporum f. sp. cubense in Musa acuminata ssp. malaccensis

Author: Chen, Andrew, Sun, Jiaman, Martin, Guillaume, Gray, Lesley-Ann, Hřibová, Eva, Christelová, Pavla, Yahiaoui, Nabila, Rounsley, Steve, Lyons, Rebecca, Batley, Jacqueline, Chen, Ning, Hamill, Sharon D., Rai, Subash K., Coin, Lachlan, Uwimana, Brigitte, D’Hont, Angelique, Doležel, Jaroslav, Edwards, David, Swennen, Rony, Aitken, Elizabeth A. B., Chen, Andrew, Sun, Jiaman, Martin, Guillaume, Gray, Lesley-Ann, Hřibová, Eva, Christelová, Pavla, Yahiaoui, Nabila, Rounsley, Steve, Lyons, Rebecca, Batley, Jacqueline, Chen, Ning, Hamill, Sharon D., Rai, Subash K., Coin, Lachlan, Uwimana, Brigitte, D’Hont, Angelique, Doležel, Jaroslav, Edwards, David, Swennen, Rony, and Aitken, Elizabeth A. B.
Abstract: Vascular wilt caused by the ascomycete fungal pathogen Fusarium oxysporum f. sp. cubense (Foc) is a major constraint of banana production around the world. The virulent race, namely Tropical Race 4, can infect all Cavendish-type banana plants and is now widespread across the globe, causing devastating losses to global banana production. In this study, we characterized Foc Subtropical Race 4 (STR4) resistance in a wild banana relative which, through estimated genome size and ancestry analysis, was confirmed to be Musa acuminata ssp. malaccensis. Using a self-derived F2 population segregating for STR4 resistance, quantitative trait loci sequencing (QTL-seq) was performed on bulks consisting of resistant and susceptible individuals. Changes in SNP index between the bulks revealed a major QTL located on the distal end of the long arm of chromosome 3. Multiple resistance genes are present in this region. Identification of chromosome regions conferring resistance to Foc can facilitate marker assisted selection in breeding programs and paves the way towards identifying genes underpinning resistance.
Published: 2023

7. Diagnosis of Multisystem Inflammatory Syndrome in Children by a Whole-Blood Transcriptional Signature.

Author: Jackson, Heather R, Jackson, Heather R, Miglietta, Luca, Habgood-Coote, Dominic, D'Souza, Giselle, Shah, Priyen, Nichols, Samuel, Vito, Ortensia, Powell, Oliver, Davidson, Maisey Salina, Shimizu, Chisato, Agyeman, Philipp KA, Beudeker, Coco R, Brengel-Pesce, Karen, Carrol, Enitan D, Carter, Michael J, De, Tisham, Eleftheriou, Irini, Emonts, Marieke, Epalza, Cristina, Georgiou, Pantelis, De Groot, Ronald, Fidler, Katy, Fink, Colin, van Keulen, Daniëlle, Kuijpers, Taco, Moll, Henriette, Papatheodorou, Irene, Paulus, Stephane, Pokorn, Marko, Pollard, Andrew J, Rivero-Calle, Irene, Rojo, Pablo, Secka, Fatou, Schlapbach, Luregn J, Tremoulet, Adriana H, Tsolia, Maria, Usuf, Effua, Van Der Flier, Michiel, Von Both, Ulrich, Vermont, Clementien, Yeung, Shunmay, Zavadska, Dace, Zenz, Werner, Coin, Lachlan JM, Cunnington, Aubrey, Burns, Jane C, Wright, Victoria, Martinon-Torres, Federico, Herberg, Jethro A, Rodriguez-Manzano, Jesus, Kaforou, Myrsini, Levin, Michael, Jackson, Heather R, Jackson, Heather R, Miglietta, Luca, Habgood-Coote, Dominic, D'Souza, Giselle, Shah, Priyen, Nichols, Samuel, Vito, Ortensia, Powell, Oliver, Davidson, Maisey Salina, Shimizu, Chisato, Agyeman, Philipp KA, Beudeker, Coco R, Brengel-Pesce, Karen, Carrol, Enitan D, Carter, Michael J, De, Tisham, Eleftheriou, Irini, Emonts, Marieke, Epalza, Cristina, Georgiou, Pantelis, De Groot, Ronald, Fidler, Katy, Fink, Colin, van Keulen, Daniëlle, Kuijpers, Taco, Moll, Henriette, Papatheodorou, Irene, Paulus, Stephane, Pokorn, Marko, Pollard, Andrew J, Rivero-Calle, Irene, Rojo, Pablo, Secka, Fatou, Schlapbach, Luregn J, Tremoulet, Adriana H, Tsolia, Maria, Usuf, Effua, Van Der Flier, Michiel, Von Both, Ulrich, Vermont, Clementien, Yeung, Shunmay, Zavadska, Dace, Zenz, Werner, Coin, Lachlan JM, Cunnington, Aubrey, Burns, Jane C, Wright, Victoria, Martinon-Torres, Federico, Herberg, Jethro A, Rodriguez-Manzano, Jesus, Kaforou, Myrsini, and Levin, Michael
Abstract: BackgroundTo identify a diagnostic blood transcriptomic signature that distinguishes multisystem inflammatory syndrome in children (MIS-C) from Kawasaki disease (KD), bacterial infections, and viral infections.MethodsChildren presenting with MIS-C to participating hospitals in the United Kingdom and the European Union between April 2020 and April 2021 were prospectively recruited. Whole-blood RNA Sequencing was performed, contrasting the transcriptomes of children with MIS-C (n = 38) to those from children with KD (n = 136), definite bacterial (DB; n = 188) and viral infections (DV; n = 138). Genes significantly differentially expressed (SDE) between MIS-C and comparator groups were identified. Feature selection was used to identify genes that optimally distinguish MIS-C from other diseases, which were subsequently translated into RT-qPCR assays and evaluated in an independent validation set comprising MIS-C (n = 37), KD (n = 19), DB (n = 56), DV (n = 43), and COVID-19 (n = 39).ResultsIn the discovery set, 5696 genes were SDE between MIS-C and combined comparator disease groups. Five genes were identified as potential MIS-C diagnostic biomarkers (HSPBAP1, VPS37C, TGFB1, MX2, and TRBV11-2), achieving an AUC of 96.8% (95% CI: 94.6%-98.9%) in the discovery set, and were translated into RT-qPCR assays. The RT-qPCR 5-gene signature achieved an AUC of 93.2% (95% CI: 88.3%-97.7%) in the independent validation set when distinguishing MIS-C from KD, DB, and DV.ConclusionsMIS-C can be distinguished from KD, DB, and DV groups using a 5-gene blood RNA expression signature. The small number of genes in the signature and good performance in both discovery and validation sets should enable the development of a diagnostic test for MIS-C.
Published: 2023

8. Identification of a Major QTL-Controlling Resistance to the Subtropical Race 4 of Fusarium oxysporum f. sp. cubense in Musa acuminata ssp. malaccensis

Author: Chen, Andrew, Sun, Jiaman, Martin, Guillaume, Gray, Lesley-Ann, Hřibová, Eva, Christelová, Pavla, Yahiaoui, Nabila, Rounsley, Steve, Lyons, Rebecca, Batley, Jacqueline, Chen, Ning, Hamill, Sharon D., Rai, Subash K., Coin, Lachlan, Uwimana, Brigitte, D’Hont, Angelique, Doležel, Jaroslav, Edwards, David, Swennen, Rony, Aitken, Elizabeth A. B., Chen, Andrew, Sun, Jiaman, Martin, Guillaume, Gray, Lesley-Ann, Hřibová, Eva, Christelová, Pavla, Yahiaoui, Nabila, Rounsley, Steve, Lyons, Rebecca, Batley, Jacqueline, Chen, Ning, Hamill, Sharon D., Rai, Subash K., Coin, Lachlan, Uwimana, Brigitte, D’Hont, Angelique, Doležel, Jaroslav, Edwards, David, Swennen, Rony, and Aitken, Elizabeth A. B.
Abstract: Vascular wilt caused by the ascomycete fungal pathogen Fusarium oxysporum f. sp. cubense (Foc) is a major constraint of banana production around the world. The virulent race, namely Tropical Race 4, can infect all Cavendish-type banana plants and is now widespread across the globe, causing devastating losses to global banana production. In this study, we characterized Foc Subtropical Race 4 (STR4) resistance in a wild banana relative which, through estimated genome size and ancestry analysis, was confirmed to be Musa acuminata ssp. malaccensis. Using a self-derived F2 population segregating for STR4 resistance, quantitative trait loci sequencing (QTL-seq) was performed on bulks consisting of resistant and susceptible individuals. Changes in SNP index between the bulks revealed a major QTL located on the distal end of the long arm of chromosome 3. Multiple resistance genes are present in this region. Identification of chromosome regions conferring resistance to Foc can facilitate marker assisted selection in breeding programs and paves the way towards identifying genes underpinning resistance.
Published: 2023

9. A multi-platform approach to identify a blood-based host protein signature for distinguishing between bacterial and viral infections in febrile children (PERFORM):a multi-cohort machine learning study

Author: Jackson, Heather R., Zandstra, Judith, Menikou, Stephanie, Hamilton, Melissa Shea, McArdle, Andrew J., Fischer, Roman, Thorne, Adam M., Huang, Honglei, Tanck, Michael W., Jansen, Machiel H., De, Tisham, Agyeman, Philipp K.A., Von Both, Ulrich, Carrol, Enitan D., Emonts, Marieke, Eleftheriou, Irini, Van der Flier, Michiel, Fink, Colin, Gloerich, Jolein, De Groot, Ronald, Moll, Henriette A., Pokorn, Marko, Pollard, Andrew J., Schlapbach, Luregn J., Tsolia, Maria N., Usuf, Effua, Wright, Victoria J., Yeung, Shunmay, Zavadska, Dace, Zenz, Werner, Coin, Lachlan J.M., Casals-Pascual, Climent, Cunnington, Aubrey J., Martinon-Torres, Federico, Herberg, Jethro A., de Jonge, Marien I., Levin, Michael, Kuijpers, Taco W., Kaforou, Myrsini, Jackson, Heather R., Zandstra, Judith, Menikou, Stephanie, Hamilton, Melissa Shea, McArdle, Andrew J., Fischer, Roman, Thorne, Adam M., Huang, Honglei, Tanck, Michael W., Jansen, Machiel H., De, Tisham, Agyeman, Philipp K.A., Von Both, Ulrich, Carrol, Enitan D., Emonts, Marieke, Eleftheriou, Irini, Van der Flier, Michiel, Fink, Colin, Gloerich, Jolein, De Groot, Ronald, Moll, Henriette A., Pokorn, Marko, Pollard, Andrew J., Schlapbach, Luregn J., Tsolia, Maria N., Usuf, Effua, Wright, Victoria J., Yeung, Shunmay, Zavadska, Dace, Zenz, Werner, Coin, Lachlan J.M., Casals-Pascual, Climent, Cunnington, Aubrey J., Martinon-Torres, Federico, Herberg, Jethro A., de Jonge, Marien I., Levin, Michael, Kuijpers, Taco W., and Kaforou, Myrsini
Abstract: BACKGROUND: Differentiating between self-resolving viral infections and bacterial infections in children who are febrile is a common challenge, causing difficulties in identifying which individuals require antibiotics. Studying the host response to infection can provide useful insights and can lead to the identification of biomarkers of infection with diagnostic potential. This study aimed to identify host protein biomarkers for future development into an accurate, rapid point-of-care test that can distinguish between bacterial and viral infections, by recruiting children presenting to health-care settings with fever or a history of fever in the previous 72 h. METHODS: In this multi-cohort machine learning study, patient data were taken from EUCLIDS, the Swiss Pediatric Sepsis study, the GENDRES study, and the PERFORM study, which were all based in Europe. We generated three high-dimensional proteomic datasets (SomaScan and two via liquid chromatography tandem mass spectrometry, referred to as MS-A and MS-B) using targeted and untargeted platforms (SomaScan and liquid chromatography mass spectrometry). Protein biomarkers were then shortlisted using differential abundance analysis, feature selection using forward selection-partial least squares (FS-PLS; 100 iterations), along with a literature search. Identified proteins were tested with Luminex and ELISA and iterative FS-PLS was done again (25 iterations) on the Luminex results alone, and the Luminex and ELISA results together. A sparse protein signature for distinguishing between bacterial and viral infections was identified from the selected proteins. The performance of this signature was finally tested using Luminex assays and by calculating disease risk scores. FINDINGS:376 children provided serum or plasma samples for use in the discovery of protein biomarkers. 79 serum samples were collected for the generation of the SomaScan dataset, 147 plasma sample
Published: 2023

10. Identification of a Major QTL-Controlling Resistance to the Subtropical Race 4 of Fusarium oxysporum f. sp. cubense in Musa acuminata ssp. malaccensis

Author: Chen, Andrew, Sun, Jiaman, Martin, Guillaume, Gray, Lesley-Ann, Hřibová, Eva, Christelová, Pavla, Yahiaoui, Nabila, Rounsley, Steve, Lyons, Rebecca, Batley, Jacqueline, Chen, Ning, Hamill, Sharon D., Rai, Subash K., Coin, Lachlan, Uwimana, Brigitte, D’Hont, Angelique, Doležel, Jaroslav, Edwards, David, Swennen, Rony, Aitken, Elizabeth A. B., Chen, Andrew, Sun, Jiaman, Martin, Guillaume, Gray, Lesley-Ann, Hřibová, Eva, Christelová, Pavla, Yahiaoui, Nabila, Rounsley, Steve, Lyons, Rebecca, Batley, Jacqueline, Chen, Ning, Hamill, Sharon D., Rai, Subash K., Coin, Lachlan, Uwimana, Brigitte, D’Hont, Angelique, Doležel, Jaroslav, Edwards, David, Swennen, Rony, and Aitken, Elizabeth A. B.
Abstract: Vascular wilt caused by the ascomycete fungal pathogen Fusarium oxysporum f. sp. cubense (Foc) is a major constraint of banana production around the world. The virulent race, namely Tropical Race 4, can infect all Cavendish-type banana plants and is now widespread across the globe, causing devastating losses to global banana production. In this study, we characterized Foc Subtropical Race 4 (STR4) resistance in a wild banana relative which, through estimated genome size and ancestry analysis, was confirmed to be Musa acuminata ssp. malaccensis. Using a self-derived F2 population segregating for STR4 resistance, quantitative trait loci sequencing (QTL-seq) was performed on bulks consisting of resistant and susceptible individuals. Changes in SNP index between the bulks revealed a major QTL located on the distal end of the long arm of chromosome 3. Multiple resistance genes are present in this region. Identification of chromosome regions conferring resistance to Foc can facilitate marker assisted selection in breeding programs and paves the way towards identifying genes underpinning resistance.
Published: 2023

11. Diagnosis of Multisystem Inflammatory Syndrome in Children by a Whole-Blood Transcriptional Signature

Author: Jackson, Heather R., Miglietta, Luca, Habgood-Coote, Dominic, D'souza, Giselle, Shah, Priyen, Nichols, Samuel, Vito, Ortensia, Powell, Oliver, Davidson, Maisey Salina, Shimizu, Chisato, Agyeman, Philipp K.A., Beudeker, Coco R., Brengel-Pesce, Karen, Carrol, Enitan D., Carter, Michael J., De, Tisham, Eleftheriou, Irini, Emonts, Marieke, Epalza, Cristina, Georgiou, Pantelis, De Groot, Ronald, Fidler, Katy, Fink, Colin, Van Keulen, Daniëlle, Kuijpers, Taco, Moll, Henriette, Papatheodorou, Irene, Paulus, Stephane, Pokorn, Marko, Pollard, Andrew J., Rivero-Calle, Irene, Rojo, Pablo, Secka, Fatou, Schlapbach, Luregn J., Tremoulet, Adriana H., Tsolia, Maria, Usuf, Effua, Van Der Flier, Michiel, Von Both, Ulrich, Vermont, Clementien, Yeung, Shunmay, Zavadska, Dace, Zenz, Werner, Coin, Lachlan J.M., Cunnington, Aubrey, Burns, Jane C., Wright, Victoria, Martinon-Torres, Federico, Herberg, Jethro A., Rodriguez-Manzano, Jesus, Kaforou, Myrsini, Levin, Michael, Jackson, Heather R., Miglietta, Luca, Habgood-Coote, Dominic, D'souza, Giselle, Shah, Priyen, Nichols, Samuel, Vito, Ortensia, Powell, Oliver, Davidson, Maisey Salina, Shimizu, Chisato, Agyeman, Philipp K.A., Beudeker, Coco R., Brengel-Pesce, Karen, Carrol, Enitan D., Carter, Michael J., De, Tisham, Eleftheriou, Irini, Emonts, Marieke, Epalza, Cristina, Georgiou, Pantelis, De Groot, Ronald, Fidler, Katy, Fink, Colin, Van Keulen, Daniëlle, Kuijpers, Taco, Moll, Henriette, Papatheodorou, Irene, Paulus, Stephane, Pokorn, Marko, Pollard, Andrew J., Rivero-Calle, Irene, Rojo, Pablo, Secka, Fatou, Schlapbach, Luregn J., Tremoulet, Adriana H., Tsolia, Maria, Usuf, Effua, Van Der Flier, Michiel, Von Both, Ulrich, Vermont, Clementien, Yeung, Shunmay, Zavadska, Dace, Zenz, Werner, Coin, Lachlan J.M., Cunnington, Aubrey, Burns, Jane C., Wright, Victoria, Martinon-Torres, Federico, Herberg, Jethro A., Rodriguez-Manzano, Jesus, Kaforou, Myrsini, and Levin, Michael
Abstract: Background: To identify a diagnostic blood transcriptomic signature that distinguishes multisystem inflammatory syndrome in children (MIS-C) from Kawasaki disease (KD), bacterial infections, and viral infections. Methods: Children presenting with MIS-C to participating hospitals in the United Kingdom and the European Union between April 2020 and April 2021 were prospectively recruited. Whole-blood RNA Sequencing was performed, contrasting the transcriptomes of children with MIS-C (n = 38) to those from children with KD (n = 136), definite bacterial (DB; n = 188) and viral infections (DV; n = 138). Genes significantly differentially expressed (SDE) between MIS-C and comparator groups were identified. Feature selection was used to identify genes that optimally distinguish MIS-C from other diseases, which were subsequently translated into RT-qPCR assays and evaluated in an independent validation set comprising MIS-C (n = 37), KD (n = 19), DB (n = 56), DV (n = 43), and COVID-19 (n = 39). Results: In the discovery set, 5696 genes were SDE between MIS-C and combined comparator disease groups. Five genes were identified as potential MIS-C diagnostic biomarkers (HSPBAP1, VPS37C, TGFB1, MX2, and TRBV11-2), achieving an AUC of 96.8% (95% CI: 94.6%-98.9%) in the discovery set, and were translated into RT-qPCR assays. The RT-qPCR 5-gene signature achieved an AUC of 93.2% (95% CI: 88.3%-97.7%) in the independent validation set when distinguishing MIS-C from KD, DB, and DV. Conclusions: MIS-C can be distinguished from KD, DB, and DV groups using a 5-gene blood RNA expression signature. The small number of genes in the signature and good performance in both discovery and validation sets should enable the development of a diagnostic test for MIS-C.
Published: 2023

12. Genetic mapping, candidate gene identification and marker validation for host plant resistance to the race 4 of Fusarium oxysporum f. sp. cubense using Musa acuminata ssp. malaccensis

Author: Chen, Andrew, Sun, Jiaman, Viljoen, Altus, Mostert, Diane, Xie, Yucong, Mangila, Leroy, Bothma, Sheryl, Lyons, Rebecca, Hribova, Eva, Christelová, Pavla, Uwimana, Brigitte, Amah, Delphine, Pearce, Stephen, Chen, Ning, Batley, Jacqueline, Edwards, David P., Dolezel, Jaroslav, Crisp, Peter, Brown, Allan F., Martin, Guillaume, Yahiaoui, Nabila, D'Hont, Angélique, Coin, Lachlan, Swennen, Rony, Aitken, Elizabeth A. B., Chen, Andrew, Sun, Jiaman, Viljoen, Altus, Mostert, Diane, Xie, Yucong, Mangila, Leroy, Bothma, Sheryl, Lyons, Rebecca, Hribova, Eva, Christelová, Pavla, Uwimana, Brigitte, Amah, Delphine, Pearce, Stephen, Chen, Ning, Batley, Jacqueline, Edwards, David P., Dolezel, Jaroslav, Crisp, Peter, Brown, Allan F., Martin, Guillaume, Yahiaoui, Nabila, D'Hont, Angélique, Coin, Lachlan, Swennen, Rony, and Aitken, Elizabeth A. B.
Abstract: Fusarium wilt of banana is a devastating disease that has decimated banana production worldwide. Host resistance to Fusarium oxysporum f. sp. Cubense (Foc), the causal agent of this disease, is genetically dissected in this study using two Musa acuminata ssp. Malaccensis segregating populations, segregating for Foc Tropical (TR4) and Subtropical (STR4) race 4 resistance. Marker loci and trait association using 11 SNP-based PCR markers allowed the candidate region to be delimited to a 12.9 cM genetic interval corresponding to a 959 kb region on chromosome 3 of 'DH-Pahang' reference assembly v4. Within this region, there was a cluster of pattern recognition receptors, namely leucine-rich repeat ectodomain containing receptor-like protein kinases, cysteine-rich cell-wall-associated protein kinases, and leaf rust 10 disease-resistance locus receptor-like proteins, positioned in an interspersed arrangement. Their transcript levels were rapidly upregulated in the resistant progenies but not in the susceptible F2 progenies at the onset of infection. This suggests that one or several of these genes may control resistance at this locus. To confirm the segregation of single-gene resistance, we generated an inter-cross between the resistant parent 'Ma850' and a susceptible line 'Ma848', to show that the STR4 resistance co-segregated with marker '28820' at this locus. Finally, an informative SNP marker 29730 allowed the locus-specific resistance to be assessed in a collection of diploid and polyploid banana plants. Of the 60 lines screened, 22 lines were predicted to carry resistance at this locus, including lines known to be TR4-resistant, such as 'Pahang', 'SH-3362', 'SH-3217', 'Ma-ITC0250', and 'DH-Pahang/CIRAD 930'. Additional screening in the International Institute for Tropical Agriculture's collection suggests that the dominant allele is common among the elite 'Matooke' NARITA hybrids, as well as in other triploid or tetraploid hybrids derived from East African highland
Published: 2023

13. Identification of a major QTL-Controlling resistance to the subtropical race 4 of Fusarium oxysporum f. sp. cubense in Musa acuminata ssp. malaccensis

Author: Chen, Andrew, Sun, Jiaman, Martin, Guillaume, Gray, Lesley-Ann, Hribova, Eva, Christelová, Pavla, Yahiaoui, Nabila, Rounsley, Steve, Lyons, Rebecca, Batley, Jacqueline, Chen, Ning, Hamill, Sharon, Rai, Subash K., Coin, Lachlan, Uwimana, Brigitte, D'Hont, Angélique, Dolezel, Jaroslav, Edwards, David P., Swennen, Rony, Aitken, Elizabeth A. B., Chen, Andrew, Sun, Jiaman, Martin, Guillaume, Gray, Lesley-Ann, Hribova, Eva, Christelová, Pavla, Yahiaoui, Nabila, Rounsley, Steve, Lyons, Rebecca, Batley, Jacqueline, Chen, Ning, Hamill, Sharon, Rai, Subash K., Coin, Lachlan, Uwimana, Brigitte, D'Hont, Angélique, Dolezel, Jaroslav, Edwards, David P., Swennen, Rony, and Aitken, Elizabeth A. B.
Abstract: Vascular wilt caused by the ascomycete fungal pathogen Fusarium oxysporum f. sp. cubense (Foc) is a major constraint of banana production around the world. The virulent race, namely Tropical Race 4, can infect all Cavendish-type banana plants and is now widespread across the globe, causing devastating losses to global banana production. In this study, we characterized Foc Subtropical Race 4 (STR4) resistance in a wild banana relative which, through estimated genome size and ancestry analysis, was confirmed to be Musa acuminata ssp. malaccensis. Using a self-derived F2 population segregating for STR4 resistance, quantitative trait loci sequencing (QTL-seq) was performed on bulks consisting of resistant and susceptible individuals. Changes in SNP index between the bulks revealed a major QTL located on the distal end of the long arm of chromosome 3. Multiple resistance genes are present in this region. Identification of chromosome regions conferring resistance to Foc can facilitate marker assisted selection in breeding programs and paves the way towards identifying genes underpinning resistance.
Published: 2023

14. Diagnosis of Multisystem Inflammatory Syndrome in Children by a Whole-Blood Transcriptional Signature

Author: Infectieziekten onderzoek1 (Bont), Infection & Immunity, NVIC bedrijfsvoering, Other research (not in main researchprogram), CDL Onderzoek Pasterkamp, Infectieziekten patientenzorg, Child Health, Jackson, Heather R., Miglietta, Luca, Habgood-Coote, Dominic, D'souza, Giselle, Shah, Priyen, Nichols, Samuel, Vito, Ortensia, Powell, Oliver, Davidson, Maisey Salina, Shimizu, Chisato, Agyeman, Philipp K.A., Beudeker, Coco R., Brengel-Pesce, Karen, Carrol, Enitan D., Carter, Michael J., De, Tisham, Eleftheriou, Irini, Emonts, Marieke, Epalza, Cristina, Georgiou, Pantelis, De Groot, Ronald, Fidler, Katy, Fink, Colin, Van Keulen, Daniëlle, Kuijpers, Taco, Moll, Henriette, Papatheodorou, Irene, Paulus, Stephane, Pokorn, Marko, Pollard, Andrew J., Rivero-Calle, Irene, Rojo, Pablo, Secka, Fatou, Schlapbach, Luregn J., Tremoulet, Adriana H., Tsolia, Maria, Usuf, Effua, Van Der Flier, Michiel, Von Both, Ulrich, Vermont, Clementien, Yeung, Shunmay, Zavadska, Dace, Zenz, Werner, Coin, Lachlan J.M., Cunnington, Aubrey, Burns, Jane C., Wright, Victoria, Martinon-Torres, Federico, Herberg, Jethro A., Rodriguez-Manzano, Jesus, Infectieziekten onderzoek1 (Bont), Infection & Immunity, NVIC bedrijfsvoering, Other research (not in main researchprogram), CDL Onderzoek Pasterkamp, Infectieziekten patientenzorg, Child Health, Jackson, Heather R., Miglietta, Luca, Habgood-Coote, Dominic, D'souza, Giselle, Shah, Priyen, Nichols, Samuel, Vito, Ortensia, Powell, Oliver, Davidson, Maisey Salina, Shimizu, Chisato, Agyeman, Philipp K.A., Beudeker, Coco R., Brengel-Pesce, Karen, Carrol, Enitan D., Carter, Michael J., De, Tisham, Eleftheriou, Irini, Emonts, Marieke, Epalza, Cristina, Georgiou, Pantelis, De Groot, Ronald, Fidler, Katy, Fink, Colin, Van Keulen, Daniëlle, Kuijpers, Taco, Moll, Henriette, Papatheodorou, Irene, Paulus, Stephane, Pokorn, Marko, Pollard, Andrew J., Rivero-Calle, Irene, Rojo, Pablo, Secka, Fatou, Schlapbach, Luregn J., Tremoulet, Adriana H., Tsolia, Maria, Usuf, Effua, Van Der Flier, Michiel, Von Both, Ulrich, Vermont, Clementien, Yeung, Shunmay, Zavadska, Dace, Zenz, Werner, Coin, Lachlan J.M., Cunnington, Aubrey, Burns, Jane C., Wright, Victoria, Martinon-Torres, Federico, Herberg, Jethro A., and Rodriguez-Manzano, Jesus
Published: 2023

15. Variation in CFHR3 determines susceptibility to meningococcal disease by controlling factor H concentrations

Author: Kumar, Vikrant, Pouw, Richard B., Autio, Matias I., Sagmeister, Manfred G., Phua, Zai Yang, Borghini, Lisa, Wright, Victoria J., Hoggart, Clive, Pan, Bangfen, Tan, Antson Kiat Yee, Binder, Alexander, Brouwer, Mieke C., Pinnock, Ellie, De Groot, Ronald, Hazelzet, Jan, Emonts, Marieke, Van Der Flier, Michiel, Reiter, Karl, Nöthen, Markus M., Hoffmann, Per, Schlapbach, Luregn J., Bellos, Evangelos, Anderson, Suzanne, Secka, Fatou, Martinón-Torres, Federico, Salas, Antonio, Fink, Colin, Carrol, Enitan D., Pollard, Andrew J., Coin, Lachlan J., Zenz, Werner, Wouters, Diana, Ang, Lay Teng, Hibberd, Martin L., Levin, Michael, Kuijpers, Taco W., Davila, Sonia, Kumar, Vikrant, Pouw, Richard B., Autio, Matias I., Sagmeister, Manfred G., Phua, Zai Yang, Borghini, Lisa, Wright, Victoria J., Hoggart, Clive, Pan, Bangfen, Tan, Antson Kiat Yee, Binder, Alexander, Brouwer, Mieke C., Pinnock, Ellie, De Groot, Ronald, Hazelzet, Jan, Emonts, Marieke, Van Der Flier, Michiel, Reiter, Karl, Nöthen, Markus M., Hoffmann, Per, Schlapbach, Luregn J., Bellos, Evangelos, Anderson, Suzanne, Secka, Fatou, Martinón-Torres, Federico, Salas, Antonio, Fink, Colin, Carrol, Enitan D., Pollard, Andrew J., Coin, Lachlan J., Zenz, Werner, Wouters, Diana, Ang, Lay Teng, Hibberd, Martin L., Levin, Michael, Kuijpers, Taco W., and Davila, Sonia
Abstract: Neisseria meningitidis protects itself from complement-mediated killing by binding complement factor H (FH). Previous studies associated susceptibility to meningococcal disease (MD) with variation in CFH, but the causal variants and underlying mechanism remained unknown. Here we attempted to define the association more accurately by sequencing the CFH-CFHR locus and imputing missing genotypes in previously obtained GWAS datasets of MD-affected individuals of European ancestry and matched controls. We identified a CFHR3 SNP that provides protection from MD (rs75703017, p value = 1.1 × 10−16) by decreasing the concentration of FH in the blood (p value = 1.4 × 10−11). We subsequently used dual-luciferase studies and CRISPR gene editing to establish that deletion of rs75703017 increased FH expression in hepatocyte by preventing promotor inhibition. Our data suggest that reduced concentrations of FH in the blood confer protection from MD; with reduced access to FH, N. meningitidis is less able to shield itself from complement-mediated killing.
Published: 2022

16. Optimising Treatment Outcomes for Children and Adults Through Rapid Genome Sequencing of Sepsis Pathogens. A Study Protocol for a Prospective, Multi-Centre Trial (DIRECT)

Author: Irwin, Adam D, Coin, Lachlan J M, Harris, Patrick N A, Cotta, Menino Osbert, Bauer, Michelle J, Buckley, Cameron, et al, Schlapbach, Luregn J; https://orcid.org/0000-0003-2281-2598, Irwin, Adam D, Coin, Lachlan J M, Harris, Patrick N A, Cotta, Menino Osbert, Bauer, Michelle J, Buckley, Cameron, et al, and Schlapbach, Luregn J; https://orcid.org/0000-0003-2281-2598
Abstract: Background Sepsis contributes significantly to morbidity and mortality globally. In Australia, 20,000 develop sepsis every year, resulting in 5,000 deaths, and more than AUD$846 million in expenditure. Prompt, appropriate antibiotic therapy is effective in improving outcomes in sepsis. Conventional culture-based methods to identify appropriate therapy have limited yield and take days to complete. Recently, nanopore technology has enabled rapid sequencing with real-time analysis of pathogen DNA. We set out to demonstrate the feasibility and diagnostic accuracy of pathogen sequencing direct from clinical samples, and estimate the impact of this approach on time to effective therapy when integrated with personalised software-guided antimicrobial dosing in children and adults on ICU with sepsis. Methods The DIRECT study is a pilot prospective, non-randomized multicentre trial of an integrated diagnostic and therapeutic algorithm combining rapid direct pathogen sequencing and software-guided, personalised antibiotic dosing in children and adults with sepsis on ICU. Participants and interventions DIRECT will collect microbiological and pharmacokinetic samples from approximately 200 children and adults with sepsis admitted to one of four ICUs in Brisbane. In Phase 1, we will evaluate Oxford Nanopore Technologies MinION sequencing direct from blood in 50 blood culture-proven sepsis patients recruited from consecutive patients with suspected sepsis. In Phase 2, a further 50 consecutive patients with suspected sepsis will be recruited in whom MinION sequencing will be combined with Bayesian software-guided (ID-ODS) personalised antimicrobial dosing. Outcome measures The primary outcome is time to effective antimicrobial therapy, defined as trough drug concentrations above the MIC of the pathogen. Secondary outcomes are diagnostic accuracy of MinION sequencing from whole blood, time to pathogen identification and susceptibility testing using sequencing direct from whole blood
Published: 2021

17. Whole-exome Sequencing for the Identification of Rare Variants in Primary Immunodeficiency Genes in Children With Sepsis: A Prospective, Population-based Cohort Study

Author: Borghesi, Alessandro, Trück, Johannes; https://orcid.org/0000-0002-0418-7381, Asgari, Samira, Sancho-Shimizu, Vanessa, Agyeman, Philipp K A, Bellos, Evangelos, Giannoni, Eric, Stocker, Martin, Posfay-Barbe, Klara M, Heininger, Ulrich, Bernhard-Stirnemann, Sara, Niederer-Loher, Anita, Kahlert, Christian R, Natalucci, Giancardlo, Relly, Christa, Riedel, Thomas, Kuehni, Claudia E, Thorball, Christian W, Chaturvedi, Nimisha, Martinon-Torres, Federico, Kuijpers, Taco W, Coin, Lachlan, Wright, Victoria, Herberg, Jethro, Levin, Michael, Aebi, Christoph, Berger, Christoph, Fellay, Jacques, Schlapbach, Luregn J; https://orcid.org/0000-0003-2281-2598, Borghesi, Alessandro, Trück, Johannes; https://orcid.org/0000-0002-0418-7381, Asgari, Samira, Sancho-Shimizu, Vanessa, Agyeman, Philipp K A, Bellos, Evangelos, Giannoni, Eric, Stocker, Martin, Posfay-Barbe, Klara M, Heininger, Ulrich, Bernhard-Stirnemann, Sara, Niederer-Loher, Anita, Kahlert, Christian R, Natalucci, Giancardlo, Relly, Christa, Riedel, Thomas, Kuehni, Claudia E, Thorball, Christian W, Chaturvedi, Nimisha, Martinon-Torres, Federico, Kuijpers, Taco W, Coin, Lachlan, Wright, Victoria, Herberg, Jethro, Levin, Michael, Aebi, Christoph, Berger, Christoph, Fellay, Jacques, and Schlapbach, Luregn J; https://orcid.org/0000-0003-2281-2598
Abstract: BACKGROUND The role of primary immunodeficiencies (PID) in susceptibility to sepsis remains unknown. It is unclear whether children with sepsis benefit from genetic investigations. We hypothesized that sepsis may represent the first manifestation of underlying PID. We applied whole-exome sequencing (WES) to a national cohort of children with sepsis to identify rare, predicted pathogenic variants in PID genes. METHODS Multicenter population-based prospective study including previously healthy children ≥28 days and <17 years admitted with blood culture-proven sepsis. Using a stringent variant filtering procedure, analysis of WES data was restricted to rare, predicted pathogenic variants in 240 PID genes for which increased susceptibility to bacterial infection has been reported. RESULTS 176 children presenting with 185 sepsis episodes underwent WES (median age 52 months, IQR 15.4-126.4). 41 unique predicted pathogenic PID variants (1 homozygous, 5 hemizygous, and 35 heterozygous) were found in 35/176 (20%) patients, including 3/176 (2%) patients carrying variants which were previously reported to lead to PID. The variants occurred in PID genes across all 8 PID categories as defined by the International Union of Immunological Societies. We did not observe a significant correlation between clinical or laboratory characteristics of patients and the presence or absence of PID variants. CONCLUSIONS Applying WES to a population-based cohort of previously healthy children with bacterial sepsis detected Variants of Uncertain Significance in PID genes in one out of five children. Future studies need to investigate the functional relevance of these variants to determine whether variants in PID genes contribute to pediatric sepsis susceptibility.
Published: 2020

18. The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia : design, results and future prospects

Author: Middeldorp, Christel M., Mahajan, Anubha, Horikoshi, Momoko, Robertson, Neil R., Beaumont, Robin N., Bradfield, Jonathan P., Bustamante, Mariona, Cousminer, Diana L., Day, Felix R., De Silva, N. Maneka, Guxens, Monica, Mook-Kanamori, Dennis O., St Pourcain, Beate, Warrington, Nicole M., Adair, Linda S., Ahlqvist, Emma, Ahluwalia, Tarunveer S., Almgren, Peter, Ang, Wei, Atalay, Mustafa, Auvinen, Juha, Bartels, Meike, Beckmann, Jacques S., Bilbao, Jose Ramon, Bond, Tom, Borja, Judith B., Cavadino, Alana, Charoen, Pimphen, Chen, Zhanghua, Coin, Lachlan, Cooper, Cyrus, Curtin, John A., Custovic, Adnan, Das, Shikta, Davies, Gareth E., Dedoussis, George V., Duijts, Liesbeth, Eastwood, Peter R., Eliasen, Anders U., Elliott, Paul, Eriksson, Johan G., Estivill, Xavier, Fadista, Joao, Fedko, Iryna O., Frayling, Timothy M., Gaillard, Romy, Gauderman, W. James, Geller, Frank, Gilliland, Frank, Gilsanz, Vincente, Granell, Raquel, Grarup, Niels, Groop, Leif, Hadley, Dexter, Hakonarson, Hakon, Hansen, Torben, Hartman, Catharina A., Hattersley, Andrew T., Hayes, M. Geoffrey, Hebebrand, Johannes, Heinrich, Joachim, Helgeland, Oyvind, Henders, Anjali K., Henderson, John, Henriksen, Tine B., Hirschhorn, Joel N., Hivert, Marie-France, Hocher, Berthold, Holloway, John W., Holt, Patrick, Hottenga, Jouke-Jan, Hypponen, Elina, Iniguez, Carmen, Johansson, Stefan, Jugessur, Astanand, Kahonen, Mika, Kalkwarf, Heidi J., Kaprio, Jaakko, Karhunen, Ville, Kemp, John P., Kerkhof, Marjan, Koppelman, Gerard H., Korner, Antje, Kotecha, Sailesh, Kreiner-Moller, Eskil, Kulohoma, Benard, Kumar, Ashish, Kutalik, Zoltan, Lahti, Jari, Lappe, Joan M., Larsson, Henrik, Lehtimaki, Terho, Lewin, Alexandra M., Li, Jin, Lichtenstein, Paul, Lindgren, Cecilia M., Lindi, Virpi, Linneberg, Allan, Liu, Xueping, Liu, Jun, Lowe, William L., Jr., Lundstrom, Sebastian, Lyytikainen, Leo-Pekka, Ma, Ronald C. W., Mace, Aurelien, Magi, Reedik, Magnus, Per, Mamun, Abdullah A., Mannikko, Minna, Martin, Nicholas G., Mbarek, Hamdi, McCarthy, Nina S., Medland, Sarah E., Melbye, Mads, Melen, Erik, Mohlke, Karen L., Monnereau, Claire, Morgen, Camilla S., Morris, Andrew P., Murray, Jeffrey C., Myhre, Ronny, Najman, Jackob M., Nivard, Michel G., Nohr, Ellen A., Nolte, Ilja M., Ntalla, Ioanna, O'Reilly, Paul, Oberfield, Sharon E., Oken, Emily, Oldehinkel, Albertine J., Pahkala, Katja, Palviainen, Teemu, Panoutsopoulou, Kalliope, Pedersen, Oluf, Pennell, Craig E., Pershagen, Goran, Pitkanen, Niina, Plomin, Robert, Power, Christine, Prasad, Rashmi B., Prokopenko, Inga, Pulkkinen, Lea, Raikkonen, Katri, Raitakari, Olli T., Reynolds, Rebecca M., Richmond, Rebecca C., Rivadeneira, Fernando, Rodriguez, Alina, Rose, Richard J., Salem, Rany, Santa-Marina, Loreto, Saw, Seang-Mei, Schnurr, Theresia M., Scott, James G., Selzam, Saskia, Shepherd, John A., Simpson, Angela, Skotte, Line, Sleiman, Patrick M. A., Snieder, Harold, Sorensen, Thorkild I. A., Standl, Marie, Steegers, Eric A. P., Strachan, David P., Straker, Leon, Strandberg, Timo, Taylor, Michelle, Teo, Yik-Ying, Thiering, Elisabeth, Torrent, Maties, Tyrrell, Jessica, Uitterlinden, Andre G., van Beijsterveldt, Toos, van der Most, Peter J., van Duijn, Cornelia M., Viikari, Jorma, Vilor-Tejedor, Natalia, Vogelezang, Suzanne, Vonk, Judith M., Vrijkotte, Tanja G. M., Vuoksimaa, Eero, Wang, Carol A., Watkins, William J., Wichmann, H-Erich, Willemsen, Gonneke, Williams, Gail M., Wilson, James F., Wray, Naomi R., Xu, Shujing, Xu, Cheng-Jian, Yaghootkar, Hanieh, Yi, Lu, Zafarmand, Mohammad Hadi, Zeggini, Eleftheria, Zemel, Babette S., Hinney, Anke, Lakka, Timo A., Whitehouse, Andrew J. O., Sunyer, Jordi, Widen, Elisabeth E., Feenstra, Bjarke, Sebert, Sylvain, Jacobsson, Bo, Njolstad, Pal R., Stoltenberg, Camilla, Smith, George Davey, Lawlor, Debbie A., Paternoster, Lavinia, Timpson, Nicholas J., Ong, Ken K., Bisgaard, Hans, Bonnelykke, Klaus, Jaddoe, Vincent W. V., Tiemeier, Henning, Jarvelin, Marjo-Riitta, Evans, David M., Perry, John R. B., Grant, Struan F. A., Boomsma, Dorret I., Freathy, Rachel M., McCarthy, Mark I., Felix, Janine F., Tiemeier, Hen-Ning, Middeldorp, Christel M., Mahajan, Anubha, Horikoshi, Momoko, Robertson, Neil R., Beaumont, Robin N., Bradfield, Jonathan P., Bustamante, Mariona, Cousminer, Diana L., Day, Felix R., De Silva, N. Maneka, Guxens, Monica, Mook-Kanamori, Dennis O., St Pourcain, Beate, Warrington, Nicole M., Adair, Linda S., Ahlqvist, Emma, Ahluwalia, Tarunveer S., Almgren, Peter, Ang, Wei, Atalay, Mustafa, Auvinen, Juha, Bartels, Meike, Beckmann, Jacques S., Bilbao, Jose Ramon, Bond, Tom, Borja, Judith B., Cavadino, Alana, Charoen, Pimphen, Chen, Zhanghua, Coin, Lachlan, Cooper, Cyrus, Curtin, John A., Custovic, Adnan, Das, Shikta, Davies, Gareth E., Dedoussis, George V., Duijts, Liesbeth, Eastwood, Peter R., Eliasen, Anders U., Elliott, Paul, Eriksson, Johan G., Estivill, Xavier, Fadista, Joao, Fedko, Iryna O., Frayling, Timothy M., Gaillard, Romy, Gauderman, W. James, Geller, Frank, Gilliland, Frank, Gilsanz, Vincente, Granell, Raquel, Grarup, Niels, Groop, Leif, Hadley, Dexter, Hakonarson, Hakon, Hansen, Torben, Hartman, Catharina A., Hattersley, Andrew T., Hayes, M. Geoffrey, Hebebrand, Johannes, Heinrich, Joachim, Helgeland, Oyvind, Henders, Anjali K., Henderson, John, Henriksen, Tine B., Hirschhorn, Joel N., Hivert, Marie-France, Hocher, Berthold, Holloway, John W., Holt, Patrick, Hottenga, Jouke-Jan, Hypponen, Elina, Iniguez, Carmen, Johansson, Stefan, Jugessur, Astanand, Kahonen, Mika, Kalkwarf, Heidi J., Kaprio, Jaakko, Karhunen, Ville, Kemp, John P., Kerkhof, Marjan, Koppelman, Gerard H., Korner, Antje, Kotecha, Sailesh, Kreiner-Moller, Eskil, Kulohoma, Benard, Kumar, Ashish, Kutalik, Zoltan, Lahti, Jari, Lappe, Joan M., Larsson, Henrik, Lehtimaki, Terho, Lewin, Alexandra M., Li, Jin, Lichtenstein, Paul, Lindgren, Cecilia M., Lindi, Virpi, Linneberg, Allan, Liu, Xueping, Liu, Jun, Lowe, William L., Jr., Lundstrom, Sebastian, Lyytikainen, Leo-Pekka, Ma, Ronald C. W., Mace, Aurelien, Magi, Reedik, Magnus, Per, Mamun, Abdullah A., Mannikko, Minna, Martin, Nicholas G., Mbarek, Hamdi, McCarthy, Nina S., Medland, Sarah E., Melbye, Mads, Melen, Erik, Mohlke, Karen L., Monnereau, Claire, Morgen, Camilla S., Morris, Andrew P., Murray, Jeffrey C., Myhre, Ronny, Najman, Jackob M., Nivard, Michel G., Nohr, Ellen A., Nolte, Ilja M., Ntalla, Ioanna, O'Reilly, Paul, Oberfield, Sharon E., Oken, Emily, Oldehinkel, Albertine J., Pahkala, Katja, Palviainen, Teemu, Panoutsopoulou, Kalliope, Pedersen, Oluf, Pennell, Craig E., Pershagen, Goran, Pitkanen, Niina, Plomin, Robert, Power, Christine, Prasad, Rashmi B., Prokopenko, Inga, Pulkkinen, Lea, Raikkonen, Katri, Raitakari, Olli T., Reynolds, Rebecca M., Richmond, Rebecca C., Rivadeneira, Fernando, Rodriguez, Alina, Rose, Richard J., Salem, Rany, Santa-Marina, Loreto, Saw, Seang-Mei, Schnurr, Theresia M., Scott, James G., Selzam, Saskia, Shepherd, John A., Simpson, Angela, Skotte, Line, Sleiman, Patrick M. A., Snieder, Harold, Sorensen, Thorkild I. A., Standl, Marie, Steegers, Eric A. P., Strachan, David P., Straker, Leon, Strandberg, Timo, Taylor, Michelle, Teo, Yik-Ying, Thiering, Elisabeth, Torrent, Maties, Tyrrell, Jessica, Uitterlinden, Andre G., van Beijsterveldt, Toos, van der Most, Peter J., van Duijn, Cornelia M., Viikari, Jorma, Vilor-Tejedor, Natalia, Vogelezang, Suzanne, Vonk, Judith M., Vrijkotte, Tanja G. M., Vuoksimaa, Eero, Wang, Carol A., Watkins, William J., Wichmann, H-Erich, Willemsen, Gonneke, Williams, Gail M., Wilson, James F., Wray, Naomi R., Xu, Shujing, Xu, Cheng-Jian, Yaghootkar, Hanieh, Yi, Lu, Zafarmand, Mohammad Hadi, Zeggini, Eleftheria, Zemel, Babette S., Hinney, Anke, Lakka, Timo A., Whitehouse, Andrew J. O., Sunyer, Jordi, Widen, Elisabeth E., Feenstra, Bjarke, Sebert, Sylvain, Jacobsson, Bo, Njolstad, Pal R., Stoltenberg, Camilla, Smith, George Davey, Lawlor, Debbie A., Paternoster, Lavinia, Timpson, Nicholas J., Ong, Ken K., Bisgaard, Hans, Bonnelykke, Klaus, Jaddoe, Vincent W. V., Tiemeier, Henning, Jarvelin, Marjo-Riitta, Evans, David M., Perry, John R. B., Grant, Struan F. A., Boomsma, Dorret I., Freathy, Rachel M., McCarthy, Mark I., Felix, Janine F., and Tiemeier, Hen-Ning
Abstract: The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites.
Published: 2019
Full Text: View/download PDF

19. The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia : design, results and future prospects

Author: Middeldorp, Christel M., Mahajan, Anubha, Horikoshi, Momoko, Robertson, Neil R., Beaumont, Robin N., Bradfield, Jonathan P., Bustamante, Mariona, Cousminer, Diana L., Day, Felix R., De Silva, N. Maneka, Guxens, Monica, Mook-Kanamori, Dennis O., St Pourcain, Beate, Warrington, Nicole M., Adair, Linda S., Ahlqvist, Emma, Ahluwalia, Tarunveer S., Almgren, Peter, Ang, Wei, Atalay, Mustafa, Auvinen, Juha, Bartels, Meike, Beckmann, Jacques S., Bilbao, Jose Ramon, Bond, Tom, Borja, Judith B., Cavadino, Alana, Charoen, Pimphen, Chen, Zhanghua, Coin, Lachlan, Cooper, Cyrus, Curtin, John A., Custovic, Adnan, Das, Shikta, Davies, Gareth E., Dedoussis, George V., Duijts, Liesbeth, Eastwood, Peter R., Eliasen, Anders U., Elliott, Paul, Eriksson, Johan G., Estivill, Xavier, Fadista, Joao, Fedko, Iryna O., Frayling, Timothy M., Gaillard, Romy, Gauderman, W. James, Geller, Frank, Gilliland, Frank, Gilsanz, Vincente, Granell, Raquel, Grarup, Niels, Groop, Leif, Hadley, Dexter, Hakonarson, Hakon, Hansen, Torben, Hartman, Catharina A., Hattersley, Andrew T., Hayes, M. Geoffrey, Hebebrand, Johannes, Heinrich, Joachim, Helgeland, Oyvind, Henders, Anjali K., Henderson, John, Henriksen, Tine B., Hirschhorn, Joel N., Hivert, Marie-France, Hocher, Berthold, Holloway, John W., Holt, Patrick, Hottenga, Jouke-Jan, Hypponen, Elina, Iniguez, Carmen, Johansson, Stefan, Jugessur, Astanand, Kahonen, Mika, Kalkwarf, Heidi J., Kaprio, Jaakko, Karhunen, Ville, Kemp, John P., Kerkhof, Marjan, Koppelman, Gerard H., Korner, Antje, Kotecha, Sailesh, Kreiner-Moller, Eskil, Kulohoma, Benard, Kumar, Ashish, Kutalik, Zoltan, Lahti, Jari, Lappe, Joan M., Larsson, Henrik, Lehtimaki, Terho, Lewin, Alexandra M., Li, Jin, Lichtenstein, Paul, Lindgren, Cecilia M., Lindi, Virpi, Linneberg, Allan, Liu, Xueping, Liu, Jun, Lowe, William L., Jr., Lundstrom, Sebastian, Lyytikainen, Leo-Pekka, Ma, Ronald C. W., Mace, Aurelien, Magi, Reedik, Magnus, Per, Mamun, Abdullah A., Mannikko, Minna, Martin, Nicholas G., Mbarek, Hamdi, McCarthy, Nina S., Medland, Sarah E., Melbye, Mads, Melen, Erik, Mohlke, Karen L., Monnereau, Claire, Morgen, Camilla S., Morris, Andrew P., Murray, Jeffrey C., Myhre, Ronny, Najman, Jackob M., Nivard, Michel G., Nohr, Ellen A., Nolte, Ilja M., Ntalla, Ioanna, O'Reilly, Paul, Oberfield, Sharon E., Oken, Emily, Oldehinkel, Albertine J., Pahkala, Katja, Palviainen, Teemu, Panoutsopoulou, Kalliope, Pedersen, Oluf, Pennell, Craig E., Pershagen, Goran, Pitkanen, Niina, Plomin, Robert, Power, Christine, Prasad, Rashmi B., Prokopenko, Inga, Pulkkinen, Lea, Raikkonen, Katri, Raitakari, Olli T., Reynolds, Rebecca M., Richmond, Rebecca C., Rivadeneira, Fernando, Rodriguez, Alina, Rose, Richard J., Salem, Rany, Santa-Marina, Loreto, Saw, Seang-Mei, Schnurr, Theresia M., Scott, James G., Selzam, Saskia, Shepherd, John A., Simpson, Angela, Skotte, Line, Sleiman, Patrick M. A., Snieder, Harold, Sorensen, Thorkild I. A., Standl, Marie, Steegers, Eric A. P., Strachan, David P., Straker, Leon, Strandberg, Timo, Taylor, Michelle, Teo, Yik-Ying, Thiering, Elisabeth, Torrent, Maties, Tyrrell, Jessica, Uitterlinden, Andre G., van Beijsterveldt, Toos, van der Most, Peter J., van Duijn, Cornelia M., Viikari, Jorma, Vilor-Tejedor, Natalia, Vogelezang, Suzanne, Vonk, Judith M., Vrijkotte, Tanja G. M., Vuoksimaa, Eero, Wang, Carol A., Watkins, William J., Wichmann, H-Erich, Willemsen, Gonneke, Williams, Gail M., Wilson, James F., Wray, Naomi R., Xu, Shujing, Xu, Cheng-Jian, Yaghootkar, Hanieh, Yi, Lu, Zafarmand, Mohammad Hadi, Zeggini, Eleftheria, Zemel, Babette S., Hinney, Anke, Lakka, Timo A., Whitehouse, Andrew J. O., Sunyer, Jordi, Widen, Elisabeth E., Feenstra, Bjarke, Sebert, Sylvain, Jacobsson, Bo, Njolstad, Pal R., Stoltenberg, Camilla, Smith, George Davey, Lawlor, Debbie A., Paternoster, Lavinia, Timpson, Nicholas J., Ong, Ken K., Bisgaard, Hans, Bonnelykke, Klaus, Jaddoe, Vincent W. V., Tiemeier, Henning, Jarvelin, Marjo-Riitta, Evans, David M., Perry, John R. B., Grant, Struan F. A., Boomsma, Dorret I., Freathy, Rachel M., McCarthy, Mark I., Felix, Janine F., Tiemeier, Hen-Ning, Middeldorp, Christel M., Mahajan, Anubha, Horikoshi, Momoko, Robertson, Neil R., Beaumont, Robin N., Bradfield, Jonathan P., Bustamante, Mariona, Cousminer, Diana L., Day, Felix R., De Silva, N. Maneka, Guxens, Monica, Mook-Kanamori, Dennis O., St Pourcain, Beate, Warrington, Nicole M., Adair, Linda S., Ahlqvist, Emma, Ahluwalia, Tarunveer S., Almgren, Peter, Ang, Wei, Atalay, Mustafa, Auvinen, Juha, Bartels, Meike, Beckmann, Jacques S., Bilbao, Jose Ramon, Bond, Tom, Borja, Judith B., Cavadino, Alana, Charoen, Pimphen, Chen, Zhanghua, Coin, Lachlan, Cooper, Cyrus, Curtin, John A., Custovic, Adnan, Das, Shikta, Davies, Gareth E., Dedoussis, George V., Duijts, Liesbeth, Eastwood, Peter R., Eliasen, Anders U., Elliott, Paul, Eriksson, Johan G., Estivill, Xavier, Fadista, Joao, Fedko, Iryna O., Frayling, Timothy M., Gaillard, Romy, Gauderman, W. James, Geller, Frank, Gilliland, Frank, Gilsanz, Vincente, Granell, Raquel, Grarup, Niels, Groop, Leif, Hadley, Dexter, Hakonarson, Hakon, Hansen, Torben, Hartman, Catharina A., Hattersley, Andrew T., Hayes, M. Geoffrey, Hebebrand, Johannes, Heinrich, Joachim, Helgeland, Oyvind, Henders, Anjali K., Henderson, John, Henriksen, Tine B., Hirschhorn, Joel N., Hivert, Marie-France, Hocher, Berthold, Holloway, John W., Holt, Patrick, Hottenga, Jouke-Jan, Hypponen, Elina, Iniguez, Carmen, Johansson, Stefan, Jugessur, Astanand, Kahonen, Mika, Kalkwarf, Heidi J., Kaprio, Jaakko, Karhunen, Ville, Kemp, John P., Kerkhof, Marjan, Koppelman, Gerard H., Korner, Antje, Kotecha, Sailesh, Kreiner-Moller, Eskil, Kulohoma, Benard, Kumar, Ashish, Kutalik, Zoltan, Lahti, Jari, Lappe, Joan M., Larsson, Henrik, Lehtimaki, Terho, Lewin, Alexandra M., Li, Jin, Lichtenstein, Paul, Lindgren, Cecilia M., Lindi, Virpi, Linneberg, Allan, Liu, Xueping, Liu, Jun, Lowe, William L., Jr., Lundstrom, Sebastian, Lyytikainen, Leo-Pekka, Ma, Ronald C. W., Mace, Aurelien, Magi, Reedik, Magnus, Per, Mamun, Abdullah A., Mannikko, Minna, Martin, Nicholas G., Mbarek, Hamdi, McCarthy, Nina S., Medland, Sarah E., Melbye, Mads, Melen, Erik, Mohlke, Karen L., Monnereau, Claire, Morgen, Camilla S., Morris, Andrew P., Murray, Jeffrey C., Myhre, Ronny, Najman, Jackob M., Nivard, Michel G., Nohr, Ellen A., Nolte, Ilja M., Ntalla, Ioanna, O'Reilly, Paul, Oberfield, Sharon E., Oken, Emily, Oldehinkel, Albertine J., Pahkala, Katja, Palviainen, Teemu, Panoutsopoulou, Kalliope, Pedersen, Oluf, Pennell, Craig E., Pershagen, Goran, Pitkanen, Niina, Plomin, Robert, Power, Christine, Prasad, Rashmi B., Prokopenko, Inga, Pulkkinen, Lea, Raikkonen, Katri, Raitakari, Olli T., Reynolds, Rebecca M., Richmond, Rebecca C., Rivadeneira, Fernando, Rodriguez, Alina, Rose, Richard J., Salem, Rany, Santa-Marina, Loreto, Saw, Seang-Mei, Schnurr, Theresia M., Scott, James G., Selzam, Saskia, Shepherd, John A., Simpson, Angela, Skotte, Line, Sleiman, Patrick M. A., Snieder, Harold, Sorensen, Thorkild I. A., Standl, Marie, Steegers, Eric A. P., Strachan, David P., Straker, Leon, Strandberg, Timo, Taylor, Michelle, Teo, Yik-Ying, Thiering, Elisabeth, Torrent, Maties, Tyrrell, Jessica, Uitterlinden, Andre G., van Beijsterveldt, Toos, van der Most, Peter J., van Duijn, Cornelia M., Viikari, Jorma, Vilor-Tejedor, Natalia, Vogelezang, Suzanne, Vonk, Judith M., Vrijkotte, Tanja G. M., Vuoksimaa, Eero, Wang, Carol A., Watkins, William J., Wichmann, H-Erich, Willemsen, Gonneke, Williams, Gail M., Wilson, James F., Wray, Naomi R., Xu, Shujing, Xu, Cheng-Jian, Yaghootkar, Hanieh, Yi, Lu, Zafarmand, Mohammad Hadi, Zeggini, Eleftheria, Zemel, Babette S., Hinney, Anke, Lakka, Timo A., Whitehouse, Andrew J. O., Sunyer, Jordi, Widen, Elisabeth E., Feenstra, Bjarke, Sebert, Sylvain, Jacobsson, Bo, Njolstad, Pal R., Stoltenberg, Camilla, Smith, George Davey, Lawlor, Debbie A., Paternoster, Lavinia, Timpson, Nicholas J., Ong, Ken K., Bisgaard, Hans, Bonnelykke, Klaus, Jaddoe, Vincent W. V., Tiemeier, Henning, Jarvelin, Marjo-Riitta, Evans, David M., Perry, John R. B., Grant, Struan F. A., Boomsma, Dorret I., Freathy, Rachel M., McCarthy, Mark I., Felix, Janine F., and Tiemeier, Hen-Ning
Abstract: The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites.
Published: 2019
Full Text: View/download PDF

20. Plasma lipid profiles discriminate bacterial from viral infection in febrile children

Author: Wang, Xinzhu, Nijman, Ruud, Camuzeaux, Stephane, Sands, Caroline, Jackson, Heather, Kaforou, Myrsini, Emonts, Marieke, Herberg, Jethro A., Maconochie, Ian, Carrol, Enitan D., Paulus, Stephane C., Zenz, Werner, Van der Flier, Michiel, de Groot, Ronald, Martinon-Torres, Federico, Schlapbach, Luregn J., Pollard, Andrew J., Fink, Colin, Kuijpers, Taco T., Anderson, Suzanne, Lewis, Matthew R., Levin, Michael, McClure, Myra, Gormley, Stuart, Hamilton, Shea, Hourmat, Bernardo, Hoggart, Clive, Sancho-Shimizu, Vanessa, Wright, Victoria, Abdulla, Amina, Agapow, Paul, Bartlett, Maeve, Bellos, Evangelos, Eleftherohorinou, Hariklia, Galassini, Rachel, Inwald, David, Mashbat, Meg, Menikou, Stefanie, Mustafa, Sobia, Nadel, Simon, Rahman, Rahmeen, Thakker, Clare, Coin, Lachlan M. J., Bokhand, S., Power, Sue, Barham, Heather, Pathan, N., Ridout, Jenna, White, Deborah, Thurston, Sarah, Faust, S., Patel, S., McCorkell, Jenni, Davies, P., Crate, Lindsey, Navarra, Helen, Carter, Stephanie, Ramaiah, R., Patel, Rekha, Tuffrey, Catherine, Gribbin, Andrew, McCready, Sharon, Peters, Mark, Hardy, Katie, Standing, Fran, O'Neill, Lauren, Abelake, Eugenia, Deep, Akash, Nsirim, Eniola, Willis, Louise, Young, Zoe, Royad, C., White, Sonia, Fortune, P. M., Hudnott, Phil, Alvez Gonzalez, Fernando, Barral-Arca, Ruth, Cebey-Lopez, Miriam, Jose Curras-Tuala, Maria, Garcia, Natalia, Garcia Vicente, Luisa, Gomez-Carballa, Alberto, Gomez Rial, Jose, Grela Beiroa, Andrea, Justicia Grande, Antonio, Leborans Iglesias, Pilar, Martinez Santos, Alba Elena, MartinonTorres, Nazareth, Martinon Sanchez, Jose Maria, Morillo Gutierrez, Beatriz, Mosquera Perez, Belen, Obando Pacheco, Pablo, Pardo-Seco, Jacobo, Pischedda, Sara, RiveroCalle, Irene, Rodriguez-Tenreiro, Carmen, Redondo-Collazo, Lorenzo, Salas Ellacuriagal, Antonio, Seren Fernandez, Sonia, Porto Silva, Maria del Sol, Vega, Ana, Vilanova Trillo, Lucia, Salas, Antonio, Beatriz Reyes, Susana, Leon Leon, Maria Cruz, Navarro Mingorance, Alvaro, Gabaldo Barrios, Xavier, Onate Vergara, Eider, Concha Torre, Andres, Vivanco, Ana, Fernandez, Reyes, Gimenez Sanchez, Francisco, Sanchez Forte, Miguel, Rojo, Pablo, Ruiz Contreras, J., Palacios, Alba, Epalza Ibarrondo, Cristina, Fernandez Cooke, Elizabeth, Navarro, Marisa, Alvarez Alvarez, Cristina, Jose Lozano, Maria, Carreras, Eduardo, Brio Sanagustin, Sonia, Neth, Olaf, Martinez Padilla, Ma del Carmen, Prieto Tato, Luis Manuel, Guillen, Sara, Fernandez Silveira, Laura, Moreno, David, van Furth, A. M. Tutu, Boeddha, N. P., Driessen, G. J. A., Emonts, M., Hazelzet, J. A., Pajkrt, D., Sanders, E. A. M., van de Beek, D., van der Ende, A., Philipsen, H. L. A., Adeel, A. O. A., Breukels, M. A., Brinkman, D. M. C., de Korte, C. C. M. M., de Vries, E., de Waal, W. J., Dekkers, R., Dings-Lammertink, A., Doedens, R. A., Donker, A. E., Dousma, M., Faber, T. E., Gerrits, G. P. J. M., Gerver, J. A. M., Heidema, J., Homan-van der Veen, J., Jacobs, M. A. M., Jansen, N. J. G., Kawczynski, P., Klucovska, K., Kneyber, M. C. J., Koopman-Keemink, Y., Langenhorst, V. J., Leusink, J., Loza, B. F., Merth, I. T., Miedema, C. J., Neeleman, C., Noordzij, J. G., Obihara, C. C., van Overbeek-van Gils, A. L. T., Poortman, G. H., Potgieter, S. T., Potjewijd, J., Rosias, P. P. R., Sprong, T., ten Tussher, G. W., Thio, B. J., Tramper-Stranders, G. A., van Deuren, M., van der Meer, H., van Kuppevelt, A. J. M., van Wermeskerken, A. M., Verwijs, W. A., Wolfs, T. F. W., Agyeman, Philipp, Aebi, Christoph, Berger, Christoph, Giannoni, Eric, Stocker, Martin, Posfay-Barbe, Klara M., Heininger, Ulrich, Bernhard-Stirnemann, Sara, Niederer-Loher, Anita, Kahlert, Christian, Hasters, Paul, Relly, Christa, Baer, Walter, Frederick, Hannah, Jennings, Rebecca, Johnston, Joanne, Kenwright, Rhian, Pinnock, Elli, Agbeko, Rachel, Secka, Fatou, Bojang, Kalifa, Sarr, Isatou, Kebbeh, Ngange, Sey, Gibbi, Momodou, Saidy Khan, Cole, Fatoumata, Thomas, Gilleh, Antonio, Martin, Klobassa, Daniela S., Binder, Alexander, Schweintzger, Nina A., Sagmeister, Manfred, Baumgart, Hinrich, Baumgartner, Markus, Behrends, Uta, Biebl, Ariane, Birnbacher, Robert, Blanke, Jan-Gerd, Boelke, Carsten, Breuling, Kai, Brunner, Juergen, Buller, Maria, Dahlem, Peter, Dietrich, Beate, Eber, Ernst, Elias, Johannes, Emhofer, Josef, Etschmaier, Rosa, Farr, Sebastian, Girtler, Ylenia, Grigorow, Irina, Heimann, Konrad, Ihm, Ulrike, Jaros, Zdenek, Kalhoff, Hermann, Kaulfersch, Wilhelm, Kemen, Christoph, Klocker, Nina, Koester, Bernhard, Kohlmaier, Benno, Komini, Eleni, Kramer, Lydia, Neubert, Antje, Ortner, Daniel, Pescollderungg, Lydia, Pfurtscheller, Klaus, Reiter, Karl, Ristic, Goran, Roedl, Siegfried, Sellner, Andrea, Sonnleitner, Astrid, Sperl, Matthias, Stelzl, Wolfgang, Till, Holger, Trobisch, Andreas, Vierzig, Anne, Vogel, Ulrich, Weingarten, Christina, Welke, Stefanie, Wimmer, Andreas, Wintergerst, Uwe, Wueller, Daniel, Zaunschirm, Andrew, Ziuraite, Ieva, Zukovskaja, Veslava, Wang, Xinzhu, Nijman, Ruud, Camuzeaux, Stephane, Sands, Caroline, Jackson, Heather, Kaforou, Myrsini, Emonts, Marieke, Herberg, Jethro A., Maconochie, Ian, Carrol, Enitan D., Paulus, Stephane C., Zenz, Werner, Van der Flier, Michiel, de Groot, Ronald, Martinon-Torres, Federico, Schlapbach, Luregn J., Pollard, Andrew J., Fink, Colin, Kuijpers, Taco T., Anderson, Suzanne, Lewis, Matthew R., Levin, Michael, McClure, Myra, Gormley, Stuart, Hamilton, Shea, Hourmat, Bernardo, Hoggart, Clive, Sancho-Shimizu, Vanessa, Wright, Victoria, Abdulla, Amina, Agapow, Paul, Bartlett, Maeve, Bellos, Evangelos, Eleftherohorinou, Hariklia, Galassini, Rachel, Inwald, David, Mashbat, Meg, Menikou, Stefanie, Mustafa, Sobia, Nadel, Simon, Rahman, Rahmeen, Thakker, Clare, Coin, Lachlan M. J., Bokhand, S., Power, Sue, Barham, Heather, Pathan, N., Ridout, Jenna, White, Deborah, Thurston, Sarah, Faust, S., Patel, S., McCorkell, Jenni, Davies, P., Crate, Lindsey, Navarra, Helen, Carter, Stephanie, Ramaiah, R., Patel, Rekha, Tuffrey, Catherine, Gribbin, Andrew, McCready, Sharon, Peters, Mark, Hardy, Katie, Standing, Fran, O'Neill, Lauren, Abelake, Eugenia, Deep, Akash, Nsirim, Eniola, Willis, Louise, Young, Zoe, Royad, C., White, Sonia, Fortune, P. M., Hudnott, Phil, Alvez Gonzalez, Fernando, Barral-Arca, Ruth, Cebey-Lopez, Miriam, Jose Curras-Tuala, Maria, Garcia, Natalia, Garcia Vicente, Luisa, Gomez-Carballa, Alberto, Gomez Rial, Jose, Grela Beiroa, Andrea, Justicia Grande, Antonio, Leborans Iglesias, Pilar, Martinez Santos, Alba Elena, MartinonTorres, Nazareth, Martinon Sanchez, Jose Maria, Morillo Gutierrez, Beatriz, Mosquera Perez, Belen, Obando Pacheco, Pablo, Pardo-Seco, Jacobo, Pischedda, Sara, RiveroCalle, Irene, Rodriguez-Tenreiro, Carmen, Redondo-Collazo, Lorenzo, Salas Ellacuriagal, Antonio, Seren Fernandez, Sonia, Porto Silva, Maria del Sol, Vega, Ana, Vilanova Trillo, Lucia, Salas, Antonio, Beatriz Reyes, Susana, Leon Leon, Maria Cruz, Navarro Mingorance, Alvaro, Gabaldo Barrios, Xavier, Onate Vergara, Eider, Concha Torre, Andres, Vivanco, Ana, Fernandez, Reyes, Gimenez Sanchez, Francisco, Sanchez Forte, Miguel, Rojo, Pablo, Ruiz Contreras, J., Palacios, Alba, Epalza Ibarrondo, Cristina, Fernandez Cooke, Elizabeth, Navarro, Marisa, Alvarez Alvarez, Cristina, Jose Lozano, Maria, Carreras, Eduardo, Brio Sanagustin, Sonia, Neth, Olaf, Martinez Padilla, Ma del Carmen, Prieto Tato, Luis Manuel, Guillen, Sara, Fernandez Silveira, Laura, Moreno, David, van Furth, A. M. Tutu, Boeddha, N. P., Driessen, G. J. A., Emonts, M., Hazelzet, J. A., Pajkrt, D., Sanders, E. A. M., van de Beek, D., van der Ende, A., Philipsen, H. L. A., Adeel, A. O. A., Breukels, M. A., Brinkman, D. M. C., de Korte, C. C. M. M., de Vries, E., de Waal, W. J., Dekkers, R., Dings-Lammertink, A., Doedens, R. A., Donker, A. E., Dousma, M., Faber, T. E., Gerrits, G. P. J. M., Gerver, J. A. M., Heidema, J., Homan-van der Veen, J., Jacobs, M. A. M., Jansen, N. J. G., Kawczynski, P., Klucovska, K., Kneyber, M. C. J., Koopman-Keemink, Y., Langenhorst, V. J., Leusink, J., Loza, B. F., Merth, I. T., Miedema, C. J., Neeleman, C., Noordzij, J. G., Obihara, C. C., van Overbeek-van Gils, A. L. T., Poortman, G. H., Potgieter, S. T., Potjewijd, J., Rosias, P. P. R., Sprong, T., ten Tussher, G. W., Thio, B. J., Tramper-Stranders, G. A., van Deuren, M., van der Meer, H., van Kuppevelt, A. J. M., van Wermeskerken, A. M., Verwijs, W. A., Wolfs, T. F. W., Agyeman, Philipp, Aebi, Christoph, Berger, Christoph, Giannoni, Eric, Stocker, Martin, Posfay-Barbe, Klara M., Heininger, Ulrich, Bernhard-Stirnemann, Sara, Niederer-Loher, Anita, Kahlert, Christian, Hasters, Paul, Relly, Christa, Baer, Walter, Frederick, Hannah, Jennings, Rebecca, Johnston, Joanne, Kenwright, Rhian, Pinnock, Elli, Agbeko, Rachel, Secka, Fatou, Bojang, Kalifa, Sarr, Isatou, Kebbeh, Ngange, Sey, Gibbi, Momodou, Saidy Khan, Cole, Fatoumata, Thomas, Gilleh, Antonio, Martin, Klobassa, Daniela S., Binder, Alexander, Schweintzger, Nina A., Sagmeister, Manfred, Baumgart, Hinrich, Baumgartner, Markus, Behrends, Uta, Biebl, Ariane, Birnbacher, Robert, Blanke, Jan-Gerd, Boelke, Carsten, Breuling, Kai, Brunner, Juergen, Buller, Maria, Dahlem, Peter, Dietrich, Beate, Eber, Ernst, Elias, Johannes, Emhofer, Josef, Etschmaier, Rosa, Farr, Sebastian, Girtler, Ylenia, Grigorow, Irina, Heimann, Konrad, Ihm, Ulrike, Jaros, Zdenek, Kalhoff, Hermann, Kaulfersch, Wilhelm, Kemen, Christoph, Klocker, Nina, Koester, Bernhard, Kohlmaier, Benno, Komini, Eleni, Kramer, Lydia, Neubert, Antje, Ortner, Daniel, Pescollderungg, Lydia, Pfurtscheller, Klaus, Reiter, Karl, Ristic, Goran, Roedl, Siegfried, Sellner, Andrea, Sonnleitner, Astrid, Sperl, Matthias, Stelzl, Wolfgang, Till, Holger, Trobisch, Andreas, Vierzig, Anne, Vogel, Ulrich, Weingarten, Christina, Welke, Stefanie, Wimmer, Andreas, Wintergerst, Uwe, Wueller, Daniel, Zaunschirm, Andrew, Ziuraite, Ieva, and Zukovskaja, Veslava
Abstract: Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection are often non-specific, and there is no definitive test for the accurate diagnosis of infection. The 'omics' approaches to identifying biomarkers from the host-response to bacterial infection are promising. In this study, lipidomic analysis was carried out with plasma samples obtained from febrile children with confirmed bacterial infection (n = 20) and confirmed viral infection (n = 20). We show for the first time that bacterial and viral infection produces distinct profile in the host lipidome. Some species of glycerophosphoinositol, sphingomyelin, lysophosphatidylcholine and cholesterol sulfate were higher in the confirmed virus infected group, while some species of fatty acids, glycerophosphocholine, glycerophosphoserine, lactosylceramide and bilirubin were lower in the confirmed virus infected group when compared with confirmed bacterial infected group. A combination of three lipids achieved an area under the receiver operating characteristic (ROC) curve of 0.911 (95% CI 0.81 to 0.98). This pilot study demonstrates the potential of metabolic biomarkers to assist clinicians in distinguishing bacterial from viral infection in febrile children, to facilitate effective clinical management and to the limit inappropriate use of antibiotics.
Published: 2019

21. New achievements for diagnostics of banana streak virus

Author: Ngo, Ha, Crew, Kathleen S., Vance, Megan E., Thomas, John E., Nguyen, Son, Duarte, Tania, Coin, Lachlan, Geering, Andrew, Ngo, Ha, Crew, Kathleen S., Vance, Megan E., Thomas, John E., Nguyen, Son, Duarte, Tania, Coin, Lachlan, and Geering, Andrew
Abstract: Banana streak virus (BSV) remains one of the most challenging viral pathogens of banana to detect and most diagnostic assays rely on serological methods. The BSV capsid protein contains an N-terminal, intrinsically disordered (NID) domain that is surface-exposed on the virion and likely is multifunctional and plays important roles in viral replication and transmission. The immunodominant continuous epitopes on the virion are also located in the NID domain, and therefore this domain is of great interest from a diagnostics perspective. Using chemically synthesized peptides to mimic the continuous epitopes of five BSV species including Banana streak Mysore virus (BSMYV), Banana streak Obino I’Ewai virus (BSOLV), Banana streak Imove’ virus (BSIMV), Banana streak Goldfinger virus (BSGFV) and Banana streak Cavendish virus (BSCAV), antisera have been raised in rabbits, and shown specificity to each virus species and sensitivity in a range of assay formats such as Western Blot, enzyme-linked immunosorbent assay (ELISA), immunosorbent electron microscopy and immunocapture PCR. This work confirmed the applicability of synthesis epitopes/peptides to produce antipeptide antibodies for BSV diagnostics when the native protein is absent. The Oxoford MinION Nanopore sequencing system is a promising new technology for point-of-care diagnostics. We have successfully used this system and generated long reads with greater than 99% accuracy, allowing accurate and sensitive detection of BSV. The long reads allow episomal from endogenous sequences to be differentiated.
Published: 2019

22. New achievements for diagnostics of banana streak virus

Author: Ngo, Ha, Crew, Kathleen S., Vance, Megan E., Thomas, John E., Nguyen, Son, Duarte, Tania, Coin, Lachlan, Geering, Andrew, Ngo, Ha, Crew, Kathleen S., Vance, Megan E., Thomas, John E., Nguyen, Son, Duarte, Tania, Coin, Lachlan, and Geering, Andrew
Abstract: Banana streak virus (BSV) remains one of the most challenging viral pathogens of banana to detect and most diagnostic assays rely on serological methods. The BSV capsid protein contains an N-terminal, intrinsically disordered (NID) domain that is surface-exposed on the virion and likely is multifunctional and plays important roles in viral replication and transmission. The immunodominant continuous epitopes on the virion are also located in the NID domain, and therefore this domain is of great interest from a diagnostics perspective. Using chemically synthesized peptides to mimic the continuous epitopes of five BSV species including Banana streak Mysore virus (BSMYV), Banana streak Obino I’Ewai virus (BSOLV), Banana streak Imove’ virus (BSIMV), Banana streak Goldfinger virus (BSGFV) and Banana streak Cavendish virus (BSCAV), antisera have been raised in rabbits, and shown specificity to each virus species and sensitivity in a range of assay formats such as Western Blot, enzyme-linked immunosorbent assay (ELISA), immunosorbent electron microscopy and immunocapture PCR. This work confirmed the applicability of synthesis epitopes/peptides to produce antipeptide antibodies for BSV diagnostics when the native protein is absent. The Oxoford MinION Nanopore sequencing system is a promising new technology for point-of-care diagnostics. We have successfully used this system and generated long reads with greater than 99% accuracy, allowing accurate and sensitive detection of BSV. The long reads allow episomal from endogenous sequences to be differentiated.
Published: 2019

23. New achievements for diagnostics of banana streak virus

Author: Ngo, Ha, Crew, Kathleen S., Vance, Megan E., Thomas, John E., Nguyen, Son, Duarte, Tania, Coin, Lachlan, Geering, Andrew, Ngo, Ha, Crew, Kathleen S., Vance, Megan E., Thomas, John E., Nguyen, Son, Duarte, Tania, Coin, Lachlan, and Geering, Andrew
Abstract: Banana streak virus (BSV) remains one of the most challenging viral pathogens of banana to detect and most diagnostic assays rely on serological methods. The BSV capsid protein contains an N-terminal, intrinsically disordered (NID) domain that is surface-exposed on the virion and likely is multifunctional and plays important roles in viral replication and transmission. The immunodominant continuous epitopes on the virion are also located in the NID domain, and therefore this domain is of great interest from a diagnostics perspective. Using chemically synthesized peptides to mimic the continuous epitopes of five BSV species including Banana streak Mysore virus (BSMYV), Banana streak Obino I’Ewai virus (BSOLV), Banana streak Imove’ virus (BSIMV), Banana streak Goldfinger virus (BSGFV) and Banana streak Cavendish virus (BSCAV), antisera have been raised in rabbits, and shown specificity to each virus species and sensitivity in a range of assay formats such as Western Blot, enzyme-linked immunosorbent assay (ELISA), immunosorbent electron microscopy and immunocapture PCR. This work confirmed the applicability of synthesis epitopes/peptides to produce antipeptide antibodies for BSV diagnostics when the native protein is absent. The Oxoford MinION Nanopore sequencing system is a promising new technology for point-of-care diagnostics. We have successfully used this system and generated long reads with greater than 99% accuracy, allowing accurate and sensitive detection of BSV. The long reads allow episomal from endogenous sequences to be differentiated.
Published: 2019

24. New achievements for diagnostics of banana streak virus

Author: Ngo, Ha, Crew, Kathleen S., Vance, Megan E., Thomas, John E., Nguyen, Son, Duarte, Tania, Coin, Lachlan, Geering, Andrew, Ngo, Ha, Crew, Kathleen S., Vance, Megan E., Thomas, John E., Nguyen, Son, Duarte, Tania, Coin, Lachlan, and Geering, Andrew
Abstract: Banana streak virus (BSV) remains one of the most challenging viral pathogens of banana to detect and most diagnostic assays rely on serological methods. The BSV capsid protein contains an N-terminal, intrinsically disordered (NID) domain that is surface-exposed on the virion and likely is multifunctional and plays important roles in viral replication and transmission. The immunodominant continuous epitopes on the virion are also located in the NID domain, and therefore this domain is of great interest from a diagnostics perspective. Using chemically synthesized peptides to mimic the continuous epitopes of five BSV species including Banana streak Mysore virus (BSMYV), Banana streak Obino I’Ewai virus (BSOLV), Banana streak Imove’ virus (BSIMV), Banana streak Goldfinger virus (BSGFV) and Banana streak Cavendish virus (BSCAV), antisera have been raised in rabbits, and shown specificity to each virus species and sensitivity in a range of assay formats such as Western Blot, enzyme-linked immunosorbent assay (ELISA), immunosorbent electron microscopy and immunocapture PCR. This work confirmed the applicability of synthesis epitopes/peptides to produce antipeptide antibodies for BSV diagnostics when the native protein is absent. The Oxoford MinION Nanopore sequencing system is a promising new technology for point-of-care diagnostics. We have successfully used this system and generated long reads with greater than 99% accuracy, allowing accurate and sensitive detection of BSV. The long reads allow episomal from endogenous sequences to be differentiated.
Published: 2019

25. Identification of regulatory variants associated with genetic susceptibility to meningococcal disease

Author: Borghini, Lisa, Png, Eileen; https://orcid.org/0000-0001-5586-6395, Binder, Alexander, Wright, Victoria J; https://orcid.org/0000-0001-7826-1516, Pinnock, Ellie, de Groot, Ronald, Hazelzet, Jan, Emonts, Marieke, Van der Flier, Michiel, Schlapbach, Luregn J; https://orcid.org/0000-0003-2281-2598, Anderson, Suzanne, Secka, Fatou, Salas, Antonio; https://orcid.org/0000-0002-2336-702X, Fink, Colin, Carrol, Enitan D, Pollard, Andrew J, Coin, Lachlan J, Kuijpers, Taco W, Martinon-Torres, Federico; https://orcid.org/0000-0002-9023-581X, Zenz, Werner, Levin, Michael, Hibberd, Martin L, Davila, Sonia, EUCLIDS consortium, Borghini, Lisa, Png, Eileen; https://orcid.org/0000-0001-5586-6395, Binder, Alexander, Wright, Victoria J; https://orcid.org/0000-0001-7826-1516, Pinnock, Ellie, de Groot, Ronald, Hazelzet, Jan, Emonts, Marieke, Van der Flier, Michiel, Schlapbach, Luregn J; https://orcid.org/0000-0003-2281-2598, Anderson, Suzanne, Secka, Fatou, Salas, Antonio; https://orcid.org/0000-0002-2336-702X, Fink, Colin, Carrol, Enitan D, Pollard, Andrew J, Coin, Lachlan J, Kuijpers, Taco W, Martinon-Torres, Federico; https://orcid.org/0000-0002-9023-581X, Zenz, Werner, Levin, Michael, Hibberd, Martin L, Davila, Sonia, and EUCLIDS consortium
Abstract: Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes.
Published: 2019

26. New achievements for diagnostics of banana streak virus

Author: Ngo, Ha, Crew, Kathleen S., Vance, Megan E., Thomas, John E., Nguyen, Son, Duarte, Tania, Coin, Lachlan, Geering, Andrew, Ngo, Ha, Crew, Kathleen S., Vance, Megan E., Thomas, John E., Nguyen, Son, Duarte, Tania, Coin, Lachlan, and Geering, Andrew
Abstract: Banana streak virus (BSV) remains one of the most challenging viral pathogens of banana to detect and most diagnostic assays rely on serological methods. The BSV capsid protein contains an N-terminal, intrinsically disordered (NID) domain that is surface-exposed on the virion and likely is multifunctional and plays important roles in viral replication and transmission. The immunodominant continuous epitopes on the virion are also located in the NID domain, and therefore this domain is of great interest from a diagnostics perspective. Using chemically synthesized peptides to mimic the continuous epitopes of five BSV species including Banana streak Mysore virus (BSMYV), Banana streak Obino I’Ewai virus (BSOLV), Banana streak Imove’ virus (BSIMV), Banana streak Goldfinger virus (BSGFV) and Banana streak Cavendish virus (BSCAV), antisera have been raised in rabbits, and shown specificity to each virus species and sensitivity in a range of assay formats such as Western Blot, enzyme-linked immunosorbent assay (ELISA), immunosorbent electron microscopy and immunocapture PCR. This work confirmed the applicability of synthesis epitopes/peptides to produce antipeptide antibodies for BSV diagnostics when the native protein is absent. The Oxoford MinION Nanopore sequencing system is a promising new technology for point-of-care diagnostics. We have successfully used this system and generated long reads with greater than 99% accuracy, allowing accurate and sensitive detection of BSV. The long reads allow episomal from endogenous sequences to be differentiated.
Published: 2019

27. Identifcation of regulatory variants associated with genetic susceptibility to meningococcal disease

Author: Universidade de Santiago de Compostela. Departamento de Ciencias Forenses, Anatomía Patolóxica, Xinecoloxía e Obstetricia, e Pediatría, Borghini, Lisa, Png, Eileen, Binder, Alexander, Wright, Victoria J., Pinnock, Ellie, de Groot, Ronald, Hazelzet, Jan, Emonts, Marieke, Van der Flier, Michiel, Schlapbach, Luregn J., Anderson, Suzanne, Secka, Fatou, Salas Ellacuriaga, Antonio, Fink, Colin, Carrol, Enitan D., Pollard, Andrew J., Coin, Lachlan J., Kuijpers, Taco W., Martinón Torres, Federico, Zenz, Werner, Levin, Michael, Hibberd, Martin L., Davila, Sonia, EUCLIDS consortium, Universidade de Santiago de Compostela. Departamento de Ciencias Forenses, Anatomía Patolóxica, Xinecoloxía e Obstetricia, e Pediatría, Borghini, Lisa, Png, Eileen, Binder, Alexander, Wright, Victoria J., Pinnock, Ellie, de Groot, Ronald, Hazelzet, Jan, Emonts, Marieke, Van der Flier, Michiel, Schlapbach, Luregn J., Anderson, Suzanne, Secka, Fatou, Salas Ellacuriaga, Antonio, Fink, Colin, Carrol, Enitan D., Pollard, Andrew J., Coin, Lachlan J., Kuijpers, Taco W., Martinón Torres, Federico, Zenz, Werner, Levin, Michael, Hibberd, Martin L., Davila, Sonia, and EUCLIDS consortium
Abstract: Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA – a NF-kB subunit, master regulator of the response to infection – under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes.
Published: 2019

28. Plasma lipid profiles discriminate bacterial from viral infection in febrile children

Author: Wang, Xinzhu, Nijman, Ruud, Camuzeaux, Stephane, Sands, Caroline, Jackson, Heather, Kaforou, Myrsini, Emonts, Marieke, Herberg, Jethro A., Maconochie, Ian, Carrol, Enitan D., Paulus, Stephane C., Zenz, Werner, Van der Flier, Michiel, de Groot, Ronald, Martinon-Torres, Federico, Schlapbach, Luregn J., Pollard, Andrew J., Fink, Colin, Kuijpers, Taco T., Anderson, Suzanne, Lewis, Matthew R., Levin, Michael, McClure, Myra, Gormley, Stuart, Hamilton, Shea, Hourmat, Bernardo, Hoggart, Clive, Sancho-Shimizu, Vanessa, Wright, Victoria, Abdulla, Amina, Agapow, Paul, Bartlett, Maeve, Bellos, Evangelos, Eleftherohorinou, Hariklia, Galassini, Rachel, Inwald, David, Mashbat, Meg, Menikou, Stefanie, Mustafa, Sobia, Nadel, Simon, Rahman, Rahmeen, Thakker, Clare, Coin, Lachlan M. J., Bokhand, S., Power, Sue, Barham, Heather, Pathan, N., Ridout, Jenna, White, Deborah, Thurston, Sarah, Faust, S., Patel, S., McCorkell, Jenni, Davies, P., Crate, Lindsey, Navarra, Helen, Carter, Stephanie, Ramaiah, R., Patel, Rekha, Tuffrey, Catherine, Gribbin, Andrew, McCready, Sharon, Peters, Mark, Hardy, Katie, Standing, Fran, O'Neill, Lauren, Abelake, Eugenia, Deep, Akash, Nsirim, Eniola, Willis, Louise, Young, Zoe, Royad, C., White, Sonia, Fortune, P. M., Hudnott, Phil, Alvez Gonzalez, Fernando, Barral-Arca, Ruth, Cebey-Lopez, Miriam, Jose Curras-Tuala, Maria, Garcia, Natalia, Garcia Vicente, Luisa, Gomez-Carballa, Alberto, Gomez Rial, Jose, Grela Beiroa, Andrea, Justicia Grande, Antonio, Leborans Iglesias, Pilar, Martinez Santos, Alba Elena, MartinonTorres, Nazareth, Martinon Sanchez, Jose Maria, Morillo Gutierrez, Beatriz, Mosquera Perez, Belen, Obando Pacheco, Pablo, Pardo-Seco, Jacobo, Pischedda, Sara, RiveroCalle, Irene, Rodriguez-Tenreiro, Carmen, Redondo-Collazo, Lorenzo, Salas Ellacuriagal, Antonio, Seren Fernandez, Sonia, Porto Silva, Maria del Sol, Vega, Ana, Vilanova Trillo, Lucia, Salas, Antonio, Beatriz Reyes, Susana, Leon Leon, Maria Cruz, Navarro Mingorance, Alvaro, Gabaldo Barrios, Xavier, Onate Vergara, Eider, Concha Torre, Andres, Vivanco, Ana, Fernandez, Reyes, Gimenez Sanchez, Francisco, Sanchez Forte, Miguel, Rojo, Pablo, Ruiz Contreras, J., Palacios, Alba, Epalza Ibarrondo, Cristina, Fernandez Cooke, Elizabeth, Navarro, Marisa, Alvarez Alvarez, Cristina, Jose Lozano, Maria, Carreras, Eduardo, Brio Sanagustin, Sonia, Neth, Olaf, Martinez Padilla, Ma del Carmen, Prieto Tato, Luis Manuel, Guillen, Sara, Fernandez Silveira, Laura, Moreno, David, van Furth, A. M. Tutu, Boeddha, N. P., Driessen, G. J. A., Emonts, M., Hazelzet, J. A., Pajkrt, D., Sanders, E. A. M., van de Beek, D., van der Ende, A., Philipsen, H. L. A., Adeel, A. O. A., Breukels, M. A., Brinkman, D. M. C., de Korte, C. C. M. M., de Vries, E., de Waal, W. J., Dekkers, R., Dings-Lammertink, A., Doedens, R. A., Donker, A. E., Dousma, M., Faber, T. E., Gerrits, G. P. J. M., Gerver, J. A. M., Heidema, J., Homan-van der Veen, J., Jacobs, M. A. M., Jansen, N. J. G., Kawczynski, P., Klucovska, K., Kneyber, M. C. J., Koopman-Keemink, Y., Langenhorst, V. J., Leusink, J., Loza, B. F., Merth, I. T., Miedema, C. J., Neeleman, C., Noordzij, J. G., Obihara, C. C., van Overbeek-van Gils, A. L. T., Poortman, G. H., Potgieter, S. T., Potjewijd, J., Rosias, P. P. R., Sprong, T., ten Tussher, G. W., Thio, B. J., Tramper-Stranders, G. A., van Deuren, M., van der Meer, H., van Kuppevelt, A. J. M., van Wermeskerken, A. M., Verwijs, W. A., Wolfs, T. F. W., Agyeman, Philipp, Aebi, Christoph, Berger, Christoph, Giannoni, Eric, Stocker, Martin, Posfay-Barbe, Klara M., Heininger, Ulrich, Bernhard-Stirnemann, Sara, Niederer-Loher, Anita, Kahlert, Christian, Hasters, Paul, Relly, Christa, Baer, Walter, Frederick, Hannah, Jennings, Rebecca, Johnston, Joanne, Kenwright, Rhian, Pinnock, Elli, Agbeko, Rachel, Secka, Fatou, Bojang, Kalifa, Sarr, Isatou, Kebbeh, Ngange, Sey, Gibbi, Momodou, Saidy Khan, Cole, Fatoumata, Thomas, Gilleh, Antonio, Martin, Klobassa, Daniela S., Binder, Alexander, Schweintzger, Nina A., Sagmeister, Manfred, Baumgart, Hinrich, Baumgartner, Markus, Behrends, Uta, Biebl, Ariane, Birnbacher, Robert, Blanke, Jan-Gerd, Boelke, Carsten, Breuling, Kai, Brunner, Juergen, Buller, Maria, Dahlem, Peter, Dietrich, Beate, Eber, Ernst, Elias, Johannes, Emhofer, Josef, Etschmaier, Rosa, Farr, Sebastian, Girtler, Ylenia, Grigorow, Irina, Heimann, Konrad, Ihm, Ulrike, Jaros, Zdenek, Kalhoff, Hermann, Kaulfersch, Wilhelm, Kemen, Christoph, Klocker, Nina, Koester, Bernhard, Kohlmaier, Benno, Komini, Eleni, Kramer, Lydia, Neubert, Antje, Ortner, Daniel, Pescollderungg, Lydia, Pfurtscheller, Klaus, Reiter, Karl, Ristic, Goran, Roedl, Siegfried, Sellner, Andrea, Sonnleitner, Astrid, Sperl, Matthias, Stelzl, Wolfgang, Till, Holger, Trobisch, Andreas, Vierzig, Anne, Vogel, Ulrich, Weingarten, Christina, Welke, Stefanie, Wimmer, Andreas, Wintergerst, Uwe, Wueller, Daniel, Zaunschirm, Andrew, Ziuraite, Ieva, Zukovskaja, Veslava, Wang, Xinzhu, Nijman, Ruud, Camuzeaux, Stephane, Sands, Caroline, Jackson, Heather, Kaforou, Myrsini, Emonts, Marieke, Herberg, Jethro A., Maconochie, Ian, Carrol, Enitan D., Paulus, Stephane C., Zenz, Werner, Van der Flier, Michiel, de Groot, Ronald, Martinon-Torres, Federico, Schlapbach, Luregn J., Pollard, Andrew J., Fink, Colin, Kuijpers, Taco T., Anderson, Suzanne, Lewis, Matthew R., Levin, Michael, McClure, Myra, Gormley, Stuart, Hamilton, Shea, Hourmat, Bernardo, Hoggart, Clive, Sancho-Shimizu, Vanessa, Wright, Victoria, Abdulla, Amina, Agapow, Paul, Bartlett, Maeve, Bellos, Evangelos, Eleftherohorinou, Hariklia, Galassini, Rachel, Inwald, David, Mashbat, Meg, Menikou, Stefanie, Mustafa, Sobia, Nadel, Simon, Rahman, Rahmeen, Thakker, Clare, Coin, Lachlan M. J., Bokhand, S., Power, Sue, Barham, Heather, Pathan, N., Ridout, Jenna, White, Deborah, Thurston, Sarah, Faust, S., Patel, S., McCorkell, Jenni, Davies, P., Crate, Lindsey, Navarra, Helen, Carter, Stephanie, Ramaiah, R., Patel, Rekha, Tuffrey, Catherine, Gribbin, Andrew, McCready, Sharon, Peters, Mark, Hardy, Katie, Standing, Fran, O'Neill, Lauren, Abelake, Eugenia, Deep, Akash, Nsirim, Eniola, Willis, Louise, Young, Zoe, Royad, C., White, Sonia, Fortune, P. M., Hudnott, Phil, Alvez Gonzalez, Fernando, Barral-Arca, Ruth, Cebey-Lopez, Miriam, Jose Curras-Tuala, Maria, Garcia, Natalia, Garcia Vicente, Luisa, Gomez-Carballa, Alberto, Gomez Rial, Jose, Grela Beiroa, Andrea, Justicia Grande, Antonio, Leborans Iglesias, Pilar, Martinez Santos, Alba Elena, MartinonTorres, Nazareth, Martinon Sanchez, Jose Maria, Morillo Gutierrez, Beatriz, Mosquera Perez, Belen, Obando Pacheco, Pablo, Pardo-Seco, Jacobo, Pischedda, Sara, RiveroCalle, Irene, Rodriguez-Tenreiro, Carmen, Redondo-Collazo, Lorenzo, Salas Ellacuriagal, Antonio, Seren Fernandez, Sonia, Porto Silva, Maria del Sol, Vega, Ana, Vilanova Trillo, Lucia, Salas, Antonio, Beatriz Reyes, Susana, Leon Leon, Maria Cruz, Navarro Mingorance, Alvaro, Gabaldo Barrios, Xavier, Onate Vergara, Eider, Concha Torre, Andres, Vivanco, Ana, Fernandez, Reyes, Gimenez Sanchez, Francisco, Sanchez Forte, Miguel, Rojo, Pablo, Ruiz Contreras, J., Palacios, Alba, Epalza Ibarrondo, Cristina, Fernandez Cooke, Elizabeth, Navarro, Marisa, Alvarez Alvarez, Cristina, Jose Lozano, Maria, Carreras, Eduardo, Brio Sanagustin, Sonia, Neth, Olaf, Martinez Padilla, Ma del Carmen, Prieto Tato, Luis Manuel, Guillen, Sara, Fernandez Silveira, Laura, Moreno, David, van Furth, A. M. Tutu, Boeddha, N. P., Driessen, G. J. A., Emonts, M., Hazelzet, J. A., Pajkrt, D., Sanders, E. A. M., van de Beek, D., van der Ende, A., Philipsen, H. L. A., Adeel, A. O. A., Breukels, M. A., Brinkman, D. M. C., de Korte, C. C. M. M., de Vries, E., de Waal, W. J., Dekkers, R., Dings-Lammertink, A., Doedens, R. A., Donker, A. E., Dousma, M., Faber, T. E., Gerrits, G. P. J. M., Gerver, J. A. M., Heidema, J., Homan-van der Veen, J., Jacobs, M. A. M., Jansen, N. J. G., Kawczynski, P., Klucovska, K., Kneyber, M. C. J., Koopman-Keemink, Y., Langenhorst, V. J., Leusink, J., Loza, B. F., Merth, I. T., Miedema, C. J., Neeleman, C., Noordzij, J. G., Obihara, C. C., van Overbeek-van Gils, A. L. T., Poortman, G. H., Potgieter, S. T., Potjewijd, J., Rosias, P. P. R., Sprong, T., ten Tussher, G. W., Thio, B. J., Tramper-Stranders, G. A., van Deuren, M., van der Meer, H., van Kuppevelt, A. J. M., van Wermeskerken, A. M., Verwijs, W. A., Wolfs, T. F. W., Agyeman, Philipp, Aebi, Christoph, Berger, Christoph, Giannoni, Eric, Stocker, Martin, Posfay-Barbe, Klara M., Heininger, Ulrich, Bernhard-Stirnemann, Sara, Niederer-Loher, Anita, Kahlert, Christian, Hasters, Paul, Relly, Christa, Baer, Walter, Frederick, Hannah, Jennings, Rebecca, Johnston, Joanne, Kenwright, Rhian, Pinnock, Elli, Agbeko, Rachel, Secka, Fatou, Bojang, Kalifa, Sarr, Isatou, Kebbeh, Ngange, Sey, Gibbi, Momodou, Saidy Khan, Cole, Fatoumata, Thomas, Gilleh, Antonio, Martin, Klobassa, Daniela S., Binder, Alexander, Schweintzger, Nina A., Sagmeister, Manfred, Baumgart, Hinrich, Baumgartner, Markus, Behrends, Uta, Biebl, Ariane, Birnbacher, Robert, Blanke, Jan-Gerd, Boelke, Carsten, Breuling, Kai, Brunner, Juergen, Buller, Maria, Dahlem, Peter, Dietrich, Beate, Eber, Ernst, Elias, Johannes, Emhofer, Josef, Etschmaier, Rosa, Farr, Sebastian, Girtler, Ylenia, Grigorow, Irina, Heimann, Konrad, Ihm, Ulrike, Jaros, Zdenek, Kalhoff, Hermann, Kaulfersch, Wilhelm, Kemen, Christoph, Klocker, Nina, Koester, Bernhard, Kohlmaier, Benno, Komini, Eleni, Kramer, Lydia, Neubert, Antje, Ortner, Daniel, Pescollderungg, Lydia, Pfurtscheller, Klaus, Reiter, Karl, Ristic, Goran, Roedl, Siegfried, Sellner, Andrea, Sonnleitner, Astrid, Sperl, Matthias, Stelzl, Wolfgang, Till, Holger, Trobisch, Andreas, Vierzig, Anne, Vogel, Ulrich, Weingarten, Christina, Welke, Stefanie, Wimmer, Andreas, Wintergerst, Uwe, Wueller, Daniel, Zaunschirm, Andrew, Ziuraite, Ieva, and Zukovskaja, Veslava
Abstract: Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection are often non-specific, and there is no definitive test for the accurate diagnosis of infection. The 'omics' approaches to identifying biomarkers from the host-response to bacterial infection are promising. In this study, lipidomic analysis was carried out with plasma samples obtained from febrile children with confirmed bacterial infection (n = 20) and confirmed viral infection (n = 20). We show for the first time that bacterial and viral infection produces distinct profile in the host lipidome. Some species of glycerophosphoinositol, sphingomyelin, lysophosphatidylcholine and cholesterol sulfate were higher in the confirmed virus infected group, while some species of fatty acids, glycerophosphocholine, glycerophosphoserine, lactosylceramide and bilirubin were lower in the confirmed virus infected group when compared with confirmed bacterial infected group. A combination of three lipids achieved an area under the receiver operating characteristic (ROC) curve of 0.911 (95% CI 0.81 to 0.98). This pilot study demonstrates the potential of metabolic biomarkers to assist clinicians in distinguishing bacterial from viral infection in febrile children, to facilitate effective clinical management and to the limit inappropriate use of antibiotics.
Published: 2019

29. The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia : design, results and future prospects

Author: Middeldorp, Christel M., Mahajan, Anubha, Horikoshi, Momoko, Robertson, Neil R., Beaumont, Robin N., Bradfield, Jonathan P., Bustamante, Mariona, Cousminer, Diana L., Day, Felix R., De Silva, N. Maneka, Guxens, Monica, Mook-Kanamori, Dennis O., St Pourcain, Beate, Warrington, Nicole M., Adair, Linda S., Ahlqvist, Emma, Ahluwalia, Tarunveer S., Almgren, Peter, Ang, Wei, Atalay, Mustafa, Auvinen, Juha, Bartels, Meike, Beckmann, Jacques S., Bilbao, Jose Ramon, Bond, Tom, Borja, Judith B., Cavadino, Alana, Charoen, Pimphen, Chen, Zhanghua, Coin, Lachlan, Cooper, Cyrus, Curtin, John A., Custovic, Adnan, Das, Shikta, Davies, Gareth E., Dedoussis, George V., Duijts, Liesbeth, Eastwood, Peter R., Eliasen, Anders U., Elliott, Paul, Eriksson, Johan G., Estivill, Xavier, Fadista, Joao, Fedko, Iryna O., Frayling, Timothy M., Gaillard, Romy, Gauderman, W. James, Geller, Frank, Gilliland, Frank, Gilsanz, Vincente, Granell, Raquel, Grarup, Niels, Groop, Leif, Hadley, Dexter, Hakonarson, Hakon, Hansen, Torben, Hartman, Catharina A., Hattersley, Andrew T., Hayes, M. Geoffrey, Hebebrand, Johannes, Heinrich, Joachim, Helgeland, Oyvind, Henders, Anjali K., Henderson, John, Henriksen, Tine B., Hirschhorn, Joel N., Hivert, Marie-France, Hocher, Berthold, Holloway, John W., Holt, Patrick, Hottenga, Jouke-Jan, Hypponen, Elina, Iniguez, Carmen, Johansson, Stefan, Jugessur, Astanand, Kahonen, Mika, Kalkwarf, Heidi J., Kaprio, Jaakko, Karhunen, Ville, Kemp, John P., Kerkhof, Marjan, Koppelman, Gerard H., Korner, Antje, Kotecha, Sailesh, Kreiner-Moller, Eskil, Kulohoma, Benard, Kumar, Ashish, Kutalik, Zoltan, Lahti, Jari, Lappe, Joan M., Larsson, Henrik, Lehtimaki, Terho, Lewin, Alexandra M., Li, Jin, Lichtenstein, Paul, Lindgren, Cecilia M., Lindi, Virpi, Linneberg, Allan, Liu, Xueping, Liu, Jun, Lowe, William L., Jr., Lundstrom, Sebastian, Lyytikainen, Leo-Pekka, Ma, Ronald C. W., Mace, Aurelien, Magi, Reedik, Magnus, Per, Mamun, Abdullah A., Mannikko, Minna, Martin, Nicholas G., Mbarek, Hamdi, McCarthy, Nina S., Medland, Sarah E., Melbye, Mads, Melen, Erik, Mohlke, Karen L., Monnereau, Claire, Morgen, Camilla S., Morris, Andrew P., Murray, Jeffrey C., Myhre, Ronny, Najman, Jackob M., Nivard, Michel G., Nohr, Ellen A., Nolte, Ilja M., Ntalla, Ioanna, O'Reilly, Paul, Oberfield, Sharon E., Oken, Emily, Oldehinkel, Albertine J., Pahkala, Katja, Palviainen, Teemu, Panoutsopoulou, Kalliope, Pedersen, Oluf, Pennell, Craig E., Pershagen, Goran, Pitkanen, Niina, Plomin, Robert, Power, Christine, Prasad, Rashmi B., Prokopenko, Inga, Pulkkinen, Lea, Raikkonen, Katri, Raitakari, Olli T., Reynolds, Rebecca M., Richmond, Rebecca C., Rivadeneira, Fernando, Rodriguez, Alina, Rose, Richard J., Salem, Rany, Santa-Marina, Loreto, Saw, Seang-Mei, Schnurr, Theresia M., Scott, James G., Selzam, Saskia, Shepherd, John A., Simpson, Angela, Skotte, Line, Sleiman, Patrick M. A., Snieder, Harold, Sorensen, Thorkild I. A., Standl, Marie, Steegers, Eric A. P., Strachan, David P., Straker, Leon, Strandberg, Timo, Taylor, Michelle, Teo, Yik-Ying, Thiering, Elisabeth, Torrent, Maties, Tyrrell, Jessica, Uitterlinden, Andre G., van Beijsterveldt, Toos, van der Most, Peter J., van Duijn, Cornelia M., Viikari, Jorma, Vilor-Tejedor, Natalia, Vogelezang, Suzanne, Vonk, Judith M., Vrijkotte, Tanja G. M., Vuoksimaa, Eero, Wang, Carol A., Watkins, William J., Wichmann, H-Erich, Willemsen, Gonneke, Williams, Gail M., Wilson, James F., Wray, Naomi R., Xu, Shujing, Xu, Cheng-Jian, Yaghootkar, Hanieh, Yi, Lu, Zafarmand, Mohammad Hadi, Zeggini, Eleftheria, Zemel, Babette S., Hinney, Anke, Lakka, Timo A., Whitehouse, Andrew J. O., Sunyer, Jordi, Widen, Elisabeth E., Feenstra, Bjarke, Sebert, Sylvain, Jacobsson, Bo, Njolstad, Pal R., Stoltenberg, Camilla, Smith, George Davey, Lawlor, Debbie A., Paternoster, Lavinia, Timpson, Nicholas J., Ong, Ken K., Bisgaard, Hans, Bonnelykke, Klaus, Jaddoe, Vincent W. V., Tiemeier, Henning, Jarvelin, Marjo-Riitta, Evans, David M., Perry, John R. B., Grant, Struan F. A., Boomsma, Dorret I., Freathy, Rachel M., McCarthy, Mark I., Felix, Janine F., Tiemeier, Hen-Ning, Middeldorp, Christel M., Mahajan, Anubha, Horikoshi, Momoko, Robertson, Neil R., Beaumont, Robin N., Bradfield, Jonathan P., Bustamante, Mariona, Cousminer, Diana L., Day, Felix R., De Silva, N. Maneka, Guxens, Monica, Mook-Kanamori, Dennis O., St Pourcain, Beate, Warrington, Nicole M., Adair, Linda S., Ahlqvist, Emma, Ahluwalia, Tarunveer S., Almgren, Peter, Ang, Wei, Atalay, Mustafa, Auvinen, Juha, Bartels, Meike, Beckmann, Jacques S., Bilbao, Jose Ramon, Bond, Tom, Borja, Judith B., Cavadino, Alana, Charoen, Pimphen, Chen, Zhanghua, Coin, Lachlan, Cooper, Cyrus, Curtin, John A., Custovic, Adnan, Das, Shikta, Davies, Gareth E., Dedoussis, George V., Duijts, Liesbeth, Eastwood, Peter R., Eliasen, Anders U., Elliott, Paul, Eriksson, Johan G., Estivill, Xavier, Fadista, Joao, Fedko, Iryna O., Frayling, Timothy M., Gaillard, Romy, Gauderman, W. James, Geller, Frank, Gilliland, Frank, Gilsanz, Vincente, Granell, Raquel, Grarup, Niels, Groop, Leif, Hadley, Dexter, Hakonarson, Hakon, Hansen, Torben, Hartman, Catharina A., Hattersley, Andrew T., Hayes, M. Geoffrey, Hebebrand, Johannes, Heinrich, Joachim, Helgeland, Oyvind, Henders, Anjali K., Henderson, John, Henriksen, Tine B., Hirschhorn, Joel N., Hivert, Marie-France, Hocher, Berthold, Holloway, John W., Holt, Patrick, Hottenga, Jouke-Jan, Hypponen, Elina, Iniguez, Carmen, Johansson, Stefan, Jugessur, Astanand, Kahonen, Mika, Kalkwarf, Heidi J., Kaprio, Jaakko, Karhunen, Ville, Kemp, John P., Kerkhof, Marjan, Koppelman, Gerard H., Korner, Antje, Kotecha, Sailesh, Kreiner-Moller, Eskil, Kulohoma, Benard, Kumar, Ashish, Kutalik, Zoltan, Lahti, Jari, Lappe, Joan M., Larsson, Henrik, Lehtimaki, Terho, Lewin, Alexandra M., Li, Jin, Lichtenstein, Paul, Lindgren, Cecilia M., Lindi, Virpi, Linneberg, Allan, Liu, Xueping, Liu, Jun, Lowe, William L., Jr., Lundstrom, Sebastian, Lyytikainen, Leo-Pekka, Ma, Ronald C. W., Mace, Aurelien, Magi, Reedik, Magnus, Per, Mamun, Abdullah A., Mannikko, Minna, Martin, Nicholas G., Mbarek, Hamdi, McCarthy, Nina S., Medland, Sarah E., Melbye, Mads, Melen, Erik, Mohlke, Karen L., Monnereau, Claire, Morgen, Camilla S., Morris, Andrew P., Murray, Jeffrey C., Myhre, Ronny, Najman, Jackob M., Nivard, Michel G., Nohr, Ellen A., Nolte, Ilja M., Ntalla, Ioanna, O'Reilly, Paul, Oberfield, Sharon E., Oken, Emily, Oldehinkel, Albertine J., Pahkala, Katja, Palviainen, Teemu, Panoutsopoulou, Kalliope, Pedersen, Oluf, Pennell, Craig E., Pershagen, Goran, Pitkanen, Niina, Plomin, Robert, Power, Christine, Prasad, Rashmi B., Prokopenko, Inga, Pulkkinen, Lea, Raikkonen, Katri, Raitakari, Olli T., Reynolds, Rebecca M., Richmond, Rebecca C., Rivadeneira, Fernando, Rodriguez, Alina, Rose, Richard J., Salem, Rany, Santa-Marina, Loreto, Saw, Seang-Mei, Schnurr, Theresia M., Scott, James G., Selzam, Saskia, Shepherd, John A., Simpson, Angela, Skotte, Line, Sleiman, Patrick M. A., Snieder, Harold, Sorensen, Thorkild I. A., Standl, Marie, Steegers, Eric A. P., Strachan, David P., Straker, Leon, Strandberg, Timo, Taylor, Michelle, Teo, Yik-Ying, Thiering, Elisabeth, Torrent, Maties, Tyrrell, Jessica, Uitterlinden, Andre G., van Beijsterveldt, Toos, van der Most, Peter J., van Duijn, Cornelia M., Viikari, Jorma, Vilor-Tejedor, Natalia, Vogelezang, Suzanne, Vonk, Judith M., Vrijkotte, Tanja G. M., Vuoksimaa, Eero, Wang, Carol A., Watkins, William J., Wichmann, H-Erich, Willemsen, Gonneke, Williams, Gail M., Wilson, James F., Wray, Naomi R., Xu, Shujing, Xu, Cheng-Jian, Yaghootkar, Hanieh, Yi, Lu, Zafarmand, Mohammad Hadi, Zeggini, Eleftheria, Zemel, Babette S., Hinney, Anke, Lakka, Timo A., Whitehouse, Andrew J. O., Sunyer, Jordi, Widen, Elisabeth E., Feenstra, Bjarke, Sebert, Sylvain, Jacobsson, Bo, Njolstad, Pal R., Stoltenberg, Camilla, Smith, George Davey, Lawlor, Debbie A., Paternoster, Lavinia, Timpson, Nicholas J., Ong, Ken K., Bisgaard, Hans, Bonnelykke, Klaus, Jaddoe, Vincent W. V., Tiemeier, Henning, Jarvelin, Marjo-Riitta, Evans, David M., Perry, John R. B., Grant, Struan F. A., Boomsma, Dorret I., Freathy, Rachel M., McCarthy, Mark I., Felix, Janine F., and Tiemeier, Hen-Ning
Abstract: The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites.
Published: 2019
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30. The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia : design, results and future prospects

Author: Middeldorp, Christel M., Mahajan, Anubha, Horikoshi, Momoko, Robertson, Neil R., Beaumont, Robin N., Bradfield, Jonathan P., Bustamante, Mariona, Cousminer, Diana L., Day, Felix R., De Silva, N. Maneka, Guxens, Monica, Mook-Kanamori, Dennis O., St Pourcain, Beate, Warrington, Nicole M., Adair, Linda S., Ahlqvist, Emma, Ahluwalia, Tarunveer S., Almgren, Peter, Ang, Wei, Atalay, Mustafa, Auvinen, Juha, Bartels, Meike, Beckmann, Jacques S., Bilbao, Jose Ramon, Bond, Tom, Borja, Judith B., Cavadino, Alana, Charoen, Pimphen, Chen, Zhanghua, Coin, Lachlan, Cooper, Cyrus, Curtin, John A., Custovic, Adnan, Das, Shikta, Davies, Gareth E., Dedoussis, George V., Duijts, Liesbeth, Eastwood, Peter R., Eliasen, Anders U., Elliott, Paul, Eriksson, Johan G., Estivill, Xavier, Fadista, Joao, Fedko, Iryna O., Frayling, Timothy M., Gaillard, Romy, Gauderman, W. James, Geller, Frank, Gilliland, Frank, Gilsanz, Vincente, Granell, Raquel, Grarup, Niels, Groop, Leif, Hadley, Dexter, Hakonarson, Hakon, Hansen, Torben, Hartman, Catharina A., Hattersley, Andrew T., Hayes, M. Geoffrey, Hebebrand, Johannes, Heinrich, Joachim, Helgeland, Oyvind, Henders, Anjali K., Henderson, John, Henriksen, Tine B., Hirschhorn, Joel N., Hivert, Marie-France, Hocher, Berthold, Holloway, John W., Holt, Patrick, Hottenga, Jouke-Jan, Hypponen, Elina, Iniguez, Carmen, Johansson, Stefan, Jugessur, Astanand, Kahonen, Mika, Kalkwarf, Heidi J., Kaprio, Jaakko, Karhunen, Ville, Kemp, John P., Kerkhof, Marjan, Koppelman, Gerard H., Korner, Antje, Kotecha, Sailesh, Kreiner-Moller, Eskil, Kulohoma, Benard, Kumar, Ashish, Kutalik, Zoltan, Lahti, Jari, Lappe, Joan M., Larsson, Henrik, Lehtimaki, Terho, Lewin, Alexandra M., Li, Jin, Lichtenstein, Paul, Lindgren, Cecilia M., Lindi, Virpi, Linneberg, Allan, Liu, Xueping, Liu, Jun, Lowe, William L., Jr., Lundstrom, Sebastian, Lyytikainen, Leo-Pekka, Ma, Ronald C. W., Mace, Aurelien, Magi, Reedik, Magnus, Per, Mamun, Abdullah A., Mannikko, Minna, Martin, Nicholas G., Mbarek, Hamdi, McCarthy, Nina S., Medland, Sarah E., Melbye, Mads, Melen, Erik, Mohlke, Karen L., Monnereau, Claire, Morgen, Camilla S., Morris, Andrew P., Murray, Jeffrey C., Myhre, Ronny, Najman, Jackob M., Nivard, Michel G., Nohr, Ellen A., Nolte, Ilja M., Ntalla, Ioanna, O'Reilly, Paul, Oberfield, Sharon E., Oken, Emily, Oldehinkel, Albertine J., Pahkala, Katja, Palviainen, Teemu, Panoutsopoulou, Kalliope, Pedersen, Oluf, Pennell, Craig E., Pershagen, Goran, Pitkanen, Niina, Plomin, Robert, Power, Christine, Prasad, Rashmi B., Prokopenko, Inga, Pulkkinen, Lea, Raikkonen, Katri, Raitakari, Olli T., Reynolds, Rebecca M., Richmond, Rebecca C., Rivadeneira, Fernando, Rodriguez, Alina, Rose, Richard J., Salem, Rany, Santa-Marina, Loreto, Saw, Seang-Mei, Schnurr, Theresia M., Scott, James G., Selzam, Saskia, Shepherd, John A., Simpson, Angela, Skotte, Line, Sleiman, Patrick M. A., Snieder, Harold, Sorensen, Thorkild I. A., Standl, Marie, Steegers, Eric A. P., Strachan, David P., Straker, Leon, Strandberg, Timo, Taylor, Michelle, Teo, Yik-Ying, Thiering, Elisabeth, Torrent, Maties, Tyrrell, Jessica, Uitterlinden, Andre G., van Beijsterveldt, Toos, van der Most, Peter J., van Duijn, Cornelia M., Viikari, Jorma, Vilor-Tejedor, Natalia, Vogelezang, Suzanne, Vonk, Judith M., Vrijkotte, Tanja G. M., Vuoksimaa, Eero, Wang, Carol A., Watkins, William J., Wichmann, H-Erich, Willemsen, Gonneke, Williams, Gail M., Wilson, James F., Wray, Naomi R., Xu, Shujing, Xu, Cheng-Jian, Yaghootkar, Hanieh, Yi, Lu, Zafarmand, Mohammad Hadi, Zeggini, Eleftheria, Zemel, Babette S., Hinney, Anke, Lakka, Timo A., Whitehouse, Andrew J. O., Sunyer, Jordi, Widen, Elisabeth E., Feenstra, Bjarke, Sebert, Sylvain, Jacobsson, Bo, Njolstad, Pal R., Stoltenberg, Camilla, Smith, George Davey, Lawlor, Debbie A., Paternoster, Lavinia, Timpson, Nicholas J., Ong, Ken K., Bisgaard, Hans, Bonnelykke, Klaus, Jaddoe, Vincent W. V., Tiemeier, Henning, Jarvelin, Marjo-Riitta, Evans, David M., Perry, John R. B., Grant, Struan F. A., Boomsma, Dorret I., Freathy, Rachel M., McCarthy, Mark I., Felix, Janine F., Tiemeier, Hen-Ning, Middeldorp, Christel M., Mahajan, Anubha, Horikoshi, Momoko, Robertson, Neil R., Beaumont, Robin N., Bradfield, Jonathan P., Bustamante, Mariona, Cousminer, Diana L., Day, Felix R., De Silva, N. Maneka, Guxens, Monica, Mook-Kanamori, Dennis O., St Pourcain, Beate, Warrington, Nicole M., Adair, Linda S., Ahlqvist, Emma, Ahluwalia, Tarunveer S., Almgren, Peter, Ang, Wei, Atalay, Mustafa, Auvinen, Juha, Bartels, Meike, Beckmann, Jacques S., Bilbao, Jose Ramon, Bond, Tom, Borja, Judith B., Cavadino, Alana, Charoen, Pimphen, Chen, Zhanghua, Coin, Lachlan, Cooper, Cyrus, Curtin, John A., Custovic, Adnan, Das, Shikta, Davies, Gareth E., Dedoussis, George V., Duijts, Liesbeth, Eastwood, Peter R., Eliasen, Anders U., Elliott, Paul, Eriksson, Johan G., Estivill, Xavier, Fadista, Joao, Fedko, Iryna O., Frayling, Timothy M., Gaillard, Romy, Gauderman, W. James, Geller, Frank, Gilliland, Frank, Gilsanz, Vincente, Granell, Raquel, Grarup, Niels, Groop, Leif, Hadley, Dexter, Hakonarson, Hakon, Hansen, Torben, Hartman, Catharina A., Hattersley, Andrew T., Hayes, M. Geoffrey, Hebebrand, Johannes, Heinrich, Joachim, Helgeland, Oyvind, Henders, Anjali K., Henderson, John, Henriksen, Tine B., Hirschhorn, Joel N., Hivert, Marie-France, Hocher, Berthold, Holloway, John W., Holt, Patrick, Hottenga, Jouke-Jan, Hypponen, Elina, Iniguez, Carmen, Johansson, Stefan, Jugessur, Astanand, Kahonen, Mika, Kalkwarf, Heidi J., Kaprio, Jaakko, Karhunen, Ville, Kemp, John P., Kerkhof, Marjan, Koppelman, Gerard H., Korner, Antje, Kotecha, Sailesh, Kreiner-Moller, Eskil, Kulohoma, Benard, Kumar, Ashish, Kutalik, Zoltan, Lahti, Jari, Lappe, Joan M., Larsson, Henrik, Lehtimaki, Terho, Lewin, Alexandra M., Li, Jin, Lichtenstein, Paul, Lindgren, Cecilia M., Lindi, Virpi, Linneberg, Allan, Liu, Xueping, Liu, Jun, Lowe, William L., Jr., Lundstrom, Sebastian, Lyytikainen, Leo-Pekka, Ma, Ronald C. W., Mace, Aurelien, Magi, Reedik, Magnus, Per, Mamun, Abdullah A., Mannikko, Minna, Martin, Nicholas G., Mbarek, Hamdi, McCarthy, Nina S., Medland, Sarah E., Melbye, Mads, Melen, Erik, Mohlke, Karen L., Monnereau, Claire, Morgen, Camilla S., Morris, Andrew P., Murray, Jeffrey C., Myhre, Ronny, Najman, Jackob M., Nivard, Michel G., Nohr, Ellen A., Nolte, Ilja M., Ntalla, Ioanna, O'Reilly, Paul, Oberfield, Sharon E., Oken, Emily, Oldehinkel, Albertine J., Pahkala, Katja, Palviainen, Teemu, Panoutsopoulou, Kalliope, Pedersen, Oluf, Pennell, Craig E., Pershagen, Goran, Pitkanen, Niina, Plomin, Robert, Power, Christine, Prasad, Rashmi B., Prokopenko, Inga, Pulkkinen, Lea, Raikkonen, Katri, Raitakari, Olli T., Reynolds, Rebecca M., Richmond, Rebecca C., Rivadeneira, Fernando, Rodriguez, Alina, Rose, Richard J., Salem, Rany, Santa-Marina, Loreto, Saw, Seang-Mei, Schnurr, Theresia M., Scott, James G., Selzam, Saskia, Shepherd, John A., Simpson, Angela, Skotte, Line, Sleiman, Patrick M. A., Snieder, Harold, Sorensen, Thorkild I. A., Standl, Marie, Steegers, Eric A. P., Strachan, David P., Straker, Leon, Strandberg, Timo, Taylor, Michelle, Teo, Yik-Ying, Thiering, Elisabeth, Torrent, Maties, Tyrrell, Jessica, Uitterlinden, Andre G., van Beijsterveldt, Toos, van der Most, Peter J., van Duijn, Cornelia M., Viikari, Jorma, Vilor-Tejedor, Natalia, Vogelezang, Suzanne, Vonk, Judith M., Vrijkotte, Tanja G. M., Vuoksimaa, Eero, Wang, Carol A., Watkins, William J., Wichmann, H-Erich, Willemsen, Gonneke, Williams, Gail M., Wilson, James F., Wray, Naomi R., Xu, Shujing, Xu, Cheng-Jian, Yaghootkar, Hanieh, Yi, Lu, Zafarmand, Mohammad Hadi, Zeggini, Eleftheria, Zemel, Babette S., Hinney, Anke, Lakka, Timo A., Whitehouse, Andrew J. O., Sunyer, Jordi, Widen, Elisabeth E., Feenstra, Bjarke, Sebert, Sylvain, Jacobsson, Bo, Njolstad, Pal R., Stoltenberg, Camilla, Smith, George Davey, Lawlor, Debbie A., Paternoster, Lavinia, Timpson, Nicholas J., Ong, Ken K., Bisgaard, Hans, Bonnelykke, Klaus, Jaddoe, Vincent W. V., Tiemeier, Henning, Jarvelin, Marjo-Riitta, Evans, David M., Perry, John R. B., Grant, Struan F. A., Boomsma, Dorret I., Freathy, Rachel M., McCarthy, Mark I., Felix, Janine F., and Tiemeier, Hen-Ning
Abstract: The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites.
Published: 2019
Full Text: View/download PDF

31. The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia : design, results and future prospects

Author: Middeldorp, Christel M., Mahajan, Anubha, Horikoshi, Momoko, Robertson, Neil R., Beaumont, Robin N., Bradfield, Jonathan P., Bustamante, Mariona, Cousminer, Diana L., Day, Felix R., De Silva, N. Maneka, Guxens, Monica, Mook-Kanamori, Dennis O., St Pourcain, Beate, Warrington, Nicole M., Adair, Linda S., Ahlqvist, Emma, Ahluwalia, Tarunveer S., Almgren, Peter, Ang, Wei, Atalay, Mustafa, Auvinen, Juha, Bartels, Meike, Beckmann, Jacques S., Bilbao, Jose Ramon, Bond, Tom, Borja, Judith B., Cavadino, Alana, Charoen, Pimphen, Chen, Zhanghua, Coin, Lachlan, Cooper, Cyrus, Curtin, John A., Custovic, Adnan, Das, Shikta, Davies, Gareth E., Dedoussis, George V., Duijts, Liesbeth, Eastwood, Peter R., Eliasen, Anders U., Elliott, Paul, Eriksson, Johan G., Estivill, Xavier, Fadista, Joao, Fedko, Iryna O., Frayling, Timothy M., Gaillard, Romy, Gauderman, W. James, Geller, Frank, Gilliland, Frank, Gilsanz, Vincente, Granell, Raquel, Grarup, Niels, Groop, Leif, Hadley, Dexter, Hakonarson, Hakon, Hansen, Torben, Hartman, Catharina A., Hattersley, Andrew T., Hayes, M. Geoffrey, Hebebrand, Johannes, Heinrich, Joachim, Helgeland, Oyvind, Henders, Anjali K., Henderson, John, Henriksen, Tine B., Hirschhorn, Joel N., Hivert, Marie-France, Hocher, Berthold, Holloway, John W., Holt, Patrick, Hottenga, Jouke-Jan, Hypponen, Elina, Iniguez, Carmen, Johansson, Stefan, Jugessur, Astanand, Kahonen, Mika, Kalkwarf, Heidi J., Kaprio, Jaakko, Karhunen, Ville, Kemp, John P., Kerkhof, Marjan, Koppelman, Gerard H., Korner, Antje, Kotecha, Sailesh, Kreiner-Moller, Eskil, Kulohoma, Benard, Kumar, Ashish, Kutalik, Zoltan, Lahti, Jari, Lappe, Joan M., Larsson, Henrik, Lehtimaki, Terho, Lewin, Alexandra M., Li, Jin, Lichtenstein, Paul, Lindgren, Cecilia M., Lindi, Virpi, Linneberg, Allan, Liu, Xueping, Liu, Jun, Lowe, William L., Jr., Lundstrom, Sebastian, Lyytikainen, Leo-Pekka, Ma, Ronald C. W., Mace, Aurelien, Magi, Reedik, Magnus, Per, Mamun, Abdullah A., Mannikko, Minna, Martin, Nicholas G., Mbarek, Hamdi, McCarthy, Nina S., Medland, Sarah E., Melbye, Mads, Melen, Erik, Mohlke, Karen L., Monnereau, Claire, Morgen, Camilla S., Morris, Andrew P., Murray, Jeffrey C., Myhre, Ronny, Najman, Jackob M., Nivard, Michel G., Nohr, Ellen A., Nolte, Ilja M., Ntalla, Ioanna, O'Reilly, Paul, Oberfield, Sharon E., Oken, Emily, Oldehinkel, Albertine J., Pahkala, Katja, Palviainen, Teemu, Panoutsopoulou, Kalliope, Pedersen, Oluf, Pennell, Craig E., Pershagen, Goran, Pitkanen, Niina, Plomin, Robert, Power, Christine, Prasad, Rashmi B., Prokopenko, Inga, Pulkkinen, Lea, Raikkonen, Katri, Raitakari, Olli T., Reynolds, Rebecca M., Richmond, Rebecca C., Rivadeneira, Fernando, Rodriguez, Alina, Rose, Richard J., Salem, Rany, Santa-Marina, Loreto, Saw, Seang-Mei, Schnurr, Theresia M., Scott, James G., Selzam, Saskia, Shepherd, John A., Simpson, Angela, Skotte, Line, Sleiman, Patrick M. A., Snieder, Harold, Sorensen, Thorkild I. A., Standl, Marie, Steegers, Eric A. P., Strachan, David P., Straker, Leon, Strandberg, Timo, Taylor, Michelle, Teo, Yik-Ying, Thiering, Elisabeth, Torrent, Maties, Tyrrell, Jessica, Uitterlinden, Andre G., van Beijsterveldt, Toos, van der Most, Peter J., van Duijn, Cornelia M., Viikari, Jorma, Vilor-Tejedor, Natalia, Vogelezang, Suzanne, Vonk, Judith M., Vrijkotte, Tanja G. M., Vuoksimaa, Eero, Wang, Carol A., Watkins, William J., Wichmann, H-Erich, Willemsen, Gonneke, Williams, Gail M., Wilson, James F., Wray, Naomi R., Xu, Shujing, Xu, Cheng-Jian, Yaghootkar, Hanieh, Yi, Lu, Zafarmand, Mohammad Hadi, Zeggini, Eleftheria, Zemel, Babette S., Hinney, Anke, Lakka, Timo A., Whitehouse, Andrew J. O., Sunyer, Jordi, Widen, Elisabeth E., Feenstra, Bjarke, Sebert, Sylvain, Jacobsson, Bo, Njolstad, Pal R., Stoltenberg, Camilla, Smith, George Davey, Lawlor, Debbie A., Paternoster, Lavinia, Timpson, Nicholas J., Ong, Ken K., Bisgaard, Hans, Bonnelykke, Klaus, Jaddoe, Vincent W. V., Tiemeier, Henning, Jarvelin, Marjo-Riitta, Evans, David M., Perry, John R. B., Grant, Struan F. A., Boomsma, Dorret I., Freathy, Rachel M., McCarthy, Mark I., Felix, Janine F., Tiemeier, Hen-Ning, Middeldorp, Christel M., Mahajan, Anubha, Horikoshi, Momoko, Robertson, Neil R., Beaumont, Robin N., Bradfield, Jonathan P., Bustamante, Mariona, Cousminer, Diana L., Day, Felix R., De Silva, N. Maneka, Guxens, Monica, Mook-Kanamori, Dennis O., St Pourcain, Beate, Warrington, Nicole M., Adair, Linda S., Ahlqvist, Emma, Ahluwalia, Tarunveer S., Almgren, Peter, Ang, Wei, Atalay, Mustafa, Auvinen, Juha, Bartels, Meike, Beckmann, Jacques S., Bilbao, Jose Ramon, Bond, Tom, Borja, Judith B., Cavadino, Alana, Charoen, Pimphen, Chen, Zhanghua, Coin, Lachlan, Cooper, Cyrus, Curtin, John A., Custovic, Adnan, Das, Shikta, Davies, Gareth E., Dedoussis, George V., Duijts, Liesbeth, Eastwood, Peter R., Eliasen, Anders U., Elliott, Paul, Eriksson, Johan G., Estivill, Xavier, Fadista, Joao, Fedko, Iryna O., Frayling, Timothy M., Gaillard, Romy, Gauderman, W. James, Geller, Frank, Gilliland, Frank, Gilsanz, Vincente, Granell, Raquel, Grarup, Niels, Groop, Leif, Hadley, Dexter, Hakonarson, Hakon, Hansen, Torben, Hartman, Catharina A., Hattersley, Andrew T., Hayes, M. Geoffrey, Hebebrand, Johannes, Heinrich, Joachim, Helgeland, Oyvind, Henders, Anjali K., Henderson, John, Henriksen, Tine B., Hirschhorn, Joel N., Hivert, Marie-France, Hocher, Berthold, Holloway, John W., Holt, Patrick, Hottenga, Jouke-Jan, Hypponen, Elina, Iniguez, Carmen, Johansson, Stefan, Jugessur, Astanand, Kahonen, Mika, Kalkwarf, Heidi J., Kaprio, Jaakko, Karhunen, Ville, Kemp, John P., Kerkhof, Marjan, Koppelman, Gerard H., Korner, Antje, Kotecha, Sailesh, Kreiner-Moller, Eskil, Kulohoma, Benard, Kumar, Ashish, Kutalik, Zoltan, Lahti, Jari, Lappe, Joan M., Larsson, Henrik, Lehtimaki, Terho, Lewin, Alexandra M., Li, Jin, Lichtenstein, Paul, Lindgren, Cecilia M., Lindi, Virpi, Linneberg, Allan, Liu, Xueping, Liu, Jun, Lowe, William L., Jr., Lundstrom, Sebastian, Lyytikainen, Leo-Pekka, Ma, Ronald C. W., Mace, Aurelien, Magi, Reedik, Magnus, Per, Mamun, Abdullah A., Mannikko, Minna, Martin, Nicholas G., Mbarek, Hamdi, McCarthy, Nina S., Medland, Sarah E., Melbye, Mads, Melen, Erik, Mohlke, Karen L., Monnereau, Claire, Morgen, Camilla S., Morris, Andrew P., Murray, Jeffrey C., Myhre, Ronny, Najman, Jackob M., Nivard, Michel G., Nohr, Ellen A., Nolte, Ilja M., Ntalla, Ioanna, O'Reilly, Paul, Oberfield, Sharon E., Oken, Emily, Oldehinkel, Albertine J., Pahkala, Katja, Palviainen, Teemu, Panoutsopoulou, Kalliope, Pedersen, Oluf, Pennell, Craig E., Pershagen, Goran, Pitkanen, Niina, Plomin, Robert, Power, Christine, Prasad, Rashmi B., Prokopenko, Inga, Pulkkinen, Lea, Raikkonen, Katri, Raitakari, Olli T., Reynolds, Rebecca M., Richmond, Rebecca C., Rivadeneira, Fernando, Rodriguez, Alina, Rose, Richard J., Salem, Rany, Santa-Marina, Loreto, Saw, Seang-Mei, Schnurr, Theresia M., Scott, James G., Selzam, Saskia, Shepherd, John A., Simpson, Angela, Skotte, Line, Sleiman, Patrick M. A., Snieder, Harold, Sorensen, Thorkild I. A., Standl, Marie, Steegers, Eric A. P., Strachan, David P., Straker, Leon, Strandberg, Timo, Taylor, Michelle, Teo, Yik-Ying, Thiering, Elisabeth, Torrent, Maties, Tyrrell, Jessica, Uitterlinden, Andre G., van Beijsterveldt, Toos, van der Most, Peter J., van Duijn, Cornelia M., Viikari, Jorma, Vilor-Tejedor, Natalia, Vogelezang, Suzanne, Vonk, Judith M., Vrijkotte, Tanja G. M., Vuoksimaa, Eero, Wang, Carol A., Watkins, William J., Wichmann, H-Erich, Willemsen, Gonneke, Williams, Gail M., Wilson, James F., Wray, Naomi R., Xu, Shujing, Xu, Cheng-Jian, Yaghootkar, Hanieh, Yi, Lu, Zafarmand, Mohammad Hadi, Zeggini, Eleftheria, Zemel, Babette S., Hinney, Anke, Lakka, Timo A., Whitehouse, Andrew J. O., Sunyer, Jordi, Widen, Elisabeth E., Feenstra, Bjarke, Sebert, Sylvain, Jacobsson, Bo, Njolstad, Pal R., Stoltenberg, Camilla, Smith, George Davey, Lawlor, Debbie A., Paternoster, Lavinia, Timpson, Nicholas J., Ong, Ken K., Bisgaard, Hans, Bonnelykke, Klaus, Jaddoe, Vincent W. V., Tiemeier, Henning, Jarvelin, Marjo-Riitta, Evans, David M., Perry, John R. B., Grant, Struan F. A., Boomsma, Dorret I., Freathy, Rachel M., McCarthy, Mark I., Felix, Janine F., and Tiemeier, Hen-Ning
Abstract: The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites.
Published: 2019
Full Text: View/download PDF

32. The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia:design, results and future prospects

Author: Middeldorp, Christel M., Mahajan, Anubha, Horikoshi, Momoko, Robertson, Neil R., Beaumont, Robin N., Bradfield, Jonathan P., Bustamante, Mariona, Cousminer, Diana L., Day, Felix R., De Silva, N. Maneka, Guxens, Monica, Mook-Kanamori, Dennis O., St Pourcain, Beate, Warrington, Nicole M., Adair, Linda S., Ahlqvist, Emma, Ahluwalia, Tarunveer S., Almgren, Peter, Ang, Wei, Atalay, Mustafa, Auvinen, Juha, Bartels, Meike, Beckmann, Jacques S., Bilbao, Jose Ramon, Bond, Tom, Borja, Judith B., Cavadino, Alana, Charoen, Pimphen, Chen, Zhanghua, Coin, Lachlan, Cooper, Cyrus, Curtin, John A., Custovic, Adnan, Das, Shikta, Davies, Gareth E., Dedoussis, George V., Duijts, Liesbeth, Eastwood, Peter R., Eliasen, Anders U., Elliott, Paul, Eriksson, Johan G., Estivill, Xavier, Fadista, Joao, Fedko, Iryna O., Frayling, Timothy M., Gaillard, Romy, Gauderman, W. James, Geller, Frank, Gilliland, Frank, Gilsanz, Vincente, Granell, Raquel, Grarup, Niels, Groop, Leif, Hadley, Dexter, Hakonarson, Hakon, Hansen, Torben, Hartman, Catharina A., Hattersley, Andrew T., Hayes, M. Geoffrey, Hebebrand, Johannes, Heinrich, Joachim, Helgeland, Oyvind, Henders, Anjali K., Henderson, John, Henriksen, Tine B., Hirschhorn, Joel N., Hivert, Marie-France, Hocher, Berthold, Holloway, John W., Holt, Patrick, Hottenga, Jouke-Jan, Hypponen, Elina, Iniguez, Carmen, Johansson, Stefan, Jugessur, Astanand, Kahonen, Mika, Kalkwarf, Heidi J., Kaprio, Jaakko, Karhunen, Ville, Kemp, John P., Kerkhof, Marjan, Koppelman, Gerard H., Korner, Antje, Kotecha, Sailesh, Kreiner-Moller, Eskil, Kulohoma, Benard, Kumar, Ashish, Kutalik, Zoltan, Lahti, Jari, Lappe, Joan M., Larsson, Henrik, Lehtimaki, Terho, Lewin, Alexandra M., Li, Jin, Lichtenstein, Paul, Lindgren, Cecilia M., Lindi, Virpi, Linneberg, Allan, Liu, Xueping, Liu, Jun, Lowe, William L., Jr., Lundstrom, Sebastian, Lyytikainen, Leo-Pekka, Ma, Ronald C. W., Mace, Aurelien, Magi, Reedik, Magnus, Per, Mamun, Abdullah A., Mannikko, Minna, Martin, Nicholas G., Mbarek, Hamdi, McCarthy, Nina S., Medland, Sarah E., Melbye, Mads, Melen, Erik, Mohlke, Karen L., Monnereau, Claire, Morgen, Camilla S., Morris, Andrew P., Murray, Jeffrey C., Myhre, Ronny, Najman, Jackob M., Nivard, Michel G., Nohr, Ellen A., Nolte, Ilja M., Ntalla, Ioanna, O'Reilly, Paul, Oberfield, Sharon E., Oken, Emily, Oldehinkel, Albertine J., Pahkala, Katja, Palviainen, Teemu, Panoutsopoulou, Kalliope, Pedersen, Oluf, Pennell, Craig E., Pershagen, Goran, Pitkanen, Niina, Plomin, Robert, Power, Christine, Prasad, Rashmi B., Prokopenko, Inga, Pulkkinen, Lea, Raikkonen, Katri, Raitakari, Olli T., Reynolds, Rebecca M., Richmond, Rebecca C., Rivadeneira, Fernando, Rodriguez, Alina, Rose, Richard J., Salem, Rany, Santa-Marina, Loreto, Saw, Seang-Mei, Schnurr, Theresia M., Scott, James G., Selzam, Saskia, Shepherd, John A., Simpson, Angela, Skotte, Line, Sleiman, Patrick M. A., Snieder, Harold, Sørensen, Thorkild I. A., Standl, Marie, Steegers, Eric A. P., Strachan, David P., Straker, Leon, Strandberg, Timo, Taylor, Michelle, Teo, Yik-Ying, Thiering, Elisabeth, Torrent, Maties, Tyrrell, Jessica, Uitterlinden, Andre G., van Beijsterveldt, Toos, van der Most, Peter J., van Duijn, Cornelia M., Viikari, Jorma, Vilor-Tejedor, Natalia, Vogelezang, Suzanne, Vonk, Judith M., Vrijkotte, Tanja G. M., Vuoksimaa, Eero, Wang, Carol A., Watkins, William J., Wichmann, H-Erich, Willemsen, Gonneke, Williams, Gail M., Wilson, James F., Wray, Naomi R., Xu, Shujing, Xu, Cheng-Jian, Yaghootkar, Hanieh, Yi, Lu, Zafarmand, Mohammad Hadi, Zeggini, Eleftheria, Zemel, Babette S., Hinney, Anke, Lakka, Timo A., Whitehouse, Andrew J. O., Sunyer, Jordi, Widen, Elisabeth E., Feenstra, Bjarke, Sebert, Sylvain, Jacobsson, Bo, Njolstad, Pal R., Stoltenberg, Camilla, Smith, George Davey, Lawlor, Debbie A., Paternoster, Lavinia, Timpson, Nicholas J., Ong, Ken K., Bisgaard, Hans, Bonnelykke, Klaus, Jaddoe, Vincent W. V., Tiemeier, Henning, Jarvelin, Marjo-Riitta, Evans, David M., Perry, John R. B., Grant, Struan F. A., Boomsma, Dorret I., Freathy, Rachel M., McCarthy, Mark I., Felix, Janine F., Sorensen, Thorkild I. A., Tiemeier, Hen-Ning, Middeldorp, Christel M., Mahajan, Anubha, Horikoshi, Momoko, Robertson, Neil R., Beaumont, Robin N., Bradfield, Jonathan P., Bustamante, Mariona, Cousminer, Diana L., Day, Felix R., De Silva, N. Maneka, Guxens, Monica, Mook-Kanamori, Dennis O., St Pourcain, Beate, Warrington, Nicole M., Adair, Linda S., Ahlqvist, Emma, Ahluwalia, Tarunveer S., Almgren, Peter, Ang, Wei, Atalay, Mustafa, Auvinen, Juha, Bartels, Meike, Beckmann, Jacques S., Bilbao, Jose Ramon, Bond, Tom, Borja, Judith B., Cavadino, Alana, Charoen, Pimphen, Chen, Zhanghua, Coin, Lachlan, Cooper, Cyrus, Curtin, John A., Custovic, Adnan, Das, Shikta, Davies, Gareth E., Dedoussis, George V., Duijts, Liesbeth, Eastwood, Peter R., Eliasen, Anders U., Elliott, Paul, Eriksson, Johan G., Estivill, Xavier, Fadista, Joao, Fedko, Iryna O., Frayling, Timothy M., Gaillard, Romy, Gauderman, W. James, Geller, Frank, Gilliland, Frank, Gilsanz, Vincente, Granell, Raquel, Grarup, Niels, Groop, Leif, Hadley, Dexter, Hakonarson, Hakon, Hansen, Torben, Hartman, Catharina A., Hattersley, Andrew T., Hayes, M. Geoffrey, Hebebrand, Johannes, Heinrich, Joachim, Helgeland, Oyvind, Henders, Anjali K., Henderson, John, Henriksen, Tine B., Hirschhorn, Joel N., Hivert, Marie-France, Hocher, Berthold, Holloway, John W., Holt, Patrick, Hottenga, Jouke-Jan, Hypponen, Elina, Iniguez, Carmen, Johansson, Stefan, Jugessur, Astanand, Kahonen, Mika, Kalkwarf, Heidi J., Kaprio, Jaakko, Karhunen, Ville, Kemp, John P., Kerkhof, Marjan, Koppelman, Gerard H., Korner, Antje, Kotecha, Sailesh, Kreiner-Moller, Eskil, Kulohoma, Benard, Kumar, Ashish, Kutalik, Zoltan, Lahti, Jari, Lappe, Joan M., Larsson, Henrik, Lehtimaki, Terho, Lewin, Alexandra M., Li, Jin, Lichtenstein, Paul, Lindgren, Cecilia M., Lindi, Virpi, Linneberg, Allan, Liu, Xueping, Liu, Jun, Lowe, William L., Jr., Lundstrom, Sebastian, Lyytikainen, Leo-Pekka, Ma, Ronald C. W., Mace, Aurelien, Magi, Reedik, Magnus, Per, Mamun, Abdullah A., Mannikko, Minna, Martin, Nicholas G., Mbarek, Hamdi, McCarthy, Nina S., Medland, Sarah E., Melbye, Mads, Melen, Erik, Mohlke, Karen L., Monnereau, Claire, Morgen, Camilla S., Morris, Andrew P., Murray, Jeffrey C., Myhre, Ronny, Najman, Jackob M., Nivard, Michel G., Nohr, Ellen A., Nolte, Ilja M., Ntalla, Ioanna, O'Reilly, Paul, Oberfield, Sharon E., Oken, Emily, Oldehinkel, Albertine J., Pahkala, Katja, Palviainen, Teemu, Panoutsopoulou, Kalliope, Pedersen, Oluf, Pennell, Craig E., Pershagen, Goran, Pitkanen, Niina, Plomin, Robert, Power, Christine, Prasad, Rashmi B., Prokopenko, Inga, Pulkkinen, Lea, Raikkonen, Katri, Raitakari, Olli T., Reynolds, Rebecca M., Richmond, Rebecca C., Rivadeneira, Fernando, Rodriguez, Alina, Rose, Richard J., Salem, Rany, Santa-Marina, Loreto, Saw, Seang-Mei, Schnurr, Theresia M., Scott, James G., Selzam, Saskia, Shepherd, John A., Simpson, Angela, Skotte, Line, Sleiman, Patrick M. A., Snieder, Harold, Sørensen, Thorkild I. A., Standl, Marie, Steegers, Eric A. P., Strachan, David P., Straker, Leon, Strandberg, Timo, Taylor, Michelle, Teo, Yik-Ying, Thiering, Elisabeth, Torrent, Maties, Tyrrell, Jessica, Uitterlinden, Andre G., van Beijsterveldt, Toos, van der Most, Peter J., van Duijn, Cornelia M., Viikari, Jorma, Vilor-Tejedor, Natalia, Vogelezang, Suzanne, Vonk, Judith M., Vrijkotte, Tanja G. M., Vuoksimaa, Eero, Wang, Carol A., Watkins, William J., Wichmann, H-Erich, Willemsen, Gonneke, Williams, Gail M., Wilson, James F., Wray, Naomi R., Xu, Shujing, Xu, Cheng-Jian, Yaghootkar, Hanieh, Yi, Lu, Zafarmand, Mohammad Hadi, Zeggini, Eleftheria, Zemel, Babette S., Hinney, Anke, Lakka, Timo A., Whitehouse, Andrew J. O., Sunyer, Jordi, Widen, Elisabeth E., Feenstra, Bjarke, Sebert, Sylvain, Jacobsson, Bo, Njolstad, Pal R., Stoltenberg, Camilla, Smith, George Davey, Lawlor, Debbie A., Paternoster, Lavinia, Timpson, Nicholas J., Ong, Ken K., Bisgaard, Hans, Bonnelykke, Klaus, Jaddoe, Vincent W. V., Tiemeier, Henning, Jarvelin, Marjo-Riitta, Evans, David M., Perry, John R. B., Grant, Struan F. A., Boomsma, Dorret I., Freathy, Rachel M., McCarthy, Mark I., Felix, Janine F., Sorensen, Thorkild I. A., and Tiemeier, Hen-Ning
Published: 2019

33. Identification of regulatory variants associated with genetic susceptibility to meningococcal disease

Author: European Commission, Meningitis Research Foundation, National Institute for Health Research (UK), Newcastle Biomedical Research Centre, Newcastle University, Newcastle upon Tyne Hospitals NHS Foundation Trust, Instituto de Salud Carlos III, Xunta de Galicia, Wyeth Farma, Fundación Instituto de Investigación Sanitaria de Santiago de Compostela, Novartis, Swiss National Science Foundation, Swiss Society of Intensive Care Medicine, Gottfried und Julia Bangerter-Rhyner-Stiftung, Vinetum and Borer Foundation, Foundation for the Health of Children and Adolescents, Austrian National Bank, Borghini, Lisa, Png, Eileen, Binder, Alexander, Wright, Vistoria J., Pinnock, Ellie, De Groot, Ronald, Hazelzet, Jan, Emonts, Marieke, Van der Flier, Michiel, Schlapbach, Luregn J., Anderson, Suzanne, Secka, Fatou, Salas, Antonio, Fink, Colin, Carrol, Enitan D., Pollard, Andrew J., Coin, Lachlan J., Kuijpers, Taco W., Martinon-Torres, Federico, Zenz, Werner, Levin, Michael, Hibberd, Martin L., Davila, Sonia, European Commission, Meningitis Research Foundation, National Institute for Health Research (UK), Newcastle Biomedical Research Centre, Newcastle University, Newcastle upon Tyne Hospitals NHS Foundation Trust, Instituto de Salud Carlos III, Xunta de Galicia, Wyeth Farma, Fundación Instituto de Investigación Sanitaria de Santiago de Compostela, Novartis, Swiss National Science Foundation, Swiss Society of Intensive Care Medicine, Gottfried und Julia Bangerter-Rhyner-Stiftung, Vinetum and Borer Foundation, Foundation for the Health of Children and Adolescents, Austrian National Bank, Borghini, Lisa, Png, Eileen, Binder, Alexander, Wright, Vistoria J., Pinnock, Ellie, De Groot, Ronald, Hazelzet, Jan, Emonts, Marieke, Van der Flier, Michiel, Schlapbach, Luregn J., Anderson, Suzanne, Secka, Fatou, Salas, Antonio, Fink, Colin, Carrol, Enitan D., Pollard, Andrew J., Coin, Lachlan J., Kuijpers, Taco W., Martinon-Torres, Federico, Zenz, Werner, Levin, Michael, Hibberd, Martin L., and Davila, Sonia
Abstract: Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA – a NF-kB subunit, master regulator of the response to infection – under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes.
Published: 2019

34. The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia:design, results and future prospects

Author: Middeldorp, Christel M., Mahajan, Anubha, Horikoshi, Momoko, Robertson, Neil R., Beaumont, Robin N., Bradfield, Jonathan P., Bustamante, Mariona, Cousminer, Diana L., Day, Felix R., De Silva, N. Maneka, Guxens, Monica, Mook-Kanamori, Dennis O., St Pourcain, Beate, Warrington, Nicole M., Adair, Linda S., Ahlqvist, Emma, Ahluwalia, Tarunveer S., Almgren, Peter, Ang, Wei, Atalay, Mustafa, Auvinen, Juha, Bartels, Meike, Beckmann, Jacques S., Bilbao, Jose Ramon, Bond, Tom, Borja, Judith B., Cavadino, Alana, Charoen, Pimphen, Chen, Zhanghua, Coin, Lachlan, Cooper, Cyrus, Curtin, John A., Custovic, Adnan, Das, Shikta, Davies, Gareth E., Dedoussis, George V., Duijts, Liesbeth, Eastwood, Peter R., Eliasen, Anders U., Elliott, Paul, Eriksson, Johan G., Estivill, Xavier, Fadista, Joao, Fedko, Iryna O., Frayling, Timothy M., Gaillard, Romy, Gauderman, W. James, Geller, Frank, Gilliland, Frank, Gilsanz, Vincente, Granell, Raquel, Grarup, Niels, Groop, Leif, Hadley, Dexter, Hakonarson, Hakon, Hansen, Torben, Hartman, Catharina A., Hattersley, Andrew T., Hayes, M. Geoffrey, Hebebrand, Johannes, Heinrich, Joachim, Helgeland, Oyvind, Henders, Anjali K., Henderson, John, Henriksen, Tine B., Hirschhorn, Joel N., Hivert, Marie-France, Hocher, Berthold, Holloway, John W., Holt, Patrick, Hottenga, Jouke-Jan, Hypponen, Elina, Iniguez, Carmen, Johansson, Stefan, Jugessur, Astanand, Kahonen, Mika, Kalkwarf, Heidi J., Kaprio, Jaakko, Karhunen, Ville, Kemp, John P., Kerkhof, Marjan, Koppelman, Gerard H., Korner, Antje, Kotecha, Sailesh, Kreiner-Moller, Eskil, Kulohoma, Benard, Kumar, Ashish, Kutalik, Zoltan, Lahti, Jari, Lappe, Joan M., Larsson, Henrik, Lehtimaki, Terho, Lewin, Alexandra M., Li, Jin, Lichtenstein, Paul, Lindgren, Cecilia M., Lindi, Virpi, Linneberg, Allan, Liu, Xueping, Liu, Jun, Lowe, William L., Jr., Lundstrom, Sebastian, Lyytikainen, Leo-Pekka, Ma, Ronald C. W., Mace, Aurelien, Magi, Reedik, Magnus, Per, Mamun, Abdullah A., Mannikko, Minna, Martin, Nicholas G., Mbarek, Hamdi, McCarthy, Nina S., Medland, Sarah E., Melbye, Mads, Melen, Erik, Mohlke, Karen L., Monnereau, Claire, Morgen, Camilla S., Morris, Andrew P., Murray, Jeffrey C., Myhre, Ronny, Najman, Jackob M., Nivard, Michel G., Nohr, Ellen A., Nolte, Ilja M., Ntalla, Ioanna, O'Reilly, Paul, Oberfield, Sharon E., Oken, Emily, Oldehinkel, Albertine J., Pahkala, Katja, Palviainen, Teemu, Panoutsopoulou, Kalliope, Pedersen, Oluf, Pennell, Craig E., Pershagen, Goran, Pitkanen, Niina, Plomin, Robert, Power, Christine, Prasad, Rashmi B., Prokopenko, Inga, Pulkkinen, Lea, Raikkonen, Katri, Raitakari, Olli T., Reynolds, Rebecca M., Richmond, Rebecca C., Rivadeneira, Fernando, Rodriguez, Alina, Rose, Richard J., Salem, Rany, Santa-Marina, Loreto, Saw, Seang-Mei, Schnurr, Theresia M., Scott, James G., Selzam, Saskia, Shepherd, John A., Simpson, Angela, Skotte, Line, Sleiman, Patrick M. A., Snieder, Harold, Sørensen, Thorkild I. A., Standl, Marie, Steegers, Eric A. P., Strachan, David P., Straker, Leon, Strandberg, Timo, Taylor, Michelle, Teo, Yik-Ying, Thiering, Elisabeth, Torrent, Maties, Tyrrell, Jessica, Uitterlinden, Andre G., van Beijsterveldt, Toos, van der Most, Peter J., van Duijn, Cornelia M., Viikari, Jorma, Vilor-Tejedor, Natalia, Vogelezang, Suzanne, Vonk, Judith M., Vrijkotte, Tanja G. M., Vuoksimaa, Eero, Wang, Carol A., Watkins, William J., Wichmann, H-Erich, Willemsen, Gonneke, Williams, Gail M., Wilson, James F., Wray, Naomi R., Xu, Shujing, Xu, Cheng-Jian, Yaghootkar, Hanieh, Yi, Lu, Zafarmand, Mohammad Hadi, Zeggini, Eleftheria, Zemel, Babette S., Hinney, Anke, Lakka, Timo A., Whitehouse, Andrew J. O., Sunyer, Jordi, Widen, Elisabeth E., Feenstra, Bjarke, Sebert, Sylvain, Jacobsson, Bo, Njolstad, Pal R., Stoltenberg, Camilla, Smith, George Davey, Lawlor, Debbie A., Paternoster, Lavinia, Timpson, Nicholas J., Ong, Ken K., Bisgaard, Hans, Bonnelykke, Klaus, Jaddoe, Vincent W. V., Tiemeier, Henning, Jarvelin, Marjo-Riitta, Evans, David M., Perry, John R. B., Grant, Struan F. A., Boomsma, Dorret I., Freathy, Rachel M., McCarthy, Mark I., Felix, Janine F., Sorensen, Thorkild I. A., Tiemeier, Hen-Ning, Middeldorp, Christel M., Mahajan, Anubha, Horikoshi, Momoko, Robertson, Neil R., Beaumont, Robin N., Bradfield, Jonathan P., Bustamante, Mariona, Cousminer, Diana L., Day, Felix R., De Silva, N. Maneka, Guxens, Monica, Mook-Kanamori, Dennis O., St Pourcain, Beate, Warrington, Nicole M., Adair, Linda S., Ahlqvist, Emma, Ahluwalia, Tarunveer S., Almgren, Peter, Ang, Wei, Atalay, Mustafa, Auvinen, Juha, Bartels, Meike, Beckmann, Jacques S., Bilbao, Jose Ramon, Bond, Tom, Borja, Judith B., Cavadino, Alana, Charoen, Pimphen, Chen, Zhanghua, Coin, Lachlan, Cooper, Cyrus, Curtin, John A., Custovic, Adnan, Das, Shikta, Davies, Gareth E., Dedoussis, George V., Duijts, Liesbeth, Eastwood, Peter R., Eliasen, Anders U., Elliott, Paul, Eriksson, Johan G., Estivill, Xavier, Fadista, Joao, Fedko, Iryna O., Frayling, Timothy M., Gaillard, Romy, Gauderman, W. James, Geller, Frank, Gilliland, Frank, Gilsanz, Vincente, Granell, Raquel, Grarup, Niels, Groop, Leif, Hadley, Dexter, Hakonarson, Hakon, Hansen, Torben, Hartman, Catharina A., Hattersley, Andrew T., Hayes, M. Geoffrey, Hebebrand, Johannes, Heinrich, Joachim, Helgeland, Oyvind, Henders, Anjali K., Henderson, John, Henriksen, Tine B., Hirschhorn, Joel N., Hivert, Marie-France, Hocher, Berthold, Holloway, John W., Holt, Patrick, Hottenga, Jouke-Jan, Hypponen, Elina, Iniguez, Carmen, Johansson, Stefan, Jugessur, Astanand, Kahonen, Mika, Kalkwarf, Heidi J., Kaprio, Jaakko, Karhunen, Ville, Kemp, John P., Kerkhof, Marjan, Koppelman, Gerard H., Korner, Antje, Kotecha, Sailesh, Kreiner-Moller, Eskil, Kulohoma, Benard, Kumar, Ashish, Kutalik, Zoltan, Lahti, Jari, Lappe, Joan M., Larsson, Henrik, Lehtimaki, Terho, Lewin, Alexandra M., Li, Jin, Lichtenstein, Paul, Lindgren, Cecilia M., Lindi, Virpi, Linneberg, Allan, Liu, Xueping, Liu, Jun, Lowe, William L., Jr., Lundstrom, Sebastian, Lyytikainen, Leo-Pekka, Ma, Ronald C. W., Mace, Aurelien, Magi, Reedik, Magnus, Per, Mamun, Abdullah A., Mannikko, Minna, Martin, Nicholas G., Mbarek, Hamdi, McCarthy, Nina S., Medland, Sarah E., Melbye, Mads, Melen, Erik, Mohlke, Karen L., Monnereau, Claire, Morgen, Camilla S., Morris, Andrew P., Murray, Jeffrey C., Myhre, Ronny, Najman, Jackob M., Nivard, Michel G., Nohr, Ellen A., Nolte, Ilja M., Ntalla, Ioanna, O'Reilly, Paul, Oberfield, Sharon E., Oken, Emily, Oldehinkel, Albertine J., Pahkala, Katja, Palviainen, Teemu, Panoutsopoulou, Kalliope, Pedersen, Oluf, Pennell, Craig E., Pershagen, Goran, Pitkanen, Niina, Plomin, Robert, Power, Christine, Prasad, Rashmi B., Prokopenko, Inga, Pulkkinen, Lea, Raikkonen, Katri, Raitakari, Olli T., Reynolds, Rebecca M., Richmond, Rebecca C., Rivadeneira, Fernando, Rodriguez, Alina, Rose, Richard J., Salem, Rany, Santa-Marina, Loreto, Saw, Seang-Mei, Schnurr, Theresia M., Scott, James G., Selzam, Saskia, Shepherd, John A., Simpson, Angela, Skotte, Line, Sleiman, Patrick M. A., Snieder, Harold, Sørensen, Thorkild I. A., Standl, Marie, Steegers, Eric A. P., Strachan, David P., Straker, Leon, Strandberg, Timo, Taylor, Michelle, Teo, Yik-Ying, Thiering, Elisabeth, Torrent, Maties, Tyrrell, Jessica, Uitterlinden, Andre G., van Beijsterveldt, Toos, van der Most, Peter J., van Duijn, Cornelia M., Viikari, Jorma, Vilor-Tejedor, Natalia, Vogelezang, Suzanne, Vonk, Judith M., Vrijkotte, Tanja G. M., Vuoksimaa, Eero, Wang, Carol A., Watkins, William J., Wichmann, H-Erich, Willemsen, Gonneke, Williams, Gail M., Wilson, James F., Wray, Naomi R., Xu, Shujing, Xu, Cheng-Jian, Yaghootkar, Hanieh, Yi, Lu, Zafarmand, Mohammad Hadi, Zeggini, Eleftheria, Zemel, Babette S., Hinney, Anke, Lakka, Timo A., Whitehouse, Andrew J. O., Sunyer, Jordi, Widen, Elisabeth E., Feenstra, Bjarke, Sebert, Sylvain, Jacobsson, Bo, Njolstad, Pal R., Stoltenberg, Camilla, Smith, George Davey, Lawlor, Debbie A., Paternoster, Lavinia, Timpson, Nicholas J., Ong, Ken K., Bisgaard, Hans, Bonnelykke, Klaus, Jaddoe, Vincent W. V., Tiemeier, Henning, Jarvelin, Marjo-Riitta, Evans, David M., Perry, John R. B., Grant, Struan F. A., Boomsma, Dorret I., Freathy, Rachel M., McCarthy, Mark I., Felix, Janine F., Sorensen, Thorkild I. A., and Tiemeier, Hen-Ning
Published: 2019

35. Diagnosis of Kawasaki Disease Using a Minimal Whole-Blood Gene Expression Signature.

Author: Wright, Victoria J, Wright, Victoria J, Herberg, Jethro A, Kaforou, Myrsini, Shimizu, Chisato, Eleftherohorinou, Hariklia, Shailes, Hannah, Barendregt, Anouk M, Menikou, Stephanie, Gormley, Stuart, Berk, Maurice, Hoang, Long Truong, Tremoulet, Adriana H, Kanegaye, John T, Coin, Lachlan JM, Glodé, Mary P, Hibberd, Martin, Kuijpers, Taco W, Hoggart, Clive J, Burns, Jane C, Levin, Michael, Immunopathology of Respiratory, Inflammatory and Infectious Disease Study (IRIS) Consortium and the Pediatric Emergency Medicine Kawasaki Disease Research Group (PEMKDRG), Wright, Victoria J, Wright, Victoria J, Herberg, Jethro A, Kaforou, Myrsini, Shimizu, Chisato, Eleftherohorinou, Hariklia, Shailes, Hannah, Barendregt, Anouk M, Menikou, Stephanie, Gormley, Stuart, Berk, Maurice, Hoang, Long Truong, Tremoulet, Adriana H, Kanegaye, John T, Coin, Lachlan JM, Glodé, Mary P, Hibberd, Martin, Kuijpers, Taco W, Hoggart, Clive J, Burns, Jane C, Levin, Michael, and Immunopathology of Respiratory, Inflammatory and Infectious Disease Study (IRIS) Consortium and the Pediatric Emergency Medicine Kawasaki Disease Research Group (PEMKDRG)
Abstract: ImportanceTo date, 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.ObjectiveTo identify a whole-blood gene expression signature that distinguishes children with KD in the first week of illness from other febrile conditions.Design, setting, and participantsThe case-control study comprised a discovery group that included a training and test set and a validation group of children with KD or comparator febrile illness. The setting was pediatric centers in the United Kingdom, Spain, the Netherlands, and the United States. The training and test discovery group comprised 404 children with infectious and inflammatory conditions (78 KD, 84 other inflammatory diseases, and 242 bacterial or viral infections) and 55 healthy controls. The independent validation group comprised 102 patients with KD, including 72 in the first 7 days of illness, and 130 febrile controls. The study dates were March 1, 2009, to November 14, 2013, and data analysis took place from January 1, 2015, to December 31, 2017.Main outcomes and measuresWhole-blood gene expression was evaluated using microarrays, and minimal transcript sets distinguishing KD were identified using a novel variable selection method (parallel regularized regression model search). 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 the Youden index.ResultsAmong 404 patients in the discovery set, there were 78 with KD (median age, 27 months; 55.1% male) and 326 febrile controls (median age, 37 months; 56.4% male). Among 202 patients in the validation set, there were 72 with KD (median age, 34 months; 62.5% male) and 130 febrile controls (median age, 17 months; 56.9% male). A 13-t
Published: 2018

36. Diagnosis of Kawasaki Disease Using a Minimal Whole-Blood Gene Expression Signature.

Author: Wright, Victoria J, Wright, Victoria J, Herberg, Jethro A, Kaforou, Myrsini, Shimizu, Chisato, Eleftherohorinou, Hariklia, Shailes, Hannah, Barendregt, Anouk M, Menikou, Stephanie, Gormley, Stuart, Berk, Maurice, Hoang, Long Truong, Tremoulet, Adriana H, Kanegaye, John T, Coin, Lachlan JM, Glodé, Mary P, Hibberd, Martin, Kuijpers, Taco W, Hoggart, Clive J, Burns, Jane C, Levin, Michael, Immunopathology of Respiratory, Inflammatory and Infectious Disease Study (IRIS) Consortium and the Pediatric Emergency Medicine Kawasaki Disease Research Group (PEMKDRG), Wright, Victoria J, Wright, Victoria J, Herberg, Jethro A, Kaforou, Myrsini, Shimizu, Chisato, Eleftherohorinou, Hariklia, Shailes, Hannah, Barendregt, Anouk M, Menikou, Stephanie, Gormley, Stuart, Berk, Maurice, Hoang, Long Truong, Tremoulet, Adriana H, Kanegaye, John T, Coin, Lachlan JM, Glodé, Mary P, Hibberd, Martin, Kuijpers, Taco W, Hoggart, Clive J, Burns, Jane C, Levin, Michael, and Immunopathology of Respiratory, Inflammatory and Infectious Disease Study (IRIS) Consortium and the Pediatric Emergency Medicine Kawasaki Disease Research Group (PEMKDRG)
Abstract: ImportanceTo date, 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.ObjectiveTo identify a whole-blood gene expression signature that distinguishes children with KD in the first week of illness from other febrile conditions.Design, setting, and participantsThe case-control study comprised a discovery group that included a training and test set and a validation group of children with KD or comparator febrile illness. The setting was pediatric centers in the United Kingdom, Spain, the Netherlands, and the United States. The training and test discovery group comprised 404 children with infectious and inflammatory conditions (78 KD, 84 other inflammatory diseases, and 242 bacterial or viral infections) and 55 healthy controls. The independent validation group comprised 102 patients with KD, including 72 in the first 7 days of illness, and 130 febrile controls. The study dates were March 1, 2009, to November 14, 2013, and data analysis took place from January 1, 2015, to December 31, 2017.Main outcomes and measuresWhole-blood gene expression was evaluated using microarrays, and minimal transcript sets distinguishing KD were identified using a novel variable selection method (parallel regularized regression model search). 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 the Youden index.ResultsAmong 404 patients in the discovery set, there were 78 with KD (median age, 27 months; 55.1% male) and 326 febrile controls (median age, 37 months; 56.4% male). Among 202 patients in the validation set, there were 72 with KD (median age, 34 months; 62.5% male) and 130 febrile controls (median age, 17 months; 56.9% male). A 13-t
Published: 2018

37. Diagnostic Test Accuracy of a 2-Transcript Host RNA Signature for Discriminating Bacterial vs Viral Infection in Febrile Children.

Author: Herberg, Jethro A, Herberg, Jethro A, Kaforou, Myrsini, Wright, Victoria J, Shailes, Hannah, Eleftherohorinou, Hariklia, Hoggart, Clive J, Cebey-López, Miriam, Carter, Michael J, Janes, Victoria A, Gormley, Stuart, Shimizu, Chisato, Tremoulet, Adriana H, Barendregt, Anouk M, Salas, Antonio, Kanegaye, John, Pollard, Andrew J, Faust, Saul N, Patel, Sanjay, Kuijpers, Taco, Martinón-Torres, Federico, Burns, Jane C, Coin, Lachlan JM, Levin, Michael, IRIS Consortium, Herberg, Jethro A, Herberg, Jethro A, Kaforou, Myrsini, Wright, Victoria J, Shailes, Hannah, Eleftherohorinou, Hariklia, Hoggart, Clive J, Cebey-López, Miriam, Carter, Michael J, Janes, Victoria A, Gormley, Stuart, Shimizu, Chisato, Tremoulet, Adriana H, Barendregt, Anouk M, Salas, Antonio, Kanegaye, John, Pollard, Andrew J, Faust, Saul N, Patel, Sanjay, Kuijpers, Taco, Martinón-Torres, Federico, Burns, Jane C, Coin, Lachlan JM, Levin, Michael, and IRIS Consortium
Abstract: ImportanceBecause clinical features do not reliably distinguish bacterial from viral infection, many children worldwide receive unnecessary antibiotic treatment, while bacterial infection is missed in others.ObjectiveTo identify a blood RNA expression signature that distinguishes bacterial from viral infection in febrile children.Design, setting, and participantsFebrile 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.ExposuresA 2-transcript RNA expression signature distinguishing bacterial infection from viral infection was evaluated against clinical and microbiological diagnosis.Main outcomes and measuresDefinite 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.ResultsThe 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 (2-transcript) signature (FAM89A and IFI44L)
Published: 2016

38. Open Letter to The American Association for the Advancement of Science

Author: Tennant, Jonathan P, Poisot, Timothée, Kubke, M Fabiana, Michonneau, François, Taylor, Michael P, Steel, Graham, Anquetin, Jérémy, Coyte, Emily, Schwessinger, Benjamin, McKiernan, Erin C, Pollard, Tom, Eckert, Aimee, Allen, Liz, Chawla, Dalmeet Singh, Silva, Elizabeth, Gardner, Nicholas, Cantley, Nathan, Dupuis, John, Pikas, Christina, Buckland, Amy, Teytelman, Lenny, Faulkes, Zen, Gay, Robert J, Brett, Peter TB, Eklund, Anders, Björk, Johannes, Gunn, William, Desjardins-Proulx, Philippe, Nicholson, Joshua M, Edmunds, Scott, Ray Wilson, Steven, Buck, Stuart, Aksoy, B Arman, Fatima, Nazeefa, Mounce, Ross, Piwowar, Heather, Thirumalai, Avinash, Priem, Jason, Aldern, Clayton, Hanwell, Marcus D, Marhaver, Kristen L, Roberts, David Michael, Hole, Brian, Grossmann, Alexander, Vaux, David L, Murtagh, John, Carter, Alecia, Holcombe, Alex O, Aleman, Ignacio Torres, Molloy, Sarah, Lamp, John, Todd, Matthew, Seneviratne, Anusha, Guidotti, Guido, McArthur, Joseph, Grohmann, Carlos H, Leeuw, Jan de, Choi, Jung H, Priego, Ernesto, Pasley, Brian, Konkiel, Stacy, Hellen, Elizabeth HB, Levy, Raphael, Coxon, Paul, Pai, Nitika Pant, Carroll, David, Dávila, Jacinto, Herrera-Valdez, Marco Arieli, Alperin, Juan Pablo, de Ruiter, Jan P, Chen, Xianwen, Hatherill, Jeanette, Mullen, Katharine, Bekinschtein, Pedro, Groom, Quentin, Meijer-Kline, Karen, Gatti-Lafranconi, Pietro, Hollister, Jeffrey, Coin, Lachlan, Choi, MooYoung, Patterson-Lomba, Oscar, Ball, Rowena, Swan, Daniel, Curry, Stephen, Noyce, Abigail, Ward, Jordan, Meghreblian, Ben, White, Ethan P, Mulcahy, Sean R, Fausto, Sibele, Barba, Lorena A, Trollope, Ed, Beckett, Stephen, Steen, Andrew D, Sarv, Mari, Ross, Noam, Amir, Erika, Eve, Martin Paul, Cecchi, Franco, Colditz, Jason B, Spear, Philip, Menon, Mythili, Clapham, Matthew, Broman, Karl W, Triggs, Graham, Crick, Tom, Marrone, Diano F, Kraus, Joseph, Buyske, Steven, Simpson, Gavin, Morgan, Colleen, Woo, Kara, Tennant, Jonathan P, Poisot, Timothée, Kubke, M Fabiana, Michonneau, François, Taylor, Michael P, Steel, Graham, Anquetin, Jérémy, Coyte, Emily, Schwessinger, Benjamin, McKiernan, Erin C, Pollard, Tom, Eckert, Aimee, Allen, Liz, Chawla, Dalmeet Singh, Silva, Elizabeth, Gardner, Nicholas, Cantley, Nathan, Dupuis, John, Pikas, Christina, Buckland, Amy, Teytelman, Lenny, Faulkes, Zen, Gay, Robert J, Brett, Peter TB, Eklund, Anders, Björk, Johannes, Gunn, William, Desjardins-Proulx, Philippe, Nicholson, Joshua M, Edmunds, Scott, Ray Wilson, Steven, Buck, Stuart, Aksoy, B Arman, Fatima, Nazeefa, Mounce, Ross, Piwowar, Heather, Thirumalai, Avinash, Priem, Jason, Aldern, Clayton, Hanwell, Marcus D, Marhaver, Kristen L, Roberts, David Michael, Hole, Brian, Grossmann, Alexander, Vaux, David L, Murtagh, John, Carter, Alecia, Holcombe, Alex O, Aleman, Ignacio Torres, Molloy, Sarah, Lamp, John, Todd, Matthew, Seneviratne, Anusha, Guidotti, Guido, McArthur, Joseph, Grohmann, Carlos H, Leeuw, Jan de, Choi, Jung H, Priego, Ernesto, Pasley, Brian, Konkiel, Stacy, Hellen, Elizabeth HB, Levy, Raphael, Coxon, Paul, Pai, Nitika Pant, Carroll, David, Dávila, Jacinto, Herrera-Valdez, Marco Arieli, Alperin, Juan Pablo, de Ruiter, Jan P, Chen, Xianwen, Hatherill, Jeanette, Mullen, Katharine, Bekinschtein, Pedro, Groom, Quentin, Meijer-Kline, Karen, Gatti-Lafranconi, Pietro, Hollister, Jeffrey, Coin, Lachlan, Choi, MooYoung, Patterson-Lomba, Oscar, Ball, Rowena, Swan, Daniel, Curry, Stephen, Noyce, Abigail, Ward, Jordan, Meghreblian, Ben, White, Ethan P, Mulcahy, Sean R, Fausto, Sibele, Barba, Lorena A, Trollope, Ed, Beckett, Stephen, Steen, Andrew D, Sarv, Mari, Ross, Noam, Amir, Erika, Eve, Martin Paul, Cecchi, Franco, Colditz, Jason B, Spear, Philip, Menon, Mythili, Clapham, Matthew, Broman, Karl W, Triggs, Graham, Crick, Tom, Marrone, Diano F, Kraus, Joseph, Buyske, Steven, Simpson, Gavin, Morgan, Colleen, and Woo, Kara
Published: 2014

39. Open Letter to The American Association for the Advancement of Science

Author: Tennant, Jonathan P, Poisot, Timothée, Kubke, M Fabiana, Michonneau, François, Taylor, Michael P, Steel, Graham, Anquetin, Jérémy, Coyte, Emily, Schwessinger, Benjamin, McKiernan, Erin C, Pollard, Tom, Eckert, Aimee, Allen, Liz, Chawla, Dalmeet Singh, Silva, Elizabeth, Gardner, Nicholas, Cantley, Nathan, Dupuis, John, Pikas, Christina, Buckland, Amy, Teytelman, Lenny, Faulkes, Zen, Gay, Robert J, Brett, Peter TB, Eklund, Anders, Björk, Johannes, Gunn, William, Desjardins-Proulx, Philippe, Nicholson, Joshua M, Edmunds, Scott, Ray Wilson, Steven, Buck, Stuart, Aksoy, B Arman, Fatima, Nazeefa, Mounce, Ross, Piwowar, Heather, Thirumalai, Avinash, Priem, Jason, Aldern, Clayton, Hanwell, Marcus D, Marhaver, Kristen L, Roberts, David Michael, Hole, Brian, Grossmann, Alexander, Vaux, David L, Murtagh, John, Carter, Alecia, Holcombe, Alex O, Aleman, Ignacio Torres, Molloy, Sarah, Lamp, John, Todd, Matthew, Seneviratne, Anusha, Guidotti, Guido, McArthur, Joseph, Grohmann, Carlos H, Leeuw, Jan de, Choi, Jung H, Priego, Ernesto, Pasley, Brian, Konkiel, Stacy, Hellen, Elizabeth HB, Levy, Raphael, Coxon, Paul, Pai, Nitika Pant, Carroll, David, Dávila, Jacinto, Herrera-Valdez, Marco Arieli, Alperin, Juan Pablo, de Ruiter, Jan P, Chen, Xianwen, Hatherill, Jeanette, Mullen, Katharine, Bekinschtein, Pedro, Groom, Quentin, Meijer-Kline, Karen, Gatti-Lafranconi, Pietro, Hollister, Jeffrey, Coin, Lachlan, Choi, MooYoung, Patterson-Lomba, Oscar, Ball, Rowena, Swan, Daniel, Curry, Stephen, Noyce, Abigail, Ward, Jordan, Meghreblian, Ben, White, Ethan P, Mulcahy, Sean R, Fausto, Sibele, Barba, Lorena A, Trollope, Ed, Beckett, Stephen, Steen, Andrew D, Sarv, Mari, Ross, Noam, Amir, Erika, Eve, Martin Paul, Cecchi, Franco, Colditz, Jason B, Spear, Philip, Menon, Mythili, Clapham, Matthew, Broman, Karl W, Triggs, Graham, Crick, Tom, Marrone, Diano F, Kraus, Joseph, Buyske, Steven, Simpson, Gavin, Morgan, Colleen, Woo, Kara, Tennant, Jonathan P, Poisot, Timothée, Kubke, M Fabiana, Michonneau, François, Taylor, Michael P, Steel, Graham, Anquetin, Jérémy, Coyte, Emily, Schwessinger, Benjamin, McKiernan, Erin C, Pollard, Tom, Eckert, Aimee, Allen, Liz, Chawla, Dalmeet Singh, Silva, Elizabeth, Gardner, Nicholas, Cantley, Nathan, Dupuis, John, Pikas, Christina, Buckland, Amy, Teytelman, Lenny, Faulkes, Zen, Gay, Robert J, Brett, Peter TB, Eklund, Anders, Björk, Johannes, Gunn, William, Desjardins-Proulx, Philippe, Nicholson, Joshua M, Edmunds, Scott, Ray Wilson, Steven, Buck, Stuart, Aksoy, B Arman, Fatima, Nazeefa, Mounce, Ross, Piwowar, Heather, Thirumalai, Avinash, Priem, Jason, Aldern, Clayton, Hanwell, Marcus D, Marhaver, Kristen L, Roberts, David Michael, Hole, Brian, Grossmann, Alexander, Vaux, David L, Murtagh, John, Carter, Alecia, Holcombe, Alex O, Aleman, Ignacio Torres, Molloy, Sarah, Lamp, John, Todd, Matthew, Seneviratne, Anusha, Guidotti, Guido, McArthur, Joseph, Grohmann, Carlos H, Leeuw, Jan de, Choi, Jung H, Priego, Ernesto, Pasley, Brian, Konkiel, Stacy, Hellen, Elizabeth HB, Levy, Raphael, Coxon, Paul, Pai, Nitika Pant, Carroll, David, Dávila, Jacinto, Herrera-Valdez, Marco Arieli, Alperin, Juan Pablo, de Ruiter, Jan P, Chen, Xianwen, Hatherill, Jeanette, Mullen, Katharine, Bekinschtein, Pedro, Groom, Quentin, Meijer-Kline, Karen, Gatti-Lafranconi, Pietro, Hollister, Jeffrey, Coin, Lachlan, Choi, MooYoung, Patterson-Lomba, Oscar, Ball, Rowena, Swan, Daniel, Curry, Stephen, Noyce, Abigail, Ward, Jordan, Meghreblian, Ben, White, Ethan P, Mulcahy, Sean R, Fausto, Sibele, Barba, Lorena A, Trollope, Ed, Beckett, Stephen, Steen, Andrew D, Sarv, Mari, Ross, Noam, Amir, Erika, Eve, Martin Paul, Cecchi, Franco, Colditz, Jason B, Spear, Philip, Menon, Mythili, Clapham, Matthew, Broman, Karl W, Triggs, Graham, Crick, Tom, Marrone, Diano F, Kraus, Joseph, Buyske, Steven, Simpson, Gavin, Morgan, Colleen, and Woo, Kara
Published: 2014

40. Open Letter to The American Association for the Advancement of Science

Author: Tennant, Jonathan P, Poisot, Timothée, Kubke, M Fabiana, Michonneau, François, Taylor, Michael P, Steel, Graham, Anquetin, Jérémy, Coyte, Emily, Schwessinger, Benjamin, McKiernan, Erin C, Pollard, Tom, Eckert, Aimee, Allen, Liz, Chawla, Dalmeet Singh, Silva, Elizabeth, Gardner, Nicholas, Cantley, Nathan, Dupuis, John, Pikas, Christina, Buckland, Amy, Teytelman, Lenny, Faulkes, Zen, Gay, Robert J, Brett, Peter TB, Eklund, Anders, Björk, Johannes, Gunn, William, Desjardins-Proulx, Philippe, Nicholson, Joshua M, Edmunds, Scott, Ray Wilson, Steven, Buck, Stuart, Aksoy, B Arman, Fatima, Nazeefa, Mounce, Ross, Piwowar, Heather, Thirumalai, Avinash, Priem, Jason, Aldern, Clayton, Hanwell, Marcus D, Marhaver, Kristen L, Roberts, David Michael, Hole, Brian, Grossmann, Alexander, Vaux, David L, Murtagh, John, Carter, Alecia, Holcombe, Alex O, Aleman, Ignacio Torres, Molloy, Sarah, Lamp, John, Todd, Matthew, Seneviratne, Anusha, Guidotti, Guido, McArthur, Joseph, Grohmann, Carlos H, Leeuw, Jan de, Choi, Jung H, Priego, Ernesto, Pasley, Brian, Konkiel, Stacy, Hellen, Elizabeth HB, Levy, Raphael, Coxon, Paul, Pai, Nitika Pant, Carroll, David, Dávila, Jacinto, Herrera-Valdez, Marco Arieli, Alperin, Juan Pablo, de Ruiter, Jan P, Chen, Xianwen, Hatherill, Jeanette, Mullen, Katharine, Bekinschtein, Pedro, Groom, Quentin, Meijer-Kline, Karen, Gatti-Lafranconi, Pietro, Hollister, Jeffrey, Coin, Lachlan, Choi, MooYoung, Patterson-Lomba, Oscar, Ball, Rowena, Swan, Daniel, Curry, Stephen, Noyce, Abigail, Ward, Jordan, Meghreblian, Ben, White, Ethan P, Mulcahy, Sean R, Fausto, Sibele, Barba, Lorena A, Trollope, Ed, Beckett, Stephen, Steen, Andrew D, Sarv, Mari, Ross, Noam, Amir, Erika, Eve, Martin Paul, Cecchi, Franco, Colditz, Jason B, Spear, Philip, Menon, Mythili, Clapham, Matthew, Broman, Karl W, Triggs, Graham, Crick, Tom, Marrone, Diano F, Kraus, Joseph, Buyske, Steven, Simpson, Gavin, Morgan, Colleen, Woo, Kara, Tennant, Jonathan P, Poisot, Timothée, Kubke, M Fabiana, Michonneau, François, Taylor, Michael P, Steel, Graham, Anquetin, Jérémy, Coyte, Emily, Schwessinger, Benjamin, McKiernan, Erin C, Pollard, Tom, Eckert, Aimee, Allen, Liz, Chawla, Dalmeet Singh, Silva, Elizabeth, Gardner, Nicholas, Cantley, Nathan, Dupuis, John, Pikas, Christina, Buckland, Amy, Teytelman, Lenny, Faulkes, Zen, Gay, Robert J, Brett, Peter TB, Eklund, Anders, Björk, Johannes, Gunn, William, Desjardins-Proulx, Philippe, Nicholson, Joshua M, Edmunds, Scott, Ray Wilson, Steven, Buck, Stuart, Aksoy, B Arman, Fatima, Nazeefa, Mounce, Ross, Piwowar, Heather, Thirumalai, Avinash, Priem, Jason, Aldern, Clayton, Hanwell, Marcus D, Marhaver, Kristen L, Roberts, David Michael, Hole, Brian, Grossmann, Alexander, Vaux, David L, Murtagh, John, Carter, Alecia, Holcombe, Alex O, Aleman, Ignacio Torres, Molloy, Sarah, Lamp, John, Todd, Matthew, Seneviratne, Anusha, Guidotti, Guido, McArthur, Joseph, Grohmann, Carlos H, Leeuw, Jan de, Choi, Jung H, Priego, Ernesto, Pasley, Brian, Konkiel, Stacy, Hellen, Elizabeth HB, Levy, Raphael, Coxon, Paul, Pai, Nitika Pant, Carroll, David, Dávila, Jacinto, Herrera-Valdez, Marco Arieli, Alperin, Juan Pablo, de Ruiter, Jan P, Chen, Xianwen, Hatherill, Jeanette, Mullen, Katharine, Bekinschtein, Pedro, Groom, Quentin, Meijer-Kline, Karen, Gatti-Lafranconi, Pietro, Hollister, Jeffrey, Coin, Lachlan, Choi, MooYoung, Patterson-Lomba, Oscar, Ball, Rowena, Swan, Daniel, Curry, Stephen, Noyce, Abigail, Ward, Jordan, Meghreblian, Ben, White, Ethan P, Mulcahy, Sean R, Fausto, Sibele, Barba, Lorena A, Trollope, Ed, Beckett, Stephen, Steen, Andrew D, Sarv, Mari, Ross, Noam, Amir, Erika, Eve, Martin Paul, Cecchi, Franco, Colditz, Jason B, Spear, Philip, Menon, Mythili, Clapham, Matthew, Broman, Karl W, Triggs, Graham, Crick, Tom, Marrone, Diano F, Kraus, Joseph, Buyske, Steven, Simpson, Gavin, Morgan, Colleen, and Woo, Kara
Published: 2014

41. Dysregulation of Complement System and CD4+T Cell Activation Pathways Implicated in Allergic Response

Author: Couto Alves, Alexessander, Bruhn, Sören, Ramasamy, Adaikalavan, Wang, Hui, Holloway, John W., Hartikainen, Anna-Liisa, Jarvelin, Marjo-Riitta, Benson, Mikael, Balding, David J., Coin, Lachlan J M., Couto Alves, Alexessander, Bruhn, Sören, Ramasamy, Adaikalavan, Wang, Hui, Holloway, John W., Hartikainen, Anna-Liisa, Jarvelin, Marjo-Riitta, Benson, Mikael, Balding, David J., and Coin, Lachlan J M.
Abstract: 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., Funding Agencies|European Commission|223367|Academy of Finland (Centre of Excellence in Complex Disease Genetics and SALVE)|1047811203151292691114194139900/24300796|University Hospital Oulu||Biocenter||University of Oulu|75617|NHLBI through STAMPEED program|5R01HL087679-021RL1MH083268-01|NIH/NIMH|5R01MH63706:02|ENGAGE project|HEALTH-F4-2007-201413|Medical Research Council, UK (PrevMetSyn/SALVE)||Academy of Finland||Biocentrum Helsinki
Published: 2013
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42. Dysregulation of Complement System and CD4+T Cell Activation Pathways Implicated in Allergic Response

Author: Couto Alves, Alexessander, Bruhn, Sören, Ramasamy, Adaikalavan, Wang, Hui, Holloway, John W., Hartikainen, Anna-Liisa, Jarvelin, Marjo-Riitta, Benson, Mikael, Balding, David J., Coin, Lachlan J M., Couto Alves, Alexessander, Bruhn, Sören, Ramasamy, Adaikalavan, Wang, Hui, Holloway, John W., Hartikainen, Anna-Liisa, Jarvelin, Marjo-Riitta, Benson, Mikael, Balding, David J., and Coin, Lachlan J M.
Abstract: 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., Funding Agencies|European Commission|223367|Academy of Finland (Centre of Excellence in Complex Disease Genetics and SALVE)|1047811203151292691114194139900/24300796|University Hospital Oulu||Biocenter||University of Oulu|75617|NHLBI through STAMPEED program|5R01HL087679-021RL1MH083268-01|NIH/NIMH|5R01MH63706:02|ENGAGE project|HEALTH-F4-2007-201413|Medical Research Council, UK (PrevMetSyn/SALVE)||Academy of Finland||Biocentrum Helsinki
Published: 2013
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43. Dysregulation of Complement System and CD4+T Cell Activation Pathways Implicated in Allergic Response

Author: Couto Alves, Alexessander, Bruhn, Sören, Ramasamy, Adaikalavan, Wang, Hui, Holloway, John W., Hartikainen, Anna-Liisa, Jarvelin, Marjo-Riitta, Benson, Mikael, Balding, David J., Coin, Lachlan J M., Couto Alves, Alexessander, Bruhn, Sören, Ramasamy, Adaikalavan, Wang, Hui, Holloway, John W., Hartikainen, Anna-Liisa, Jarvelin, Marjo-Riitta, Benson, Mikael, Balding, David J., and Coin, Lachlan J M.
Abstract: 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., Funding Agencies|European Commission|223367|Academy of Finland (Centre of Excellence in Complex Disease Genetics and SALVE)|1047811203151292691114194139900/24300796|University Hospital Oulu||Biocenter||University of Oulu|75617|NHLBI through STAMPEED program|5R01HL087679-021RL1MH083268-01|NIH/NIMH|5R01MH63706:02|ENGAGE project|HEALTH-F4-2007-201413|Medical Research Council, UK (PrevMetSyn/SALVE)||Academy of Finland||Biocentrum Helsinki
Published: 2013
Full Text: View/download PDF

44. Dysregulation of Complement System and CD4+T Cell Activation Pathways Implicated in Allergic Response

Author: Couto Alves, Alexessander, Bruhn, Sören, Ramasamy, Adaikalavan, Wang, Hui, Holloway, John W., Hartikainen, Anna-Liisa, Jarvelin, Marjo-Riitta, Benson, Mikael, Balding, David J., Coin, Lachlan J M., Couto Alves, Alexessander, Bruhn, Sören, Ramasamy, Adaikalavan, Wang, Hui, Holloway, John W., Hartikainen, Anna-Liisa, Jarvelin, Marjo-Riitta, Benson, Mikael, Balding, David J., and Coin, Lachlan J M.
Abstract: 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., Funding Agencies|European Commission|223367|Academy of Finland (Centre of Excellence in Complex Disease Genetics and SALVE)|1047811203151292691114194139900/24300796|University Hospital Oulu||Biocenter||University of Oulu|75617|NHLBI through STAMPEED program|5R01HL087679-021RL1MH083268-01|NIH/NIMH|5R01MH63706:02|ENGAGE project|HEALTH-F4-2007-201413|Medical Research Council, UK (PrevMetSyn/SALVE)||Academy of Finland||Biocentrum Helsinki
Published: 2013
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45. Meta-analysis of genome-wide association studies identifies ten loci influencing allergic sensitization

Author: Bønnelykke, Klaus, Matheson, Melanie C, Pers, Tune H, Granell, Raquel, Strachan, David P, Alves, Alexessander Couto, Linneberg, Allan, Curtin, John A, Warrington, Nicole M, Standl, Marie, Kerkhof, Marjan, Jonsdottir, Ingileif, Bukvic, Blazenka K, Kaakinen, Marika, Sleimann, Patrick, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Schramm, Katharina, Baltic, Svetlana, Kreiner-Møller, Eskil, Simpson, Angela, Pourcain, Beate St, Coin, Lachlan, Hui, Jennie, Walters, Eugene H, Tiesler, Carla M T, Duffy, David L, Jones, Graham, Ring, Susan M, McArdle, Wendy L, Price, Loren, Robertson, Colin F, Pekkanen, Juha, Tang, Clara S, Thiering, Elisabeth, Montgomery, Grant W, Hartikainen, Anna-Liisa, Dharmage, Shyamali C, Husemoen, Lise L, Herder, Christian, Kemp, John P, Elliot, Paul, James, Alan, Waldenberger, Melanie, Abramson, Michael J, Fairfax, Benjamin P, Knight, Julian C, Gupta, Ramneek, Thompson, Philip J, Holt, Patrick, Sly, Peter, Hirschhorn, Joel N, Blekic, Mario, Weidinger, Stephan, Hakonarsson, Hakon, Stefansson, Kari, Heinrich, Joachim, Postma, Dirkje S, Custovic, Adnan, Pennell, Craig E, Jarvelin, Marjo-Riitta, Koppelman, Gerard H, Timpson, Nicholas, Ferreira, Manuel A, Bisgaard, Hans, Henderson, A John, (AAGC), Australian Asthma Genetics Consortium, Bønnelykke, Klaus, Matheson, Melanie C, Pers, Tune H, Granell, Raquel, Strachan, David P, Alves, Alexessander Couto, Linneberg, Allan, Curtin, John A, Warrington, Nicole M, Standl, Marie, Kerkhof, Marjan, Jonsdottir, Ingileif, Bukvic, Blazenka K, Kaakinen, Marika, Sleimann, Patrick, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Schramm, Katharina, Baltic, Svetlana, Kreiner-Møller, Eskil, Simpson, Angela, Pourcain, Beate St, Coin, Lachlan, Hui, Jennie, Walters, Eugene H, Tiesler, Carla M T, Duffy, David L, Jones, Graham, Ring, Susan M, McArdle, Wendy L, Price, Loren, Robertson, Colin F, Pekkanen, Juha, Tang, Clara S, Thiering, Elisabeth, Montgomery, Grant W, Hartikainen, Anna-Liisa, Dharmage, Shyamali C, Husemoen, Lise L, Herder, Christian, Kemp, John P, Elliot, Paul, James, Alan, Waldenberger, Melanie, Abramson, Michael J, Fairfax, Benjamin P, Knight, Julian C, Gupta, Ramneek, Thompson, Philip J, Holt, Patrick, Sly, Peter, Hirschhorn, Joel N, Blekic, Mario, Weidinger, Stephan, Hakonarsson, Hakon, Stefansson, Kari, Heinrich, Joachim, Postma, Dirkje S, Custovic, Adnan, Pennell, Craig E, Jarvelin, Marjo-Riitta, Koppelman, Gerard H, Timpson, Nicholas, Ferreira, Manuel A, Bisgaard, Hans, Henderson, A John, and (AAGC), Australian Asthma Genetics Consortium
Published: 2013

46. Dysregulation of Complement System and CD4+T Cell Activation Pathways Implicated in Allergic Response

Author: Couto Alves, Alexessander, Bruhn, Sören, Ramasamy, Adaikalavan, Wang, Hui, Holloway, John W., Hartikainen, Anna-Liisa, Jarvelin, Marjo-Riitta, Benson, Mikael, Balding, David J., Coin, Lachlan J M., Couto Alves, Alexessander, Bruhn, Sören, Ramasamy, Adaikalavan, Wang, Hui, Holloway, John W., Hartikainen, Anna-Liisa, Jarvelin, Marjo-Riitta, Benson, Mikael, Balding, David J., and Coin, Lachlan J M.
Abstract: 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., Funding Agencies|European Commission|223367|Academy of Finland (Centre of Excellence in Complex Disease Genetics and SALVE)|1047811203151292691114194139900/24300796|University Hospital Oulu||Biocenter||University of Oulu|75617|NHLBI through STAMPEED program|5R01HL087679-021RL1MH083268-01|NIH/NIMH|5R01MH63706:02|ENGAGE project|HEALTH-F4-2007-201413|Medical Research Council, UK (PrevMetSyn/SALVE)||Academy of Finland||Biocentrum Helsinki
Published: 2013
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47. Meta-analysis of genome-wide association studies identifies ten loci influencing allergic sensitization

Author: Bønnelykke, Klaus, Matheson, Melanie C, Pers, Tune H, Granell, Raquel, Strachan, David P, Alves, Alexessander Couto, Linneberg, Allan, Curtin, John A, Warrington, Nicole M, Standl, Marie, Kerkhof, Marjan, Jonsdottir, Ingileif, Bukvic, Blazenka K, Kaakinen, Marika, Sleimann, Patrick, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Schramm, Katharina, Baltic, Svetlana, Kreiner-Møller, Eskil, Simpson, Angela, Pourcain, Beate St, Coin, Lachlan, Hui, Jennie, Walters, Eugene H, Tiesler, Carla M T, Duffy, David L, Jones, Graham, Ring, Susan M, McArdle, Wendy L, Price, Loren, Robertson, Colin F, Pekkanen, Juha, Tang, Clara S, Thiering, Elisabeth, Montgomery, Grant W, Hartikainen, Anna-Liisa, Dharmage, Shyamali C, Husemoen, Lise L, Herder, Christian, Kemp, John P, Elliot, Paul, James, Alan, Waldenberger, Melanie, Abramson, Michael J, Fairfax, Benjamin P, Knight, Julian C, Gupta, Ramneek, Thompson, Philip J, Holt, Patrick, Sly, Peter, Hirschhorn, Joel N, Blekic, Mario, Weidinger, Stephan, Hakonarsson, Hakon, Stefansson, Kari, Heinrich, Joachim, Postma, Dirkje S, Custovic, Adnan, Pennell, Craig E, Jarvelin, Marjo-Riitta, Koppelman, Gerard H, Timpson, Nicholas, Ferreira, Manuel A, Bisgaard, Hans, Henderson, A John, (AAGC), Australian Asthma Genetics Consortium, Bønnelykke, Klaus, Matheson, Melanie C, Pers, Tune H, Granell, Raquel, Strachan, David P, Alves, Alexessander Couto, Linneberg, Allan, Curtin, John A, Warrington, Nicole M, Standl, Marie, Kerkhof, Marjan, Jonsdottir, Ingileif, Bukvic, Blazenka K, Kaakinen, Marika, Sleimann, Patrick, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Schramm, Katharina, Baltic, Svetlana, Kreiner-Møller, Eskil, Simpson, Angela, Pourcain, Beate St, Coin, Lachlan, Hui, Jennie, Walters, Eugene H, Tiesler, Carla M T, Duffy, David L, Jones, Graham, Ring, Susan M, McArdle, Wendy L, Price, Loren, Robertson, Colin F, Pekkanen, Juha, Tang, Clara S, Thiering, Elisabeth, Montgomery, Grant W, Hartikainen, Anna-Liisa, Dharmage, Shyamali C, Husemoen, Lise L, Herder, Christian, Kemp, John P, Elliot, Paul, James, Alan, Waldenberger, Melanie, Abramson, Michael J, Fairfax, Benjamin P, Knight, Julian C, Gupta, Ramneek, Thompson, Philip J, Holt, Patrick, Sly, Peter, Hirschhorn, Joel N, Blekic, Mario, Weidinger, Stephan, Hakonarsson, Hakon, Stefansson, Kari, Heinrich, Joachim, Postma, Dirkje S, Custovic, Adnan, Pennell, Craig E, Jarvelin, Marjo-Riitta, Koppelman, Gerard H, Timpson, Nicholas, Ferreira, Manuel A, Bisgaard, Hans, Henderson, A John, and (AAGC), Australian Asthma Genetics Consortium
Published: 2013

48. Genome-Wide Association Studies of Asthma in Population-Based Cohorts Confirm Known and Suggested Loci and Identify an Additional Association near HLA

Author: Ramasamy, Adaikalavan, Kuokkanen, Mikko, Vedantam, Sailaja, Gajdos, Zofia K., Alves, Alexessander Couto, Lyon, Helen N., Ferreira, Manuel A. R., Strachan, David P., Zhao, Jing Hua, Abramson, Michael J., Brown, Matthew A., Coin, Lachlan, Dharmage, Shyamali C., Duffy, David L., Haahtela, Tari, Heath, Andrew C., Janson, Christer, Kahonen, Mika, Khaw, Kay-Tee, Laitinen, Jaana, Le Souef, Peter, Lehtimaki, Terho, Madden, Pamela A. F., Marks, Guy B., Martin, Nicholas G., Matheson, Melanie C., Palmer, Cameron D., Palotie, Aarno, Pouta, Anneli, Robertson, Colin F., Viikari, Jorma, Widen, Elisabeth, Wjst, Matthias, Jarvis, Deborah L., Montgomery, Grant W., Thompson, Philip J., Wareham, Nick, Eriksson, Johan, Jousilahti, Pekka, Laitinen, Tarja, Pekkanen, Juha, Raitakari, Olli T., O'Connor, George T., Salomaa, Veikko, Jarvelin, Marjo-Riitta, Hirschhorn, Joel N., Ramasamy, Adaikalavan, Kuokkanen, Mikko, Vedantam, Sailaja, Gajdos, Zofia K., Alves, Alexessander Couto, Lyon, Helen N., Ferreira, Manuel A. R., Strachan, David P., Zhao, Jing Hua, Abramson, Michael J., Brown, Matthew A., Coin, Lachlan, Dharmage, Shyamali C., Duffy, David L., Haahtela, Tari, Heath, Andrew C., Janson, Christer, Kahonen, Mika, Khaw, Kay-Tee, Laitinen, Jaana, Le Souef, Peter, Lehtimaki, Terho, Madden, Pamela A. F., Marks, Guy B., Martin, Nicholas G., Matheson, Melanie C., Palmer, Cameron D., Palotie, Aarno, Pouta, Anneli, Robertson, Colin F., Viikari, Jorma, Widen, Elisabeth, Wjst, Matthias, Jarvis, Deborah L., Montgomery, Grant W., Thompson, Philip J., Wareham, Nick, Eriksson, Johan, Jousilahti, Pekka, Laitinen, Tarja, Pekkanen, Juha, Raitakari, Olli T., O'Connor, George T., Salomaa, Veikko, Jarvelin, Marjo-Riitta, and Hirschhorn, Joel N.
Abstract: Rationale: Asthma has substantial morbidity and mortality and a strong genetic component, but identification of genetic risk factors is limited by availability of suitable studies. Objectives: To test if population-based cohorts with self-reported physician-diagnosed asthma and genome-wide association (GWA) data could be used to validate known associations with asthma and identify novel associations. Methods: The APCAT (Analysis in Population-based Cohorts of Asthma Traits) consortium consists of 1,716 individuals with asthma and 16,888 healthy controls from six European-descent population-based cohorts. We examined associations in APCAT of thirteen variants previously reported as genome-wide significant (P < 5x10(-8)) and three variants reported as suggestive (P < 5 x 10(-7)). We also searched for novel associations in APCAT (Stage 1) and followed-up the most promising variants in 4,035 asthmatics and 11,251 healthy controls (Stage 2). Finally, we conducted the first genome-wide screen for interactions with smoking or hay fever. Main Results: We observed association in the same direction for all thirteen previously reported variants and nominally replicated ten of them. One variant that was previously suggestive, rs11071559 in RORA, now reaches genome-wide significance when combined with our data (P = 2.4x10(-9)). We also identified two genome-wide significant associations: rs13408661 near IL1RL1/IL18R1 (PStage1+Stage2 = 1.1x10(-9)), which is correlated with a variant recently shown to be associated with asthma (rs3771180), and rs9268516 in the HLA region (PStage1+Stage2 = 1.1x10(-8)), which appears to be independent of previously reported associations in this locus. Finally, we found no strong evidence for gene-environment interactions with smoking or hay fever status. Conclusions: Population-based cohorts with simple asthma phenotypes represent a valuable and largely untapped resource for genetic studies of asthma.
Published: 2012
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49. A genome-wide association search for type 2 diabetes genes in African Americans.

Author: Palmer, Nicholette D, McDonough, Caitrin W, Hicks, Pamela J, Roh, Bong H, Wing, Maria R, An, S Sandy, Hester, Jessica M, Cooke, Jessica N, Bostrom, Meredith A, Rudock, Megan E, Talbert, Matthew E, Lewis, Joshua P, Ferrara, Assiamira, Lu, Lingyi, Ziegler, Julie T, Sale, Michele M, Divers, Jasmin, Shriner, Daniel, Adeyemo, Adebowale, Rotimi, Charles N, Ng, Maggie C Y, Langefeld, Carl D, Freedman, Barry I, Bowden, Donald W, Voight, Benjamin F, Scott, Laura J, Steinthorsdottir, Valgerdur, Morris, Andrew P, Dina, Christian, Welch, Ryan P, Zeggini, Eleftheria, Huth, Cornelia, Aulchenko, Yurii S, Thorleifsson, Gudmar, McCulloch, Laura J, Ferreira, Teresa, Grallert, Harald, Amin, Najaf, Wu, Guanming, Willer, Cristen J, Raychaudhuri, Soumya, McCarroll, Steve A, Langenberg, Claudia, Hofmann, Oliver M, Dupuis, Josée, Qi, Lu, Segrè, Ayellet V, van Hoek, Mandy, Navarro, Pau, Ardlie, Kristin, Balkau, Beverley, Benediktsson, Rafn, Bennett, Amanda J, Blagieva, Roza, Boerwinkle, Eric, Bonnycastle, Lori L, Boström, Kristina Bengtsson, Bravenboer, Bert, Bumpstead, Suzannah, Burtt, Noël P, Charpentier, Guillaume, Chines, Peter S, Cornelis, Marilyn, Couper, David J, Crawford, Gabe, Doney, Alex S F, Elliott, Katherine S, Elliott, Amanda L, Erdos, Michael R, Fox, Caroline S, Franklin, Christopher S, Ganser, Martha, Gieger, Christian, Grarup, Niels, Green, Todd, Griffin, Simon, Groves, Christopher J, Guiducci, Candace, Hadjadj, Samy, Hassanali, Neelam, Herder, Christian, Isomaa, Bo, Jackson, Anne U, Johnson, Paul R V, Jørgensen, Torben, Kao, Wen H L, Klopp, Norman, Kong, Augustine, Kraft, Peter, Kuusisto, Johanna, Lauritzen, Torsten, Li, Man, Lieverse, Aloysius, Lindgren, Cecilia M, Lyssenko, Valeriya, Marre, Michel, Meitinger, Thomas, Midthjell, Kristian, Morken, Mario A, Narisu, Narisu, Nilsson, Peter, Owen, Katharine R, Payne, Felicity, Perry, John R B, Petersen, Ann-Kristin, Platou, Carl, Proença, Christine, Prokopenko, Inga, Rathmann, Wolfgang, Rayner, N William, Robertson, Neil R, Rocheleau, Ghislain, Roden, Michael, Sampson, Michael J, Saxena, Richa, Shields, Beverley M, Shrader, Peter, Sigurdsson, Gunnar, Sparsø, Thomas, Strassburger, Klaus, Stringham, Heather M, Sun, Qi, Swift, Amy J, Thorand, Barbara, Tichet, Jean, Tuomi, Tiinamaija, van Dam, Rob M, van Haeften, Timon W, van Herpt, Thijs, van Vliet-Ostaptchouk, Jana V, Walters, G Bragi, Weedon, Michael N, Wijmenga, Cisca, Witteman, Jacqueline, Bergman, Richard N, Cauchi, Stephane, Collins, Francis S, Gloyn, Anna L, Gyllensten, Ulf, Hansen, Torben, Hide, Winston A, Hitman, Graham A, Hofman, Albert, Hunter, David J, Hveem, Kristian, Laakso, Markku, Mohlke, Karen L, Morris, Andrew D, Palmer, Colin N A, Pramstaller, Peter P, Rudan, Igor, Sijbrands, Eric, Stein, Lincoln D, Tuomilehto, Jaakko, Uitterlinden, Andre, Walker, Mark, Wareham, Nicholas J, Watanabe, Richard M, Abecasis, Goncalo R, Boehm, Bernhard O, Campbell, Harry, Daly, Mark J, Hattersley, Andrew T, Hu, Frank B, Meigs, James B, Pankow, James S, Pedersen, Oluf, Wichmann, H-Erich, Barroso, Inês, Florez, Jose C, Frayling, Timothy M, Groop, Leif, Sladek, Rob, Thorsteinsdottir, Unnur, Wilson, James F, Illig, Thomas, Froguel, Philippe, van Duijn, Cornelia M, Stefansson, Kari, Altshuler, David, Boehnke, Michael, McCarthy, Mark I, Soranzo, Nicole, Wheeler, Eleanor, Glazer, Nicole L, Bouatia-Naji, Nabila, Mägi, Reedik, Randall, Joshua, Johnson, Toby, Elliott, Paul, Rybin, Denis, Henneman, Peter, Dehghan, Abbas, Hottenga, Jouke Jan, Song, Kijoung, Goel, Anuj, Egan, Josephine M, Lajunen, Taina, Doney, Alex, Kanoni, Stavroula, Cavalcanti-Proença, Christine, Kumari, Meena, Timpson, Nicholas J, Zabena, Carina, Ingelsson, Erik, An, Ping, O'Connell, Jeffrey, Luan, Jian'an, Elliott, Amanda, McCarroll, Steven A, Roccasecca, Rosa Maria, Pattou, François, Sethupathy, Praveen, Ariyurek, Yavuz, Barter, Philip, Beilby, John P, Ben-Shlomo, Yoav, Bergmann, Sven, Bochud, Murielle, Bonnefond, Amélie, Borch-Johnsen, Knut, Böttcher, Yvonne, Brunner, Eric, Bumpstead, Suzannah J, Chen, Yii-Der Ida, Chines, Peter, Clarke, Robert, Coin, Lachlan J M, Cooper, Matthew N, Crisponi, Laura, Day, Ian N M, de Geus, Eco J C, Delplanque, Jerome, Fedson, Annette C, Fischer-Rosinsky, Antje, Forouhi, Nita G, Frants, Rune, Franzosi, Maria Grazia, Galan, Pilar, Goodarzi, Mark O, Graessler, Jürgen, Grundy, Scott, Gwilliam, Rhian, Hallmans, Göran, Hammond, Naomi, Han, Xijing, Hartikainen, Anna-Liisa, Hayward, Caroline, Heath, Simon C, Hercberg, Serge, Hicks, Andrew A, Hillman, David R, Hingorani, Aroon D, Hui, Jennie, Hung, Joe, Jula, Antti, Kaakinen, Marika, Kaprio, Jaakko, Kesaniemi, Y Antero, Kivimaki, Mika, Knight, Beatrice, Koskinen, Seppo, Kovacs, Peter, Kyvik, Kirsten Ohm, Lathrop, G Mark, Lawlor, Debbie A, Le Bacquer, Olivier, Lecoeur, Cécile, Li, Yun, Mahley, Robert, Mangino, Massimo, Manning, Alisa K, Martínez-Larrad, María Teresa, McAteer, Jarred B, McPherson, Ruth, Meisinger, Christa, Melzer, David, Meyre, David, Mitchell, Braxton D, Mukherjee, Sutapa, Naitza, Silvia, Neville, Matthew J, Oostra, Ben A, Orrù, Marco, Pakyz, Ruth, Paolisso, Giuseppe, Pattaro, Cristian, Pearson, Daniel, Peden, John F, Pedersen, Nancy L, Perola, Markus, Pfeiffer, Andreas F H, Pichler, Irene, Polasek, Ozren, Posthuma, Danielle, Potter, Simon C, Pouta, Anneli, Province, Michael A, Psaty, Bruce M, Rayner, Nigel W, Rice, Kenneth, Ripatti, Samuli, Rivadeneira, Fernando, Rolandsson, Olov, Sandbaek, Annelli, Sandhu, Manjinder, Sanna, Serena, Sayer, Avan Aihie, Scheet, Paul, Seedorf, Udo, Sharp, Stephen J, Shields, Beverley, Sijbrands, Eric J G, Silveira, Angela, Simpson, Laila, Singleton, Andrew, Smith, Nicholas L, Sovio, Ulla, Swift, Amy, Syddall, Holly, Syvänen, Ann-Christine, Tanaka, Toshiko, Tönjes, Anke, Uitterlinden, André G, van Dijk, Ko Willems, Varma, Dhiraj, Visvikis-Siest, Sophie, Vitart, Veronique, Vogelzangs, Nicole, Waeber, Gérard, Wagner, Peter J, Walley, Andrew, Ward, Kim L, Watkins, Hugh, Wild, Sarah H, Willemsen, Gonneke, Witteman, Jaqueline C M, Yarnell, John W G, Zelenika, Diana, Zethelius, Björn, Zhai, Guangju, Zhao, Jing Hua, Zillikens, M Carola, Borecki, Ingrid B, Loos, Ruth J F, Meneton, Pierre, Magnusson, Patrik K E, Nathan, David M, Williams, Gordon H, Silander, Kaisa, Salomaa, Veikko, Smith, George Davey, Bornstein, Stefan R, Schwarz, Peter, Spranger, Joachim, Karpe, Fredrik, Shuldiner, Alan R, Cooper, Cyrus, Dedoussis, George V, Serrano-Ríos, Manuel, Lind, Lars, Palmer, Lyle J, Franks, Paul W, Ebrahim, Shah, Marmot, Michael, Kao, W H Linda, Pramstaller, Peter Paul, Wright, Alan F, Stumvoll, Michael, Hamsten, Anders, Buchanan, Thomas A, Valle, Timo T, Rotter, Jerome I, Siscovick, David S, Penninx, Brenda W J H, Boomsma, Dorret I, Deloukas, Panos, Spector, Timothy D, Ferrucci, Luigi, Cao, Antonio, Scuteri, Angelo, Schlessinger, David, Uda, Manuela, Ruokonen, Aimo, Jarvelin, Marjo-Riitta, Waterworth, Dawn M, Vollenweider, Peter, Peltonen, Leena, Mooser, Vincent, Sladek, Robert, Palmer, Nicholette D, McDonough, Caitrin W, Hicks, Pamela J, Roh, Bong H, Wing, Maria R, An, S Sandy, Hester, Jessica M, Cooke, Jessica N, Bostrom, Meredith A, Rudock, Megan E, Talbert, Matthew E, Lewis, Joshua P, Ferrara, Assiamira, Lu, Lingyi, Ziegler, Julie T, Sale, Michele M, Divers, Jasmin, Shriner, Daniel, Adeyemo, Adebowale, Rotimi, Charles N, Ng, Maggie C Y, Langefeld, Carl D, Freedman, Barry I, Bowden, Donald W, Voight, Benjamin F, Scott, Laura J, Steinthorsdottir, Valgerdur, Morris, Andrew P, Dina, Christian, Welch, Ryan P, Zeggini, Eleftheria, Huth, Cornelia, Aulchenko, Yurii S, Thorleifsson, Gudmar, McCulloch, Laura J, Ferreira, Teresa, Grallert, Harald, Amin, Najaf, Wu, Guanming, Willer, Cristen J, Raychaudhuri, Soumya, McCarroll, Steve A, Langenberg, Claudia, Hofmann, Oliver M, Dupuis, Josée, Qi, Lu, Segrè, Ayellet V, van Hoek, Mandy, Navarro, Pau, Ardlie, Kristin, Balkau, Beverley, Benediktsson, Rafn, Bennett, Amanda J, Blagieva, Roza, Boerwinkle, Eric, Bonnycastle, Lori L, Boström, Kristina Bengtsson, Bravenboer, Bert, Bumpstead, Suzannah, Burtt, Noël P, Charpentier, Guillaume, Chines, Peter S, Cornelis, Marilyn, Couper, David J, Crawford, Gabe, Doney, Alex S F, Elliott, Katherine S, Elliott, Amanda L, Erdos, Michael R, Fox, Caroline S, Franklin, Christopher S, Ganser, Martha, Gieger, Christian, Grarup, Niels, Green, Todd, Griffin, Simon, Groves, Christopher J, Guiducci, Candace, Hadjadj, Samy, Hassanali, Neelam, Herder, Christian, Isomaa, Bo, Jackson, Anne U, Johnson, Paul R V, Jørgensen, Torben, Kao, Wen H L, Klopp, Norman, Kong, Augustine, Kraft, Peter, Kuusisto, Johanna, Lauritzen, Torsten, Li, Man, Lieverse, Aloysius, Lindgren, Cecilia M, Lyssenko, Valeriya, Marre, Michel, Meitinger, Thomas, Midthjell, Kristian, Morken, Mario A, Narisu, Narisu, Nilsson, Peter, Owen, Katharine R, Payne, Felicity, Perry, John R B, Petersen, Ann-Kristin, Platou, Carl, Proença, Christine, Prokopenko, Inga, Rathmann, Wolfgang, Rayner, N William, Robertson, Neil R, Rocheleau, Ghislain, Roden, Michael, Sampson, Michael J, Saxena, Richa, Shields, Beverley M, Shrader, Peter, Sigurdsson, Gunnar, Sparsø, Thomas, Strassburger, Klaus, Stringham, Heather M, Sun, Qi, Swift, Amy J, Thorand, Barbara, Tichet, Jean, Tuomi, Tiinamaija, van Dam, Rob M, van Haeften, Timon W, van Herpt, Thijs, van Vliet-Ostaptchouk, Jana V, Walters, G Bragi, Weedon, Michael N, Wijmenga, Cisca, Witteman, Jacqueline, Bergman, Richard N, Cauchi, Stephane, Collins, Francis S, Gloyn, Anna L, Gyllensten, Ulf, Hansen, Torben, Hide, Winston A, Hitman, Graham A, Hofman, Albert, Hunter, David J, Hveem, Kristian, Laakso, Markku, Mohlke, Karen L, Morris, Andrew D, Palmer, Colin N A, Pramstaller, Peter P, Rudan, Igor, Sijbrands, Eric, Stein, Lincoln D, Tuomilehto, Jaakko, Uitterlinden, Andre, Walker, Mark, Wareham, Nicholas J, Watanabe, Richard M, Abecasis, Goncalo R, Boehm, Bernhard O, Campbell, Harry, Daly, Mark J, Hattersley, Andrew T, Hu, Frank B, Meigs, James B, Pankow, James S, Pedersen, Oluf, Wichmann, H-Erich, Barroso, Inês, Florez, Jose C, Frayling, Timothy M, Groop, Leif, Sladek, Rob, Thorsteinsdottir, Unnur, Wilson, James F, Illig, Thomas, Froguel, Philippe, van Duijn, Cornelia M, Stefansson, Kari, Altshuler, David, Boehnke, Michael, McCarthy, Mark I, Soranzo, Nicole, Wheeler, Eleanor, Glazer, Nicole L, Bouatia-Naji, Nabila, Mägi, Reedik, Randall, Joshua, Johnson, Toby, Elliott, Paul, Rybin, Denis, Henneman, Peter, Dehghan, Abbas, Hottenga, Jouke Jan, Song, Kijoung, Goel, Anuj, Egan, Josephine M, Lajunen, Taina, Doney, Alex, Kanoni, Stavroula, Cavalcanti-Proença, Christine, Kumari, Meena, Timpson, Nicholas J, Zabena, Carina, Ingelsson, Erik, An, Ping, O'Connell, Jeffrey, Luan, Jian'an, Elliott, Amanda, McCarroll, Steven A, Roccasecca, Rosa Maria, Pattou, François, Sethupathy, Praveen, Ariyurek, Yavuz, Barter, Philip, Beilby, John P, Ben-Shlomo, Yoav, Bergmann, Sven, Bochud, Murielle, Bonnefond, Amélie, Borch-Johnsen, Knut, Böttcher, Yvonne, Brunner, Eric, Bumpstead, Suzannah J, Chen, Yii-Der Ida, Chines, Peter, Clarke, Robert, Coin, Lachlan J M, Cooper, Matthew N, Crisponi, Laura, Day, Ian N M, de Geus, Eco J C, Delplanque, Jerome, Fedson, Annette C, Fischer-Rosinsky, Antje, Forouhi, Nita G, Frants, Rune, Franzosi, Maria Grazia, Galan, Pilar, Goodarzi, Mark O, Graessler, Jürgen, Grundy, Scott, Gwilliam, Rhian, Hallmans, Göran, Hammond, Naomi, Han, Xijing, Hartikainen, Anna-Liisa, Hayward, Caroline, Heath, Simon C, Hercberg, Serge, Hicks, Andrew A, Hillman, David R, Hingorani, Aroon D, Hui, Jennie, Hung, Joe, Jula, Antti, Kaakinen, Marika, Kaprio, Jaakko, Kesaniemi, Y Antero, Kivimaki, Mika, Knight, Beatrice, Koskinen, Seppo, Kovacs, Peter, Kyvik, Kirsten Ohm, Lathrop, G Mark, Lawlor, Debbie A, Le Bacquer, Olivier, Lecoeur, Cécile, Li, Yun, Mahley, Robert, Mangino, Massimo, Manning, Alisa K, Martínez-Larrad, María Teresa, McAteer, Jarred B, McPherson, Ruth, Meisinger, Christa, Melzer, David, Meyre, David, Mitchell, Braxton D, Mukherjee, Sutapa, Naitza, Silvia, Neville, Matthew J, Oostra, Ben A, Orrù, Marco, Pakyz, Ruth, Paolisso, Giuseppe, Pattaro, Cristian, Pearson, Daniel, Peden, John F, Pedersen, Nancy L, Perola, Markus, Pfeiffer, Andreas F H, Pichler, Irene, Polasek, Ozren, Posthuma, Danielle, Potter, Simon C, Pouta, Anneli, Province, Michael A, Psaty, Bruce M, Rayner, Nigel W, Rice, Kenneth, Ripatti, Samuli, Rivadeneira, Fernando, Rolandsson, Olov, Sandbaek, Annelli, Sandhu, Manjinder, Sanna, Serena, Sayer, Avan Aihie, Scheet, Paul, Seedorf, Udo, Sharp, Stephen J, Shields, Beverley, Sijbrands, Eric J G, Silveira, Angela, Simpson, Laila, Singleton, Andrew, Smith, Nicholas L, Sovio, Ulla, Swift, Amy, Syddall, Holly, Syvänen, Ann-Christine, Tanaka, Toshiko, Tönjes, Anke, Uitterlinden, André G, van Dijk, Ko Willems, Varma, Dhiraj, Visvikis-Siest, Sophie, Vitart, Veronique, Vogelzangs, Nicole, Waeber, Gérard, Wagner, Peter J, Walley, Andrew, Ward, Kim L, Watkins, Hugh, Wild, Sarah H, Willemsen, Gonneke, Witteman, Jaqueline C M, Yarnell, John W G, Zelenika, Diana, Zethelius, Björn, Zhai, Guangju, Zhao, Jing Hua, Zillikens, M Carola, Borecki, Ingrid B, Loos, Ruth J F, Meneton, Pierre, Magnusson, Patrik K E, Nathan, David M, Williams, Gordon H, Silander, Kaisa, Salomaa, Veikko, Smith, George Davey, Bornstein, Stefan R, Schwarz, Peter, Spranger, Joachim, Karpe, Fredrik, Shuldiner, Alan R, Cooper, Cyrus, Dedoussis, George V, Serrano-Ríos, Manuel, Lind, Lars, Palmer, Lyle J, Franks, Paul W, Ebrahim, Shah, Marmot, Michael, Kao, W H Linda, Pramstaller, Peter Paul, Wright, Alan F, Stumvoll, Michael, Hamsten, Anders, Buchanan, Thomas A, Valle, Timo T, Rotter, Jerome I, Siscovick, David S, Penninx, Brenda W J H, Boomsma, Dorret I, Deloukas, Panos, Spector, Timothy D, Ferrucci, Luigi, Cao, Antonio, Scuteri, Angelo, Schlessinger, David, Uda, Manuela, Ruokonen, Aimo, Jarvelin, Marjo-Riitta, Waterworth, Dawn M, Vollenweider, Peter, Peltonen, Leena, Mooser, Vincent, and Sladek, Robert
Abstract: African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
Published: 2012
Full Text: View/download PDF

50. A genome-wide association search for type 2 diabetes genes in African Americans.

Author: Palmer, Nicholette D, McDonough, Caitrin W, Hicks, Pamela J, Roh, Bong H, Wing, Maria R, An, S Sandy, Hester, Jessica M, Cooke, Jessica N, Bostrom, Meredith A, Rudock, Megan E, Talbert, Matthew E, Lewis, Joshua P, Ferrara, Assiamira, Lu, Lingyi, Ziegler, Julie T, Sale, Michele M, Divers, Jasmin, Shriner, Daniel, Adeyemo, Adebowale, Rotimi, Charles N, Ng, Maggie C Y, Langefeld, Carl D, Freedman, Barry I, Bowden, Donald W, Voight, Benjamin F, Scott, Laura J, Steinthorsdottir, Valgerdur, Morris, Andrew P, Dina, Christian, Welch, Ryan P, Zeggini, Eleftheria, Huth, Cornelia, Aulchenko, Yurii S, Thorleifsson, Gudmar, McCulloch, Laura J, Ferreira, Teresa, Grallert, Harald, Amin, Najaf, Wu, Guanming, Willer, Cristen J, Raychaudhuri, Soumya, McCarroll, Steve A, Langenberg, Claudia, Hofmann, Oliver M, Dupuis, Josée, Qi, Lu, Segrè, Ayellet V, van Hoek, Mandy, Navarro, Pau, Ardlie, Kristin, Balkau, Beverley, Benediktsson, Rafn, Bennett, Amanda J, Blagieva, Roza, Boerwinkle, Eric, Bonnycastle, Lori L, Boström, Kristina Bengtsson, Bravenboer, Bert, Bumpstead, Suzannah, Burtt, Noël P, Charpentier, Guillaume, Chines, Peter S, Cornelis, Marilyn, Couper, David J, Crawford, Gabe, Doney, Alex S F, Elliott, Katherine S, Elliott, Amanda L, Erdos, Michael R, Fox, Caroline S, Franklin, Christopher S, Ganser, Martha, Gieger, Christian, Grarup, Niels, Green, Todd, Griffin, Simon, Groves, Christopher J, Guiducci, Candace, Hadjadj, Samy, Hassanali, Neelam, Herder, Christian, Isomaa, Bo, Jackson, Anne U, Johnson, Paul R V, Jørgensen, Torben, Kao, Wen H L, Klopp, Norman, Kong, Augustine, Kraft, Peter, Kuusisto, Johanna, Lauritzen, Torsten, Li, Man, Lieverse, Aloysius, Lindgren, Cecilia M, Lyssenko, Valeriya, Marre, Michel, Meitinger, Thomas, Midthjell, Kristian, Morken, Mario A, Narisu, Narisu, Nilsson, Peter, Owen, Katharine R, Payne, Felicity, Perry, John R B, Petersen, Ann-Kristin, Platou, Carl, Proença, Christine, Prokopenko, Inga, Rathmann, Wolfgang, Rayner, N William, Robertson, Neil R, Rocheleau, Ghislain, Roden, Michael, Sampson, Michael J, Saxena, Richa, Shields, Beverley M, Shrader, Peter, Sigurdsson, Gunnar, Sparsø, Thomas, Strassburger, Klaus, Stringham, Heather M, Sun, Qi, Swift, Amy J, Thorand, Barbara, Tichet, Jean, Tuomi, Tiinamaija, van Dam, Rob M, van Haeften, Timon W, van Herpt, Thijs, van Vliet-Ostaptchouk, Jana V, Walters, G Bragi, Weedon, Michael N, Wijmenga, Cisca, Witteman, Jacqueline, Bergman, Richard N, Cauchi, Stephane, Collins, Francis S, Gloyn, Anna L, Gyllensten, Ulf, Hansen, Torben, Hide, Winston A, Hitman, Graham A, Hofman, Albert, Hunter, David J, Hveem, Kristian, Laakso, Markku, Mohlke, Karen L, Morris, Andrew D, Palmer, Colin N A, Pramstaller, Peter P, Rudan, Igor, Sijbrands, Eric, Stein, Lincoln D, Tuomilehto, Jaakko, Uitterlinden, Andre, Walker, Mark, Wareham, Nicholas J, Watanabe, Richard M, Abecasis, Goncalo R, Boehm, Bernhard O, Campbell, Harry, Daly, Mark J, Hattersley, Andrew T, Hu, Frank B, Meigs, James B, Pankow, James S, Pedersen, Oluf, Wichmann, H-Erich, Barroso, Inês, Florez, Jose C, Frayling, Timothy M, Groop, Leif, Sladek, Rob, Thorsteinsdottir, Unnur, Wilson, James F, Illig, Thomas, Froguel, Philippe, van Duijn, Cornelia M, Stefansson, Kari, Altshuler, David, Boehnke, Michael, McCarthy, Mark I, Soranzo, Nicole, Wheeler, Eleanor, Glazer, Nicole L, Bouatia-Naji, Nabila, Mägi, Reedik, Randall, Joshua, Johnson, Toby, Elliott, Paul, Rybin, Denis, Henneman, Peter, Dehghan, Abbas, Hottenga, Jouke Jan, Song, Kijoung, Goel, Anuj, Egan, Josephine M, Lajunen, Taina, Doney, Alex, Kanoni, Stavroula, Cavalcanti-Proença, Christine, Kumari, Meena, Timpson, Nicholas J, Zabena, Carina, Ingelsson, Erik, An, Ping, O'Connell, Jeffrey, Luan, Jian'an, Elliott, Amanda, McCarroll, Steven A, Roccasecca, Rosa Maria, Pattou, François, Sethupathy, Praveen, Ariyurek, Yavuz, Barter, Philip, Beilby, John P, Ben-Shlomo, Yoav, Bergmann, Sven, Bochud, Murielle, Bonnefond, Amélie, Borch-Johnsen, Knut, Böttcher, Yvonne, Brunner, Eric, Bumpstead, Suzannah J, Chen, Yii-Der Ida, Chines, Peter, Clarke, Robert, Coin, Lachlan J M, Cooper, Matthew N, Crisponi, Laura, Day, Ian N M, de Geus, Eco J C, Delplanque, Jerome, Fedson, Annette C, Fischer-Rosinsky, Antje, Forouhi, Nita G, Frants, Rune, Franzosi, Maria Grazia, Galan, Pilar, Goodarzi, Mark O, Graessler, Jürgen, Grundy, Scott, Gwilliam, Rhian, Hallmans, Göran, Hammond, Naomi, Han, Xijing, Hartikainen, Anna-Liisa, Hayward, Caroline, Heath, Simon C, Hercberg, Serge, Hicks, Andrew A, Hillman, David R, Hingorani, Aroon D, Hui, Jennie, Hung, Joe, Jula, Antti, Kaakinen, Marika, Kaprio, Jaakko, Kesaniemi, Y Antero, Kivimaki, Mika, Knight, Beatrice, Koskinen, Seppo, Kovacs, Peter, Kyvik, Kirsten Ohm, Lathrop, G Mark, Lawlor, Debbie A, Le Bacquer, Olivier, Lecoeur, Cécile, Li, Yun, Mahley, Robert, Mangino, Massimo, Manning, Alisa K, Martínez-Larrad, María Teresa, McAteer, Jarred B, McPherson, Ruth, Meisinger, Christa, Melzer, David, Meyre, David, Mitchell, Braxton D, Mukherjee, Sutapa, Naitza, Silvia, Neville, Matthew J, Oostra, Ben A, Orrù, Marco, Pakyz, Ruth, Paolisso, Giuseppe, Pattaro, Cristian, Pearson, Daniel, Peden, John F, Pedersen, Nancy L, Perola, Markus, Pfeiffer, Andreas F H, Pichler, Irene, Polasek, Ozren, Posthuma, Danielle, Potter, Simon C, Pouta, Anneli, Province, Michael A, Psaty, Bruce M, Rayner, Nigel W, Rice, Kenneth, Ripatti, Samuli, Rivadeneira, Fernando, Rolandsson, Olov, Sandbaek, Annelli, Sandhu, Manjinder, Sanna, Serena, Sayer, Avan Aihie, Scheet, Paul, Seedorf, Udo, Sharp, Stephen J, Shields, Beverley, Sijbrands, Eric J G, Silveira, Angela, Simpson, Laila, Singleton, Andrew, Smith, Nicholas L, Sovio, Ulla, Swift, Amy, Syddall, Holly, Syvänen, Ann-Christine, Tanaka, Toshiko, Tönjes, Anke, Uitterlinden, André G, van Dijk, Ko Willems, Varma, Dhiraj, Visvikis-Siest, Sophie, Vitart, Veronique, Vogelzangs, Nicole, Waeber, Gérard, Wagner, Peter J, Walley, Andrew, Ward, Kim L, Watkins, Hugh, Wild, Sarah H, Willemsen, Gonneke, Witteman, Jaqueline C M, Yarnell, John W G, Zelenika, Diana, Zethelius, Björn, Zhai, Guangju, Zhao, Jing Hua, Zillikens, M Carola, Borecki, Ingrid B, Loos, Ruth J F, Meneton, Pierre, Magnusson, Patrik K E, Nathan, David M, Williams, Gordon H, Silander, Kaisa, Salomaa, Veikko, Smith, George Davey, Bornstein, Stefan R, Schwarz, Peter, Spranger, Joachim, Karpe, Fredrik, Shuldiner, Alan R, Cooper, Cyrus, Dedoussis, George V, Serrano-Ríos, Manuel, Lind, Lars, Palmer, Lyle J, Franks, Paul W, Ebrahim, Shah, Marmot, Michael, Kao, W H Linda, Pramstaller, Peter Paul, Wright, Alan F, Stumvoll, Michael, Hamsten, Anders, Buchanan, Thomas A, Valle, Timo T, Rotter, Jerome I, Siscovick, David S, Penninx, Brenda W J H, Boomsma, Dorret I, Deloukas, Panos, Spector, Timothy D, Ferrucci, Luigi, Cao, Antonio, Scuteri, Angelo, Schlessinger, David, Uda, Manuela, Ruokonen, Aimo, Jarvelin, Marjo-Riitta, Waterworth, Dawn M, Vollenweider, Peter, Peltonen, Leena, Mooser, Vincent, Sladek, Robert, Palmer, Nicholette D, McDonough, Caitrin W, Hicks, Pamela J, Roh, Bong H, Wing, Maria R, An, S Sandy, Hester, Jessica M, Cooke, Jessica N, Bostrom, Meredith A, Rudock, Megan E, Talbert, Matthew E, Lewis, Joshua P, Ferrara, Assiamira, Lu, Lingyi, Ziegler, Julie T, Sale, Michele M, Divers, Jasmin, Shriner, Daniel, Adeyemo, Adebowale, Rotimi, Charles N, Ng, Maggie C Y, Langefeld, Carl D, Freedman, Barry I, Bowden, Donald W, Voight, Benjamin F, Scott, Laura J, Steinthorsdottir, Valgerdur, Morris, Andrew P, Dina, Christian, Welch, Ryan P, Zeggini, Eleftheria, Huth, Cornelia, Aulchenko, Yurii S, Thorleifsson, Gudmar, McCulloch, Laura J, Ferreira, Teresa, Grallert, Harald, Amin, Najaf, Wu, Guanming, Willer, Cristen J, Raychaudhuri, Soumya, McCarroll, Steve A, Langenberg, Claudia, Hofmann, Oliver M, Dupuis, Josée, Qi, Lu, Segrè, Ayellet V, van Hoek, Mandy, Navarro, Pau, Ardlie, Kristin, Balkau, Beverley, Benediktsson, Rafn, Bennett, Amanda J, Blagieva, Roza, Boerwinkle, Eric, Bonnycastle, Lori L, Boström, Kristina Bengtsson, Bravenboer, Bert, Bumpstead, Suzannah, Burtt, Noël P, Charpentier, Guillaume, Chines, Peter S, Cornelis, Marilyn, Couper, David J, Crawford, Gabe, Doney, Alex S F, Elliott, Katherine S, Elliott, Amanda L, Erdos, Michael R, Fox, Caroline S, Franklin, Christopher S, Ganser, Martha, Gieger, Christian, Grarup, Niels, Green, Todd, Griffin, Simon, Groves, Christopher J, Guiducci, Candace, Hadjadj, Samy, Hassanali, Neelam, Herder, Christian, Isomaa, Bo, Jackson, Anne U, Johnson, Paul R V, Jørgensen, Torben, Kao, Wen H L, Klopp, Norman, Kong, Augustine, Kraft, Peter, Kuusisto, Johanna, Lauritzen, Torsten, Li, Man, Lieverse, Aloysius, Lindgren, Cecilia M, Lyssenko, Valeriya, Marre, Michel, Meitinger, Thomas, Midthjell, Kristian, Morken, Mario A, Narisu, Narisu, Nilsson, Peter, Owen, Katharine R, Payne, Felicity, Perry, John R B, Petersen, Ann-Kristin, Platou, Carl, Proença, Christine, Prokopenko, Inga, Rathmann, Wolfgang, Rayner, N William, Robertson, Neil R, Rocheleau, Ghislain, Roden, Michael, Sampson, Michael J, Saxena, Richa, Shields, Beverley M, Shrader, Peter, Sigurdsson, Gunnar, Sparsø, Thomas, Strassburger, Klaus, Stringham, Heather M, Sun, Qi, Swift, Amy J, Thorand, Barbara, Tichet, Jean, Tuomi, Tiinamaija, van Dam, Rob M, van Haeften, Timon W, van Herpt, Thijs, van Vliet-Ostaptchouk, Jana V, Walters, G Bragi, Weedon, Michael N, Wijmenga, Cisca, Witteman, Jacqueline, Bergman, Richard N, Cauchi, Stephane, Collins, Francis S, Gloyn, Anna L, Gyllensten, Ulf, Hansen, Torben, Hide, Winston A, Hitman, Graham A, Hofman, Albert, Hunter, David J, Hveem, Kristian, Laakso, Markku, Mohlke, Karen L, Morris, Andrew D, Palmer, Colin N A, Pramstaller, Peter P, Rudan, Igor, Sijbrands, Eric, Stein, Lincoln D, Tuomilehto, Jaakko, Uitterlinden, Andre, Walker, Mark, Wareham, Nicholas J, Watanabe, Richard M, Abecasis, Goncalo R, Boehm, Bernhard O, Campbell, Harry, Daly, Mark J, Hattersley, Andrew T, Hu, Frank B, Meigs, James B, Pankow, James S, Pedersen, Oluf, Wichmann, H-Erich, Barroso, Inês, Florez, Jose C, Frayling, Timothy M, Groop, Leif, Sladek, Rob, Thorsteinsdottir, Unnur, Wilson, James F, Illig, Thomas, Froguel, Philippe, van Duijn, Cornelia M, Stefansson, Kari, Altshuler, David, Boehnke, Michael, McCarthy, Mark I, Soranzo, Nicole, Wheeler, Eleanor, Glazer, Nicole L, Bouatia-Naji, Nabila, Mägi, Reedik, Randall, Joshua, Johnson, Toby, Elliott, Paul, Rybin, Denis, Henneman, Peter, Dehghan, Abbas, Hottenga, Jouke Jan, Song, Kijoung, Goel, Anuj, Egan, Josephine M, Lajunen, Taina, Doney, Alex, Kanoni, Stavroula, Cavalcanti-Proença, Christine, Kumari, Meena, Timpson, Nicholas J, Zabena, Carina, Ingelsson, Erik, An, Ping, O'Connell, Jeffrey, Luan, Jian'an, Elliott, Amanda, McCarroll, Steven A, Roccasecca, Rosa Maria, Pattou, François, Sethupathy, Praveen, Ariyurek, Yavuz, Barter, Philip, Beilby, John P, Ben-Shlomo, Yoav, Bergmann, Sven, Bochud, Murielle, Bonnefond, Amélie, Borch-Johnsen, Knut, Böttcher, Yvonne, Brunner, Eric, Bumpstead, Suzannah J, Chen, Yii-Der Ida, Chines, Peter, Clarke, Robert, Coin, Lachlan J M, Cooper, Matthew N, Crisponi, Laura, Day, Ian N M, de Geus, Eco J C, Delplanque, Jerome, Fedson, Annette C, Fischer-Rosinsky, Antje, Forouhi, Nita G, Frants, Rune, Franzosi, Maria Grazia, Galan, Pilar, Goodarzi, Mark O, Graessler, Jürgen, Grundy, Scott, Gwilliam, Rhian, Hallmans, Göran, Hammond, Naomi, Han, Xijing, Hartikainen, Anna-Liisa, Hayward, Caroline, Heath, Simon C, Hercberg, Serge, Hicks, Andrew A, Hillman, David R, Hingorani, Aroon D, Hui, Jennie, Hung, Joe, Jula, Antti, Kaakinen, Marika, Kaprio, Jaakko, Kesaniemi, Y Antero, Kivimaki, Mika, Knight, Beatrice, Koskinen, Seppo, Kovacs, Peter, Kyvik, Kirsten Ohm, Lathrop, G Mark, Lawlor, Debbie A, Le Bacquer, Olivier, Lecoeur, Cécile, Li, Yun, Mahley, Robert, Mangino, Massimo, Manning, Alisa K, Martínez-Larrad, María Teresa, McAteer, Jarred B, McPherson, Ruth, Meisinger, Christa, Melzer, David, Meyre, David, Mitchell, Braxton D, Mukherjee, Sutapa, Naitza, Silvia, Neville, Matthew J, Oostra, Ben A, Orrù, Marco, Pakyz, Ruth, Paolisso, Giuseppe, Pattaro, Cristian, Pearson, Daniel, Peden, John F, Pedersen, Nancy L, Perola, Markus, Pfeiffer, Andreas F H, Pichler, Irene, Polasek, Ozren, Posthuma, Danielle, Potter, Simon C, Pouta, Anneli, Province, Michael A, Psaty, Bruce M, Rayner, Nigel W, Rice, Kenneth, Ripatti, Samuli, Rivadeneira, Fernando, Rolandsson, Olov, Sandbaek, Annelli, Sandhu, Manjinder, Sanna, Serena, Sayer, Avan Aihie, Scheet, Paul, Seedorf, Udo, Sharp, Stephen J, Shields, Beverley, Sijbrands, Eric J G, Silveira, Angela, Simpson, Laila, Singleton, Andrew, Smith, Nicholas L, Sovio, Ulla, Swift, Amy, Syddall, Holly, Syvänen, Ann-Christine, Tanaka, Toshiko, Tönjes, Anke, Uitterlinden, André G, van Dijk, Ko Willems, Varma, Dhiraj, Visvikis-Siest, Sophie, Vitart, Veronique, Vogelzangs, Nicole, Waeber, Gérard, Wagner, Peter J, Walley, Andrew, Ward, Kim L, Watkins, Hugh, Wild, Sarah H, Willemsen, Gonneke, Witteman, Jaqueline C M, Yarnell, John W G, Zelenika, Diana, Zethelius, Björn, Zhai, Guangju, Zhao, Jing Hua, Zillikens, M Carola, Borecki, Ingrid B, Loos, Ruth J F, Meneton, Pierre, Magnusson, Patrik K E, Nathan, David M, Williams, Gordon H, Silander, Kaisa, Salomaa, Veikko, Smith, George Davey, Bornstein, Stefan R, Schwarz, Peter, Spranger, Joachim, Karpe, Fredrik, Shuldiner, Alan R, Cooper, Cyrus, Dedoussis, George V, Serrano-Ríos, Manuel, Lind, Lars, Palmer, Lyle J, Franks, Paul W, Ebrahim, Shah, Marmot, Michael, Kao, W H Linda, Pramstaller, Peter Paul, Wright, Alan F, Stumvoll, Michael, Hamsten, Anders, Buchanan, Thomas A, Valle, Timo T, Rotter, Jerome I, Siscovick, David S, Penninx, Brenda W J H, Boomsma, Dorret I, Deloukas, Panos, Spector, Timothy D, Ferrucci, Luigi, Cao, Antonio, Scuteri, Angelo, Schlessinger, David, Uda, Manuela, Ruokonen, Aimo, Jarvelin, Marjo-Riitta, Waterworth, Dawn M, Vollenweider, Peter, Peltonen, Leena, Mooser, Vincent, and Sladek, Robert
Abstract: African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
Published: 2012
Full Text: View/download PDF

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