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4. An N-ethyl-N-nitrosourea (ENU) mutagenized mouse model for autosomal dominant non-syndromic kyphoscoliosis due to vertebral fusion

Author

Esapa, CT, Piret, SE, Nesbit, MA, Thomas, GP, Coulton, LA, Gallagher, OM, Simon, MM, Kumar, S, Mallon, AM, Ballantuono, I, Brown, MA, Croucher, PI, Potter, PK, Brown, SDM, Cox, R, and Thakker, RV

Abstract

Kyphosis and scoliosis are common spinal disorders that occur as part of complex syndromes or as non-syndromic, idiopathic diseases. Familial and twin studies implicate genetic involvement, although the causative genes for idiopathic kyphoscoliosis remain to be identified. To facilitate these studies, we investigated progeny of mice treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU) and assessed them for morphological and radiographic abnormalities. This identified a mouse with kyphoscoliosis due to fused lumbar vertebrae, which was inherited as an autosomal dominant trait; the phenotype was designated as hereditary vertebral fusion (HVF) and the locus as Hvf. Micro-computed tomography (CT) analysis confirmed the occurrence of non-syndromic kyphoscoliosis due to fusion of lumbar vertebrae in HVF mice, consistent with a pattern of blocked vertebrae due to failure of segmentation. Micro-CT scans also showed the lumbar vertebral column of HVF mice to have generalized disc narrowing, displacement with compression of the neural spine, and distorted transverse processes. Histology of lumbar vertebrae revealed HVF mice to have irregularly shaped vertebral bodies and displacement of intervertebral discs and ossification centers. Genetic mapping using a panel of single nucleotide polymorphic (SNP) loci arranged in chromosome sets and DNA samples from 23 HVF (8 males and 15 females) mice, localized Hvf to chromosome 4A3 and within a 5 Mb region containing 9 protein coding genes, 2 processed transcripts, 3 microRNAs, 5 small nuclear RNAs, 3 large intergenic non-coding RNAs, and 24 pseudogenes. However, genome sequence analysis in this interval did not identify any abnormalities in the coding exons, or exon-intron boundaries of any of these genes. Thus, our studies have established a mouse model for a monogenic form of non-syndromic kyphoscoliosis due to fusion of lumbar vertebrae, and further identification of the underlying genetic defect will help elucidate the molecular mechanisms involved in kyphoscoliosis.

Published
2018

5. Postpartum physiology, psychology and paediatric follow up study (P4 Study) – Study protocol

Author

Davis, GK, Roberts, L, Mangos, G, Henry, A, Pettit, F, O'Sullivan, A, Homer, CSE, Craig, M, Harvey, SB, and Brown, MA

Subjects
Depression, Postpartum Period, Child Behavior, Infant, Blood Pressure, Hypertension, Pregnancy-Induced, Anxiety, Kidney, Stress Disorders, Post-Traumatic, Child Development, Vascular Stiffness, Liver, Pre-Eclampsia, Pregnancy, Research Design, Case-Control Studies, Child, Preschool, Body Composition, Blood Vessels, Humans, Ventricular Function, Female, Prospective Studies, Compliance
Abstract

© 2016 International Society for the Study of Hypertension in Pregnancy Background Women who have had hypertension in pregnancy are at greater risk of long term cardiovascular disease (CVD). Little is known about their cardiovascular risk postpartum or the effects on the woman's mental health and the outcomes of their infants. In this project we will study the physiological and psychological health of women and the physical health and development of their infants six months, two years and five years after birth. We will establish normal blood pressure (BP) and metabolic function for women who were normotensive in pregnancy and use these to assess women who had gestational hypertension (GH) or preeclampsia (PE). Design/methods Women will be asked to participate if they have given birth in the preceding six months. They will be excluded if they had diabetes, hypertension, renal or other serious maternal disease prior to pregnancy or congenital anomaly in the pregnancy. We will recruit 292 women who were normotensive and their babies, 100 who had GH and 100 who had PE and their babies. They will be assessed at six months, two and five years after birth. At each assessment mothers will have their blood pressure (BP) assessed peripherally with a liquid crystal sphygmomanometer and 24 h ambulatory blood pressure monitoring (ABPM), and centrally with non-invasive applanation tonometry. Additional physiological testing will include: body composition; energy balance; vascular compliance; cardiac function; liver and renal function, lipids and biochemistry; glucose and insulin; and urinalysis. Psychological status will be assessed with validated self-report questionnaires for depression, anxiety, post-traumatic stress disorder (PTSD) and mother-infant bonding. The babies will have a medical examination by a paediatrician at each assessment. Their behavioural development will be assessed with an Ages and Stages Questionnaire completed by their mother at each assessment and a developmental assessment by a child psychologist at two and five years. Conclusions This study will re-define normal BP and other physiological parameters for young parous women thereby permitting a more sensitive assessment of post-partum BP and other cardiovascular risk markers in women who have had GH or PE. It will also determine the extent, if any, of psychological disorders in these women and developmental or other concerns in their babies. Trials registration Australian and New Zealand Clinical Trials Registry Number: ACTRN12613001260718.

Published
2016

16. Genome-Wide Association Study Implicates HLA-C*01:02 as a Risk Factor at the Major Histocompatibility Complex Locus in Schizophrenia

Author

Strange, A, Riley, BP, Spencer, CCA, Morris, DW, Pirinen, M, O'Dushlaine, CT, Su, Z, Maher, BS, Freeman, C, Cormican, P, Bellenguez, C, Kenny, EM, Band, G, Wormley, B, Donohoe, G, Dilthey, A, Moutsianas, L, Quinn, E, Edkins, S, Judge, R, Coleman, K, Hunt, S, Tropea, D, Roche, S, Cummings, L, Kelleher, E, McKeon, P, Dinan, T, McDonald, C, Murphy, KC, O'Callaghan, E, O'Neill, FA, Waddington, JL, Walsh, D, Giannoulatou, E, Langford, C, Deloukas, P, Gray, E, Dronov, S, Potter, S, Pearson, R, Vukcevic, D, Tashakkori-Ghanbaria, A, Blackwell, JM, Bramon, E, Brown, MA, Casas, JP, Duncanson, A, Jankowski, J, Markus, HS, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Viswanathan, AC, Wood, NW, Stone, J, Scolnick, E, Purcell, S, Sklar, P, Ripke, S, Walters, J, Owen, MJ, O'Donovan, MC, Peltonen, L, McVean, G, Kendler, KS, Gill, M, Donnelly, P, Corvin, A, Conso, ISG, Consortium, SGENE, Psychiat, SWG, and Consor, WTCC

Subjects
Adult, Male, Genotype, Locus (genetics), Single-nucleotide polymorphism, Genome-wide association study, Human leukocyte antigen, HLA-C Antigens, Major histocompatibility complex, Polymorphism, Single Nucleotide, Article, HLA-C, Calcium Channels, T-Type, Young Adult, Risk Factors, Databases, Genetic, tourette-syndrome, SNP, Humans, genetics, Genetic Predisposition to Disease, Allele, gene, Biological Psychiatry, Aged, Genetics, cacna1i, breakpoint, Aged, 80 and over, biology, deletions, polygene score, classical hla alleles, Middle Aged, hlac, major histocompatibility complex, disruption, biology.protein, Schizophrenia, Female, immp2l, Ireland, Genome-Wide Association Study
Abstract

BACKGROUND: We performed a genome-wide association study (GWAS) to identify common risk variants for schizophrenia. METHODS: The discovery scan included 1606 patients and 1794 controls from Ireland, using 6,212,339 directly genotyped or imputed single nucleotide polymorphisms (SNPs). A subset of this sample (270 cases and 860 controls) was subsequently included in the Psychiatric GWAS Consortium-schizophrenia GWAS meta-analysis. RESULTS: One hundred eight SNPs were taken forward for replication in an independent sample of 13,195 cases and 31,021 control subjects. The most significant associations in discovery, corrected for genomic inflation, were (rs204999, p combined = 1.34 × 10(-9) and in combined samples (rs2523722 p combined = 2.88 × 10(-16)) mapped to the major histocompatibility complex (MHC) region. We imputed classical human leukocyte antigen (HLA) alleles at the locus; the most significant finding was with HLA-C*01:02. This association was distinct from the top SNP signal. The HLA alleles DRB1*03:01 and B*08:01 were protective, replicating a previous study. CONCLUSIONS: This study provides further support for involvement of MHC class I molecules in schizophrenia. We found evidence of association with previously reported risk alleles at the TCF4, VRK2, and ZNF804A loci.

Published
2016

36. Determination of Surface Potential and Electrical Double-Layer Structure at the Aqueous Electrolyte-Nanoparticle Interface

Author

Brown, MA, Abbas, Z, Kleibert, A, Green, RG, Goel, A, May, S, and Squires, TM

Subjects
Quantum Physics, Physics, QC1-999, Condensed Matter Physics, Astronomical and Space Sciences
Abstract

The structure of the electrical double layer has been debated for well over a century, since it mediates colloidal interactions, regulates surface structure, controls reactivity, sets capacitance, and represents the central element of electrochemical supercapacitors. The surface potential of such surfaces generally exceeds the electrokinetic potential, often substantially. Traditionally, a Stern layer of nonspecifically adsorbed ions has been invoked to rationalize the difference between these two potentials; however, the inability to directly measure the surface potential of dispersed systems has rendered quantitative measurements of the Stern layer potential, and other quantities associated with the outer Helmholtz plane, impossible. Here, we use x-ray photoelectron spectroscopy from a liquid microjet to measure the absolute surface potentials of silica nanoparticles dispersed in aqueous electrolytes. We quantitatively determine the impact of specific cations (Li+, Na+, K+, and Cs+) in chloride electrolytes on the surface potential, the location of the shear plane, and the capacitance of the Stern layer. We find that the magnitude of the surface potential increases linearly with the hydrated-cation radius. Interpreting our data using the simplest assumptions and most straightforward understanding of Gouy-Chapman-Stern theory reveals a Stern layer whose thickness corresponds to a single layer of water molecules hydrating the silica surface, plus the radius of the hydrated cation. These results subject electrical double-layer theories to direct and falsifiable tests to reveal a physically intuitive and quantitatively verified picture of the Stern layer that is consistent across multiple electrolytes and solution conditions., Physical Review X, 6 (1), ISSN:2160-3308

Published
2016

37. McRae Trust - a study of issues around livestock greenhouse gas emissions and the implications for farmers

Author

R.A. Dynes, A.P. Rhodes, and Brown Ma

Subjects
business.industry, Environmental protection, Greenhouse gas, Environmental science, Livestock, General Medicine, business
Abstract

McRae Trust Farm was used to examine how hill country farming policies and management affected the quantity of livestock greenhouse gas (GHG) emissions, profitability, and risk. Land use decisions were subject to the opportunities and constraints inherent in the natural soil capital of the farm. Analysis was undertaken using FARMAX® and OVERSEER®. Features of the pastoral farming system in 2009 were compared with 1990, and data around livestock GHG emissions was compared with the methodology proposed in the Climate Change (Agriculture Sector) Regulations 2010 which is intended to be the basis for calculating farmers' liability in 2015. Changing livestock policies can potentially change livestock GHG emissions by around 10%. Reduced emission intensity (kg CO2-e/kg meat & fibre) is achievable, but total GHG emissions may be increased over the baseline. Profitability, as measured by Economic Farm Surplus, may be increased or decreased with no relationship with the level of GHG emissions. Between 1990 and 2009, intensity of GHG emissions has been reduced by about 5% on this farm. An area of 12 ha of forestry will assist in reducing GHG liability in the initial period of agriculture's inclusion in the Emissions Trading Scheme (ETS).

Published
2011

38. Association study of genes related to bone formation and resorption and the extent of radiographic change in ankylosing spondylitis

Author

Cortes, A, Maksymowych, WP, Wordsworth, BP, Inman, RD, Danoy, P, Rahman, P, Stone, MA, Corr, M, Gensler, Lianne S, Gladman, D, Morgan, A, Marzo-Ortega, H, Ward, MM, SPARCC (Spondyloarthritis Research Consortium of Canada), TASC (Australo-Anglo-American Spondyloarthritis Consortium), Learch, TJ, Reveille, JD, Brown, MA, and Weisman, MH

Subjects
Ankylosing, Adult, Male, Genotype, Clinical Sciences, Immunology, SPARCC, Severity of Illness Index, Osteogenesis, Genetics, Humans, 2.1 Biological and endogenous factors, Bone Resorption, Polymorphism, Aetiology, Genetic Association Studies, Lumbar Vertebrae, Receptor Activator of Nuclear Factor-kappa B, Single Nucleotide, Exons, Middle Aged, Arthritis & Rheumatology, Radiography, Haplotypes, x-ray, genetic association study, Musculoskeletal, Cervical Vertebrae, Cyclooxygenase 1, Public Health and Health Services, Female, TASC, Spondylitis, Ankylosing spondylitis
Abstract

ObjectiveTo identify genetic associations with severity of radiographic damage in ankylosing spondylitis (AS).MethodWe studied 1537 AS cases of European descent; all fulfilled the modified New York Criteria. Radiographic severity was assessed from digitised lateral radiographs of the cervical and lumbar spine using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). A two-phase genotyping design was used. In phase 1, 498 single nucleotide polymorphisms (SNPs) were genotyped in 688 cases; these were selected to capture >90% of the common haplotypic variation in the exons, exon-intron boundaries, and 5 kb flanking DNA in the 5' and 3' UTR of 74 genes involved in anabolic or catabolic bone pathways. In phase 2, 15 SNPs exhibiting p

Published
2015

39. Systemic Therapeutic Approaches with Sexual Minorities and Their Families

Author

Josephine Bonomo Ms, Jeremiah M. Brown Ma, Barbara V. Andrews, and Janie K. Long

Subjects
Gender Studies, Family therapy, Class (computer programming), Race (biology), Psychotherapist, business.industry, Ethnic group, Medicine, business, Systemic therapy, Social Sciences (miscellaneous)
Abstract

GLBTQ families encompass very diverse forms, all of which are interwoven with other differences such as class, race, ethnicity, religious and spiritual beliefs. This article will familiarize the reader with some challenges faced by families of sexual minorities and how different family therapy approaches might be applied. Training issues for therapists are identified and future areas for development are discussed.

Published
2006

40. THE NORE MUTINY—SEDITION OR SHIPS' BISCUITS? A REAPPRAISAL

Author

Anthony G. Brown Ma

Subjects
History, Mutiny, media_common.quotation_subject, Art, Ancient history, Oceanography, Sedition, media_common
Abstract

(2006). THE NORE MUTINY—SEDITION OR SHIPS' BISCUITS? A REAPPRAISAL. The Mariner's Mirror: Vol. 92, No. 1, pp. 60-74.

Published
2006

42. Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke

Author

Bellenguez, C, Bevan, S, Gschwendtner, A, Spencer, CCA, Burgess, AI, Pirinen, M, Jackson, CA, Traylor, M, Strange, A, Su, Z, Band, G, Syme, PD, Malik, R, Pera, J, Bo, N, Lemmens, R, Freeman, C, Schanz, R, James, T, Poole, D, Murphy, L, Segal, H, Cortellini, L, Cheng, YC, Woo, D, Nalls, MA, Müller-Myhsok, B, Meisinger, C, Seedorf, U, Ross-Adams, H, Boonen, S, Wloch-Kopec, D, Valant, V, Slark, J, Furie, K, Delavaran, H, Langford, C, Deloukas, P, Edkins, S, Hunt, S, Gray, E, Dronov, S, Peltonen, L, Gretarsdottir, S, Thorleifsson, G, Thorsteinsdottir, U, Stefansson, K, Boncoraglio, GB, Parati, EA, Attia, J, Holliday, E, Levi, C, Franzosi, MG, Goel, A, Helgadottir, A, Blackwell, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Duncanson, A, Jankowski, J, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Viswanathan, AC, Wood, NW, Worrall, BB, Kittner, SJ, Mitchell, BD, Kissela, B, Meschia, JF, Thijs, V, Lindgren, A, MacLeod, MJ, Slowik, A, and Walters, M

Subjects
medicine.medical_specialty, Neurology, Genotype, Locus (genetics), Genome-wide association study, Disease, Biology, Bioinformatics, Polymorphism, Single Nucleotide, Histone Deacetylases, White People, Article, 03 medical and health sciences, 0302 clinical medicine, Odds Ratio, medicine, Genetics, Humans, Genetic Predisposition to Disease, 030304 developmental biology, 0303 health sciences, Atrial fibrillation, Odds ratio, medicine.disease, Confidence interval, 3. Good health, Repressor Proteins, Stroke, Chromosomes, Human, Pair 7, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Genetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 × 10 -11; odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28-1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes. © 2012 Nature America, Inc. All rights reserved.

Published
2012

43. Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke

Author

Bellenguez, C, Bevan, S, Gschwendtner, A, Spencer, CCA, Burgess, AI, Pirinen, M, Jackson, CA, Traylor, M, Strange, A, Su, Z, Band, G, Syme, PD, Malik, R, Pera, J, Bo, N, Lemmens, R, Freeman, C, Schanz, R, James, T, Poole, D, Murphy, L, Segal, H, Cortellini, L, Cheng, Y-C, Woo, D, Nalls, MA, Müller-Myhsok, B, Meisinger, C, Seedorf, U, Ross-Adams, H, Boonen, S, Wloch-Kopec, D, Valant, V, Slark, J, Furie, K, Delavaran, H, Langford, C, Deloukas, P, Edkins, S, Hunt, S, Gray, E, Dronov, S, Peltonen, L, Gretarsdottir, S, Thorleifsson, G, Thorsteinsdottir, U, Stefansson, K, Boncoraglio, GB, Parati, EA, Attia, J, Holliday, E, Levi, C, Franzosi, M-G, Goel, A, Helgadottir, A, Blackwell, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Duncanson, A, Jankowski, J, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Viswanathan, AC, Wood, NW, Worrall, BB, Kittner, SJ, Mitchell, BD, Kissela, B, Meschia, JF, Thijs, V, Lindgren, A, MacLeod, MJ, Slowik, A, Walters, M, Rosand, J, Sharma, P, Farrall, M, Sudlow, CLM, Rothwell, PM, Dichgans, M, Donnelly, P, and Markus, HS

Published
2012

44. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease

Author

Jostins, Luke, Ripke, Stephan, Weersma, Rinse K., Duerr, Richard H., Mcgovern, Dermot P., Hui, Ken Y., Lee, James C., Philip Schumm, L., Sharma, Yashoda, Anderson, Carl A., Essers, Jonah, Mitrovic, Mitja, Ning, Kaida, Cleynen, Isabelle, Theatre, Emilie, Spain, Sarah L., Raychaudhuri, Soumya, Goyette, Philippe, Wei, Zhi, Abraham, Clara, Achkar, Jean Paul, Ahmad, Tariq, Amininejad, Leila, Ananthakrishnan, Ashwin N., Andersen, Vibeke, Andrews, Jane M., Baidoo, Leonard, Balschun, Tobias, Bampton, Peter A., Bitton, Alain, Boucher, Gabrielle, Brand, Stephan, Büning, Carsten, Cohain, Ariella, Cichon, Sven, D'Amato, Mauro, De Jong, Dirk, Devaney, Kathy L., Dubinsky, Marla, Edwards, Cathryn, Ellinghaus, David, Ferguson, Lynnette R., Franchimont, Denis, Fransen, Karin, Gearry, Richard, Georges, Michel, Gieger, Christian, Glas, Jürgen, Haritunians, Talin, Hart, Ailsa, Hawkey, Chris, Hedl, Matija, Xinli, Hu, Karlsen, Tom H., Kupcinskas, Limas, Kugathasan, Subra, Latiano, Anna, Laukens, Debby, Lawrance, Ian C., Lees, Charlie W., Louis, Edouard, Mahy, Gillian, Mansfield, John, Morgan, Angharad R., Mowat, Craig, Newman, William, Palmieri, Orazio, Ponsioen, Cyriel Y., Potocnik, Uros, Prescott, Natalie J., Regueiro, Miguel, Rotter, Jerome I., Russell, Richard K., Sanderson, Jeremy D., Sans, Miquel, Satsangi, Jack, Schreiber, Stefan, Simms, Lisa A., Sventoraityte, Jurgita, Targan, Stephan R., Taylor, Kent D., Tremelling, Mark, Verspaget, Hein W., De Vos, Martine, Wijmenga, Cisca, Wilson, David C., Winkelmann, Juliane, Xavier, Ramnik J., Zeissig, Sebastian, Zhang, Bin, Zhang, Clarence K., Zhao, Hongyu, Silverberg, Mark S., Annese, Vito, Hakonarson, Hakon, Brant, Steven R., Radford Smith, Graham, Mathew, Christopher G., Rioux, John D., Schadt, Eric E., Daly, Mark J., Franke, Andre, Parkes, Miles, Vermeire, Severine, Barrett, Jeffrey C., Cho, Judy H., Barclay, M, Peyrin Biroulet, L, Chamaillard, M, Colombel, Jf, Cottone, M, Croft, A, D'Incà, R, Halfvarson J, Hanigan K, Henderson, P, Hugot, Jp, Karban, A, Kennedy, Na, Khan, Ma, Lémann, M, Levine, A, Massey, D, Milla, M, Montgomery, Gw, Ng, Sm, Oikonomou, I, Peeters, H, Proctor, Dd, Rahier, Jf, Roberts, R, Rutgeerts, P, Seibold, F, Stronati, Laura, Taylor, Km, Törkvist, L, Ublick, K, Van Limbergen, J, Van Gossum, A, Vatn, Mh, Zhang, H, Zhang, W, Andrews, Jm, Bampton, Pa, Florin, Th, Gearry, R, Krishnaprasad, K, Lawrance, Ic, Mahy, G, Radford Smith, G, Roberts, Rl, Simms, La, Amininijad, L, Cleynen, I, Dewit, O, Franchimont, D, Georges, M, Laukens, D, Theatre, E, Vermeire, S, Aumais, G, Baidoo, L, Barrie AM 3rd, Beck, K, Bernard, Ej, Binion, Dg, Bitton, A, Brant, Sr, Cho, Jh, Cohen, A, Croitoru, K, Daly, Mj, Datta, Lw, Deslandres, C, Duerr, Rh, Dutridge, D, Ferguson, J, Fultz, J, Goyette, P, Greenberg, Gr, Haritunians, T, Jobin, G, Katz, S, Lahaie, Rg, Mcgovern, Dp, Nelson, L, Ning, K, Paré, P, Regueiro, Md, Rioux, Jd, Ruggiero, E, Schumm, L, Schwartz, M, Scott, R, Sharma, Y, Silverberg, Ms, Spears, D, Steinhart, A, Stempak, Jm, Swoger, Jm, Tsagarelis, C, Zhang, C, Zhao, H, Aerts, J, Ahmad, T, Arbury, H, Attwood, A, Auton, A, Ball, Sg, Balmforth, Aj, Barnes, C, Barrett, Jc, Barroso, I, Barton, A, Bennett, Aj, Bhaskar, S, Blaszczyk, K, Bowes, J, Brand, Oj, Braund, Ps, Bredin, F, Breen, G, Brown, Mj, Bruce, In, Bull, J, Burren, Os, Burton, J, Byrnes, J, Caesar, S, Cardin, N, Clee, Cm, Coffey, Aj, Connell, Jm, Conrad, Df, Cooper, Jd, Dominiczak, Af, Downes, K, Drummond, He, Dudakia, D, Dunham, A, Ebbs, B, Eccles, D, Edkins, S, Edwards, C, Elliot, A, Emery, P, Evans, Dm, Evans, G, Eyre, S, Farmer, A, Ferrier, In, Flynn, E, Forbes, A, Forty, L, Franklyn, Ja, Frayling, Tm, Freathy, Rm, Giannoulatou, E, Gibbs, P, Gilbert, P, Gordon Smith, K, Gray, E, Green, E, Groves, Cj, Grozeva, D, Gwilliam, R, Hall, A, Hammond, N, Hardy, M, Harrison, P, Hassanali, N, Hebaishi, H, Hines, S, Hinks, A, Hitman, Ga, Hocking, L, Holmes, C, Howard, E, Howard, P, Howson, Jm, Hughes, D, Hunt, S, Isaacs, Jd, Jain, M, Jewell, Dp, Johnson, T, Jolley, Jd, Jones, Ir, Jones, La, Kirov, G, Langford, Cf, Lango Allen, H, Lathrop, Gm, Lee, J, Lee, Kl, Lees, C, Lewis, K, Lindgren, Cm, Maisuria Armer, M, Maller, J, Mansfield, J, Marchini, Jl, Martin, P, Massey, Dc, Mcardle, Wl, Mcguffin, P, Mclay, Ke, Mcvean, G, Mentzer, A, Mimmack, Ml, Morgan, Ae, Morris, Ap, Mowat, C, Munroe, Pb, Myers, S, Newman, W, Nimmo, Er, O'Donovan, Mc, Onipinla, A, Ovington, Nr, Owen, Mj, Palin, K, Palotie, A, Parnell, K, Pearson, R, Pernet, D, Perry, Jr, Phillips, A, Plagnol, V, Prescott, Nj, Prokopenko, I, Quail, Ma, Rafelt, S, Rayner, Nw, Reid, Dm, Renwick, A, Ring, Sm, Robertson, N, Robson, S, Russell, E, St Clair, D, Sambrook, Jg, Sanderson, Jd, Sawcer, Sj, Schuilenburg, H, Scott, Ce, Seal, S, Shaw Hawkins, S, Shields, Bm, Simmonds, Mj, Smyth, Dj, Somaskantharajah, E, Spanova, K, Steer, S, Stephens, J, Stevens, He, Stirrups, K, Stone, Ma, Strachan, Dp, Su, Z, Symmons, Dp, Thompson, Jr, Thomson, W, Tobin, Md, Travers, Me, Turnbull, C, Vukcevic, D, Wain, Lv, Walker, M, Walker, Nm, Wallace, C, Warren Perry, M, Watkins, Na, Webster, J, Weedon, Mn, Wilson, Ag, Woodburn, M, Wordsworth, Bp, Yau, C, Young, Ah, Zeggini, E, Brown, Ma, Burton, Pr, Caulfield, Mj, Compston, A, Farrall, M, Gough, Sc, Hall, As, Hattersley, At, Hill, Av, Mathew, Cg, Pembrey, M, Satsangi, J, Stratton, Mr, Worthington, J, Hurles, Me, Duncanson, A, Ouwehand, Wh, Parkes, M, Rahman, N, Todd, Ja, Samani, Nj, Kwiatkowski, Dp, Mccarthy, Mi, Craddock, N, Deloukas, P, Donnelly, P, Blackwell, Jm, Bramon, E, Casas, Jp, Corvin, A, Jankowski, J, Markus, Hs, Palmer, Cn, Plomin, R, Rautanen, A, Trembath, Rc, Viswanathan, Ac, Wood, Nw, Spencer, Cc, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Pirinen, M, Strange, A, Blackburn, H, Bumpstead, Sj, Dronov, S, Gillman, M, Jayakumar, A, Mccann, Ot, Liddle, J, Potter, Sc, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, Whittaker, P., AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Gastroenterology and Hepatology, and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)

Subjects
Genome-wide association study, Disease, SUSCEPTIBILITY, Inflammatory bowel disease, NUMBER, 0302 clinical medicine, Crohn Disease, NETWORK, Genetics, 0303 health sciences, Multidisciplinary, Genomics, Ulcerative colitis, 3. Good health, Colitis, Ulcerative, Genetic Predisposition to Disease, Genome, Human, Haplotypes, Humans, Inflammatory Bowel Diseases, Mycobacterium, Mycobacterium Infections, Mycobacterium tuberculosis, Phenotype, Polymorphism, Single Nucleotide, Reproducibility of Results, Genome-Wide Association Study, Host-Pathogen Interactions, IRGM, Medical genetics, 030211 gastroenterology & hepatology, EXPRESSION, medicine.medical_specialty, Immunology, Biology, Molecular gastro-enterology and hepatology Pathogenesis and modulation of inflammation [IGMD 2], TUBERCULOSIS, 03 medical and health sciences, Medical research, medicine, Allele, METAANALYSIS, 030304 developmental biology, HYPER-IGE SYNDROME, MUTATIONS, medicine.disease, RISK LOCI, Genetic architecture, digestive system diseases
Abstract

Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations(1). Genome-wide association studies and subsequent meta-analyses of these two diseases(2,3) as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy(4), in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases(5). Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.

Published
2012

45. Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility

Author

Evans, Dm, Spencer, Cc, Pointon, Jj, Su, Z, Harvey, D, Kochan, G, Oppermann, U, Dilthey, A, Pirinen, M, Stone, Ma, Appleton, L, Moutsianas, L, Leslie, S, Wordsworth, T, Kenna, Tj, Karaderi, T, Thomas, Gp, Ward, Mm, Weisman, Mh, Farrar, C, Bradbury, La, Danoy, P, Inman, Rd, Maksymowych, W, Gladman, D, Rahman, P, Spondyloarthritis Research Consortium of Canada, Morgan, A, Marzo Ortega, H, Bowness, P, Gaffney, K, Gaston, Js, Smith, M, Bruges Armas, J, Couto, Ar, Sorrentino, Rosa, Paladini, Fabiana, Ferreira, Ma, Xu, H, Liu, Y, Jiang, L, Lopez Larrea, C, Díaz Peña, R, López Vázquez, A, Zayats, T, Band, G, Bellenguez, C, Blackburn, H, Blackwell, Jm, Bramon, E, Bumpstead, Sj, Casas, Jp, Corvin, A, Craddock, N, Deloukas, P, Dronov, S, Duncanson, A, Edkins, S, Freeman, C, Gillman, M, Gray, E, Gwilliam, R, Hammond, N, Hunt, Se, Jankowski, J, Jayakumar, A, Langford, C, Liddle, J, Markus, Hs, Mathew, Cg, Mccann, Ot, Mccarthy, Mi, Palmer, Cn, Peltonen, L, Plomin, R, Potter, Sc, Rautanen, A, Ravindrarajah, R, Ricketts, M, Samani, N, Sawcer, Sj, Strange, A, Trembath, Rc, Viswanathan, Ac, Waller, M, Weston, P, Whittaker, P, Widaa, S, Wood, Nw, Mcvean, G, Reveille, Jd, Wordsworth, Bp, Brown, Ma, Donnelly, P, Australo Anglo American Spondyloarthritis Consortium, and Wellcome Trust Case Control Consortium, 2

Subjects
Receptors, Peptide, HLA-B27, ERAP1, ANKYLOSING SPONDYLITIS, Inflammatory arthritis, Population, Genome-wide association study, Human leukocyte antigen, Biology, CD8-Positive T-Lymphocytes, Bioinformatics, Aminopeptidases, White People, Minor Histocompatibility Antigens, Meta-Analysis as Topic, Genetics, medicine, Humans, Spondylitis, Ankylosing, education, Spondylitis, HLA-B27 Antigen, education.field_of_study, Ankylosing spondylitis, HLA-B27, Polymorphism, Genetic, Interleukin-12 Subunit p40, Membrane Proteins, medicine.disease, Endoplasmic reticulum aminopeptidase 2, Peptide Fragments, CARD Signaling Adaptor Proteins, Core Binding Factor Alpha 3 Subunit, Latent TGF-beta Binding Proteins, Receptors, Tumor Necrosis Factor, Type I, Case-Control Studies, Immunology, Disease Susceptibility, Receptors, Prostaglandin E, EP4 Subtype, Genome-Wide Association Study
Abstract

Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 × 10(-8) in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 × 10(-6) overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27-positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.

Published
2011

48. General discussion

Author

Lyklema, J, Prieve, DC, Brown, MA, Bike, SG, Oxtoby, D, Silberberg, A, Smalley, MV, Gast, AP, Stoylov, SP, Tadros, TF, Morantz, DJ, Shaw, J, Goodwin, JW, Albery, WJ, Zukoski, CF, Van De Ven, TGM, Kuin, AJ, Overbeek, JTG, Wennerström, H, Duisterwinkel, AE, Klein, R, Penfold, J, Frens, G, Saville, DA, Vincent, B, Groot, RD, and Russel, WB

Published
1990

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