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509 results on '"Mowat, C"'

1. The JCMT Gould Belt Survey: A First Look at the Auriga-California Molecular Cloud with SCUBA-2

Author

Broekhoven-Fiene, H., Matthews, B. C., Harvey, P., Kirk, H., Chen, M., Currie, M. J., Pattle, K., Lane, J., Buckle, J., Di Francesco, J., Drabek-Maunder, E., Johnstone, D., Berry, D. S., Fich, M., Hatchell, J., Jenness, T., Mottram, J. C., Nutter, D., Pineda, J. E., Quinn, C., Salji, C., Tisi, S., Hogerheijde, M. R., Ward-Thompson, D., Bastien, P., Bresnahan, D., Butner, H., Chrysostomou, A., Coude, S., Davis, C. J., Duarte-Cabral, A., Fiege, J., Friberg, P., Friesen, R., Fuller, G. A., Graves, S., Greaves, J., Gregson, J., Holland, W., Joncas, G., Kirk, J. M., Knee, L. B. G., Mairs, S., Marsh, K., Moriarty-Schieven, G., Mowat, C., Rawlings, J., Richer, J., Robertson, D., Rosolowsky, E., Rumble, D., Sadavoy, S., Thomas, H., Tothill, N., Viti, S., White, G. J., Wilson, C. D., Wouterloot, J., Yates, J., and Zhu, M.

Subjects
Astrophysics - Astrophysics of Galaxies
Abstract

We present 850 and 450 micron observations of the dense regions within the Auriga-California molecular cloud using SCUBA-2 as part of the JCMT Gould Belt Legacy Survey to identify candidate protostellar objects, measure the masses of their circumstellar material (disk and envelope), and compare the star formation to that in the Orion A molecular cloud. We identify 59 candidate protostars based on the presence of compact submillimeter emission, complementing these observations with existing Herschel/SPIRE maps. Of our candidate protostars, 24 are associated with young stellar objects (YSOs) in the Spitzer and Herschel/PACS catalogs of 166 and 60 YSOs, respectively (177 unique), confirming their protostellar nature. The remaining 35 candidate protostars are in regions, particularly around LkHalpha 101, where the background cloud emission is too bright to verify or rule out the presence of the compact 70 micron emission that is expected for a protostellar source. We keep these candidate protostars in our sample but note that they may indeed be prestellar in nature. Our observations are sensitive to the high end of the mass distribution in Auriga-Cal. We find that the disparity between the richness of infrared star forming objects in Orion A and the sparsity in Auriga-Cal extends to the submillimeter, suggesting that the relative star formation rates have not varied over the Class II lifetime and that Auriga-Cal will maintain a lower star formation efficiency., Comment: 39 pages (54 including the Appendix), 9 figures, 3 tables, in press in ApJ

Published
2018
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2. The JCMT Gould Belt Survey: A First Look at IC 5146

Author

Johnstone, D., Ciccone, S., Kirk, H., Mairs, S., Buckle, J., Berry, D. S., Broekhoven-Fiene, H., Currie, M. J., Hatchell, J., Jenness, T., Mottram, J. C., Pattle, K., Di Francesco, S. Tisi J., Hogerheijde, M. R., Ward-Thompson, D., Bastien, P., Bresnahan, D., Butner, H., Chen, M., Chrysostomou, A., Coude, S., Davis, C. J., Drabek-Maunder, E., Duarte-Cabral, A., Fich, M., Fiege, J., Friberg, P., Friesen, R., Fuller, G. A., Graves, S., Greaves, J., Gregson, J., Holland, W., Joncas, G., Kirk, J. M., Knee, L. B. G., Marsh, K., Matthews, B. C., Moriarty-Schieven, G., Mowat, C., Nutter, D., Pineda, J. E., Salji, C., Rawlings, J., Richer, J., Robertson, D., Rosolowsky, E., Rumble, D., Sadavoy, S., Thomas, H., Tothill, N., Viti, S., White, G. J., Wouterloot, J., Yates, J., and Zhu, M.

Subjects
Astrophysics - Astrophysics of Galaxies, Astrophysics - Solar and Stellar Astrophysics
Abstract

We present 450 and 850 micron submillimetre continuum observations of the IC5146 star-forming region taken as part of the JCMT Gould Belt Survey. We investigate the location of bright submillimetre (clumped) emission with the larger-scale molecular cloud through comparison with extinction maps, and find that these denser structures correlate with higher cloud column density. Ninety-six individual submillimetre clumps are identified using FellWalker and their physical properties are examined. These clumps are found to be relatively massive, ranging from 0.5to 116 MSun with a mean mass of 8 MSun and a median mass of 3.7 MSun. A stability analysis for the clumps suggest that the majority are (thermally) Jeans stable, with M/M_J < 1. We further compare the locations of known protostars with the observed submillimetre emission, finding that younger protostars, i.e., Class 0 and I sources, are strongly correlated with submillimetre peaks and that the clumps with protostars are among the most Jeans unstable. Finally, we contrast the evolutionary conditions in the two major star-forming regions within IC5146: the young cluster associated with the Cocoon Nebula and the more distributed star formation associated with the Northern Streamer filaments. The Cocoon Nebula appears to have converted a higher fraction of its mass into dense clumps and protostars, the clumps are more likely to be Jeans unstable, and a larger fraction of these remaining clumps contain embedded protostars. The Northern Streamer, however, has a larger number of clumps in total and a larger fraction of the known protostars are still embedded within these clumps., Comment: 30 pages, 11 figures, 8 tables, accepted by ApJ

Published
2017
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3. The JCMT Gould Belt Survey: A First Look at Southern Orion A with SCUBA-2

Author

Mairs, Steve, Johnstone, D., Kirk, H., Buckle, J., Berry, D. S., Broekhoven-Fiene, H., Currie, M. J., Fich, M., Graves, S., Hatchell, J., Jenness, T., Mottram, J. C., Nutter, D., Pattle, K., Pineda, J. E., Salji, C., Di Francesco, J., Hogerheijde, M. R., Ward-Thompson, D., Bastien, P., Bresnahan, D., Butner, H., Chen, M., Chrysostomou, A., Coudé, S., Davis, C. J., Drabek-Maunder, E., Duarte-Cabral, A., Fiege, J., Friberg, P., Friesen, R., Fuller, G. A., Greaves, J., Gregson, J., Holland, W., Joncas, G., Kirk, J. M., Knee, L. B. G., Marsh, K., Matthews, B. C., Moriarty-Schieven, G., Mowat, C., Rawlings, J., Richer, J., Robertson, D., Rosolowsky, E., Rumble, D., Sadavoy, S., Thomas, H., Tothill, N., Viti, S., White, G. J., Wouterloot, J., Yates, J., and Zhu, M.

Subjects
Astrophysics - Solar and Stellar Astrophysics, Astrophysics - Astrophysics of Galaxies
Abstract

We present the JCMT Gould Belt Survey's first look results of the southern extent of the Orion A Molecular Cloud ($\delta \leq -5\mathrm{:}31\mathrm{:}27.5$). Employing a two-step structure identification process, we construct individual catalogues for large-scale regions of significant emission labelled as islands and smaller-scale subregions called fragments using the 850 $\mu$m continuum maps obtained using SCUBA-2. We calculate object masses, sizes, column densities, and concentrations. We discuss fragmentation in terms of a Jeans instability analysis and highlight interesting structures as candidates for follow-up studies. Furthermore, we associate the detected emission with young stellar objects (YSOs) identified by Spitzer and Herschel. We find that although the population of active star-forming regions contains a wide variety of sizes and morphologies, there is a strong positive correlation between the concentration of an emission region and its calculated Jeans instability. There are, however, a number of highly unstable subregions in dense areas of the map that show no evidence of star formation. We find that only $\sim$72\% of the YSOs defined as Class 0+I and flat-spectrum protostars coincide with dense 850 $\mu$m emission structures (column densities $>3.7\times10^{21}\mathrm{\:cm}^{-2}$). The remaining 28\% of these objects, which are expected to be embedded in dust and gas, may be misclassified. Finally, we suggest that there is an evolution in the velocity dispersion of young stellar objects such that sources which are more evolved are associated with higher velocities., Comment: 31 Pages, 19 Figures, Accepted for publication in Monthly Notices of the Royal Astronomical Society (MNRAS)

Published
2016
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4. The JCMT Gould Belt Survey: Evidence for Dust Grain Evolution in Perseus Star-forming Clumps

Author

Chen, Michael Chun-Yuan, Di Francesco, J., Johnstone, D., Sadavoy, S., Hatchell, J., Mottram, J. C., Kirk, H., Buckle, J., Berry, D. S., Broekhoven-Fiene, H., Currie, M. J., Fich, M., Jenness, T., Nutter, D., Pattle, K., Pineda, J. E., Quinn, C., Salji, C., Tisi, S., Hogerheijde, M. R., Ward-Thompson, D., Bastien, P., Bresnahan, D., Butner, H., Chrysostomou, A., Coude, S., Davis, C. J., Drabek-Maunder, E., Duarte-Cabral, A., Fiege, J., Friberg, P., Friesen, R., Fuller, G. A., Graves, S., Greaves, J., Gregson, J., Holland, W., Joncas, G., Kirk, J. M., Knee, L. B. G., Mairs, S., Marsh, K., Matthews, B. C., Moriarty-Schieven, G., Mowat, C., Pezzuto, S., Rawlings, J., Richer, J., Robertson, D., Rosolowsky, E., Rumble, D., Schneider-Bontemps, N., Thomas, H., Tothill, N., Viti, S., White, G. J., Wouterloot, J., Yates, J., and Zhu, M.

Subjects
Astrophysics - Astrophysics of Galaxies, Astrophysics - Solar and Stellar Astrophysics
Abstract

The dust emissivity spectral index, $\beta$, is a critical parameter for deriving the mass and temperature of star-forming structures, and consequently their gravitational stability. The $\beta$ value is dependent on various dust grain properties, such as size, porosity, and surface composition, and is expected to vary as dust grains evolve. Here we present $\beta$, dust temperature, and optical depth maps of the star-forming clumps in the Perseus Molecular Cloud determined from fitting SEDs to combined Herschel and JCMT observations in the 160 $\mu$m, 250 $\mu$m, 350 $\mu$m, 500 $\mu$m, and 850 $\mu$m bands. Most of the derived $\beta$, and dust temperature values fall within the ranges of 1.0 - 2.7 and 8 - 20 K, respectively. In Perseus, we find the $\beta$ distribution differs significantly from clump to clump, indicative of grain growth. Furthermore, we also see significant, localized $\beta$ variations within individual clumps and find low $\beta$ regions correlate with local temperature peaks, hinting at the possible origins of low $\beta$ grains. Throughout Perseus, we also see indications of heating from B stars and embedded protostars, as well evidence of outflows shaping the local landscape., Comment: Accepted to ApJ, 15 figures, 3 tables

Published
2016
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5. The JCMT Gould Belt Survey: Evidence for radiative heating and contamination in the W40 complex

Author

Rumble, D., Hatchell, J., Pattle, K., Kirk, H., Wilson, T., Buckle, J., Berry, D. S., Broekhoven-Fiene, H., Currie, M. J., Fich, M., Jenness, T., Johnstone, D., Mottram, J. C., Nutter, D., Pineda, J. E., Quinn, C., Salji, C., Tisi, S., Walker-Smith, S., Di Francesco, J., Hogerheijde, M. R., Ward-Thompson, D., Bastien, P., Bresnahan, D., Butner, H., Chen, M., Chrysostomou, A., Coude, S., Davis, C. J., Drabek-Maunder, E., Duarte-Cabral, A., Fiege, J., Friberg, P., Friesen, R., Fuller, G. A., Graves, S., Greaves, J., Gregson, J., Holland, W., Joncas, G., Kirk, J. M., Knee, L. B. G., Mairs, S., Matthews, B. C., Moriarty-Schieven, G., Mowat, C., Rawlings, J., Richer, J., Robertson, D., Rosolowsky, E., Sadavoy, S., Thomas, H., Tothill, N., Viti, S., White, G. J., Wouterloot, J., Yates, J., and Zhu, M.

Subjects
Astrophysics - Astrophysics of Galaxies, Astrophysics - Solar and Stellar Astrophysics
Abstract

We present SCUBA-2 450{\mu}m and 850{\mu}m observations of the W40 complex in the Serpens-Aquila region as part of the James Clerk Maxwell Telescope (JCMT) Gould Belt Survey (GBS) of nearby star-forming regions. We investigate radiative heating by constructing temperature maps from the ratio of SCUBA-2 fluxes using a fixed dust opacity spectral index, {\beta} = 1.8, and a beam convolution kernel to achieve a common 14.8" resolution. We identify 82 clumps ranging between 10 and 36K with a mean temperature of 20{\pm}3K. Clump temperature is strongly correlated with proximity to the external OB association and there is no evidence that the embedded protostars significantly heat the dust. We identify 31 clumps that have cores with densities greater than 105cm{^{-3}}. Thirteen of these cores contain embedded Class 0/I protostars. Many cores are associated with bright-rimmed clouds seen in Herschel 70 {\mu}m images. From JCMT HARP observations of the 12CO 3-2 line, we find contamination of the 850{\mu}m band of up to 20 per cent. We investigate the free-free contribution to SCUBA-2 bands from large-scale and ultracompact H ii regions using archival VLA data and find the contribution is limited to individual stars, accounting for 9 per cent of flux per beam at 450 {\mu}m or 12 per cent at 850 {\mu}m in these cases. We conclude that radiative heating has potentially influenced the formation of stars in the Dust Arc sub-region, favouring Jeans stable clouds in the warm east and fragmentation in the cool west., Comment: 27 pages, 25 figures, 7 tables, 3 online catalogues

Published
2016
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6. The JCMT Gould Belt Survey: A First Look at Dense Cores in Orion B

Author

Kirk, H., Di Francesco, J., Johnstone, D., Duarte-Cabral, A., Sadavoy, S., Hatchell, J., Mottram, J. C., Buckle, J., Berry, D. S., Broekhoven-Fiene, H., Currie, M. J., Fich, M., Jenness, T., Nutter, D., Pattle, K., Pineda, J. E., Quinn, C., Salji, C., Tisi, S., Hogerheijde, M. R., Ward-Thompson, D., Bastien, P., Bresnahan, D., Butner, H., Chen, M., Chrysostomou, A., Coude, S., Davis, C. J., Drabek-Maunder, E., Fiege, J., Friberg, P., Friesen, R., Fuller, G. A., Graves, S., Greaves, J., Gregson, J., Holland, W., Joncas, G., Kirk, J. M., Knee, L. B. G., Mairs, S., Marsh, K., Matthews, B. C., Moriarty-Schieven, G., Mowat, C., Rawlings, J., Richer, J., Robertson, D., Rosolowsky, E., Rumble, D., Thomas, H., Tothill, N., Viti, S., White, G. J., Wouterloot, J., Yates, J., and Zhu, M.

Subjects
Astrophysics - Solar and Stellar Astrophysics, Astrophysics - Astrophysics of Galaxies
Abstract

We present a first look at the SCUBA-2 observations of three sub-regions of the Orion B molecular cloud: LDN 1622, NGC 2023/2024, and NGC 2068/2071, from the JCMT Gould Belt Legacy Survey. We identify 29, 564, and 322 dense cores in L1622, NGC 2023/2024, and NGC 2068/2071 respectively, using the SCUBA-2 850 micron map, and present their basic properties, including their peak fluxes, total fluxes, and sizes, and an estimate of the corresponding 450 micron peak fluxes and total fluxes, using the FellWalker source extraction algorithm. Assuming a constant temperature of 20 K, the starless dense cores have a mass function similar to that found in previous dense core analyses, with a Salpeter-like slope at the high-mass end. The majority of cores appear stable to gravitational collapse when considering only thermal pressure; indeed, most of the cores which have masses above the thermal Jeans mass are already associated with at least one protostar. At higher cloud column densities, above 1-2 x 10^23 cm^-2, most of the mass is found within dense cores, while at lower cloud column densities, below 1 x 10^23 cm^-2, this fraction drops to 10% or lower. Overall, the fraction of dense cores associated with a protostar is quite small (<8%), but becomes larger for the densest and most centrally concentrated cores. NGC 2023 / 2024 and NGC 2068/2071 appear to be on the path to forming a significant number of stars in the future, while L1622 has little additional mass in dense cores to form many new stars., Comment: Accepted for publication in ApJ; 28 pages, 19 figures. Data associated with the paper, including the full table 4, can be found at https://doi.org/10.11570/16.0003

Published
2015
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7. P518 Dietary and non-dietary predictors of treatment response to adalimumab in anti-TNFα-naïve adults with Crohn’s disease

Author

Jatkowska, A, primary, White, B, additional, Campbell, I, additional, Brownson, E, additional, Short, B, additional, Clowe, J, additional, Seenan, J P, additional, Gaya, D R, additional, Din, S, additional, Ho, G T, additional, Robertson, E, additional, Mowat, C, additional, Milling, S, additional, MacDonald, J, additional, and Gerasimidis, K, additional

Published
2024
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8. P681 Preliminary data from the Biologic and Partial Enteral Nutrition in Crohn’s Disease Study (BIOPIC)

Author

White, B, primary, Jatkowska, A, additional, Campbell, I, additional, Brownson, E, additional, Short, B, additional, Clowe, J, additional, Seenan, J P, additional, Gaya, D, additional, Din, S, additional, Ho, G T, additional, Robertson, E, additional, Mowat, C, additional, Milling, S, additional, Macdonald, J, additional, and Gerasimidis, K, additional

Published
2024
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11. Author Correction: Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease (Nature Communications, (2020), 11, 1, (995), 10.1038/s41467-019-14275-y)

Author

Serra E. G., Schwerd T., Moutsianas L., Cavounidis A., Fachal L., Pandey S., Kammermeier J., Croft N. M., Posovszky C., Rodrigues A., Russell R. K., Barakat F., Auth M. K. H., Heuschkel R., Zilbauer M., Fyderek K., Braegger C., Travis S. P., Satsangi J., Parkes M., Thapar N., Ferry H., Matte J. C., Gilmour K. C., Wedrychowicz A., Sullivan P., Moore C., Sambrook J., Ouwehand W., Roberts D., Danesh J., Baeumler T. A., Fulga T. A., Carrami E. M., Ahmed A., Wilson R., Barrett J. C., Elkadri A., Griffiths A. M., Zurek M., Strisciuglio C., Elawad M., Lo B., Arancibia-Carcamo C., Bailey A., Barnes E., Bird-Lieberman E. L., Brain O., Braden B., Collier J., East J., Howarth L., Keshav S., Klenerman P., Leedham S., Palmer R., Powrie F., Simmons A., Walker M., Tolkien Z., Kaptoge S., Allen D., Mehenny S., Mant J., Di Angelantonio E., Thompson S. G., Yilmaz B., Juillerat P., Geuking M., Wiest R., Macpherson A. J., Bravo F. D., Brugger L., Carstens O., Bigler U. G., Heimgartner B., Rusticeanu M., Schmid-Uebelhart S., Strebel B., Tatu A., Tutuian R., Oyas O., Ramon C., Stelling J., Franc Y., Fournier N., Pittet V. E. H., Burnand B., Egger M., Golay D., Marot A., Musso L., Rossel J. -B., Seematter V., Sommer J., Vulliamy R., Michetti P., Maillard M. H., Keller C., Nydegger A., Schoepfe A., Archanioti E., Ezri J., Fraga M., Schoepfer A., Muller C., Rogler G., Biedermann L., Blattmann M., Burk S., Dora B., Fried M., Misselwitz B., Mullhaupt B., Obialo N., Pohl D., Raschle N., Scharl M., Vavricka S., Von Kanel R., Zeitz J., Abdelrahman K., Ademi G., Borovicka J., Brand S., Frei R., Haarer J., Knellwolf-Grieger C., Krieger-Grubel C., Kunzler P., Meyenberger C., Meyer P., Rohrich N., Sawatzki M., Schelling M., Semadeni G. -M., Sulz M., Zimmermann D., Aepli P., Criblez D. H., Hess C., Richterich J. -P., Spalinger J., Staudenmann D., Stulz A., Wohrle S., Thomas A., Anderegg C., Kohler H., Kusche R., Antonino A. -T., Arrigoni E., Bengoa J. M., Cunningham S., de Saussure P., Girard L., de Jong D. B., Basturk P., Brunner S., Degen L., Hruz P., Bakker C. K. -D., Niess J., Balsiger B., Haldemann J., Saner G., Seibold F., Bauerfeind P., Becocci A., Belli D., Binek J., Hengstler P., Boehm S., Boldanov T., Buhr P., Koller R., Rueger V., Senning A., Burri E., Buyse S., Cao D. -T., D'Angelo F., Delarive J., Doerig C., Hessler R., Preissler C., Rentsch R., Risti B., Ritz M. A., Steuerwald M., Vogtlin J., Sagmeister M., Sauter B., Schibli S., Sokollik C., Schlauri H., Schnegg J. -F., Seirafi M., Spangenberger H., Stadler P., Staub P., Stenz V., Tempia-Caliera M., Thorens J., Truninger K., Urfer P., Viani F., Vouillamoz D., Zander S., Wyli T., Jostins L., Kennedy N. A., Ahmad T., Lamb C. A., Edwards C., Hart A., Hawkey C., Mansfield J. C., Mowat C., Newman W. G., Tremelling M., Lee J. C., Prescott N. J., Mathew C. G., Lees C. W., McGovern D. P. B., Targan S. R., Botwin G., Mengesha E., Fleshner P., Landers C., Li D., Rioux J. D., Bitton A., Cote-Daigneault J., Daly M. J., Xavier R., Morris K., Boucher G., Cho J. H., Abraham C., Merad M., Sands B., Peter I., Hao K., Itan Y., Duerr R. H., Konnikova L., Schwartz M. B., Proksell S., Johnston E., Miladinova V., Chen W., Brant S. R., Datta L., Silverberg M. S., Schumm L. P., Birch S., Giri M., Gettler K., Sharma Y., Stevens C., Lazarev M., Haritunians T., Snapper S. B., Shah N., Muise A. M., Wilson D. C., Uhlig H. H., Anderson C. A., Serra, E. G., Schwerd, T., Moutsianas, L., Cavounidis, A., Fachal, L., Pandey, S., Kammermeier, J., Croft, N. M., Posovszky, C., Rodrigues, A., Russell, R. K., Barakat, F., Auth, M. K. H., Heuschkel, R., Zilbauer, M., Fyderek, K., Braegger, C., Travis, S. P., Satsangi, J., Parkes, M., Thapar, N., Ferry, H., Matte, J. C., Gilmour, K. C., Wedrychowicz, A., Sullivan, P., Moore, C., Sambrook, J., Ouwehand, W., Roberts, D., Danesh, J., Baeumler, T. A., Fulga, T. A., Carrami, E. M., Ahmed, A., Wilson, R., Barrett, J. C., Elkadri, A., Griffiths, A. M., Zurek, M., Strisciuglio, C., Elawad, M., Lo, B., Arancibia-Carcamo, C., Bailey, A., Barnes, E., Bird-Lieberman, E. L., Brain, O., Braden, B., Collier, J., East, J., Howarth, L., Keshav, S., Klenerman, P., Leedham, S., Palmer, R., Powrie, F., Simmons, A., Walker, M., Tolkien, Z., Kaptoge, S., Allen, D., Mehenny, S., Mant, J., Di Angelantonio, E., Thompson, S. G., Yilmaz, B., Juillerat, P., Geuking, M., Wiest, R., Macpherson, A. J., Bravo, F. D., Brugger, L., Carstens, O., Bigler, U. G., Heimgartner, B., Rusticeanu, M., Schmid-Uebelhart, S., Strebel, B., Tatu, A., Tutuian, R., Oyas, O., Ramon, C., Stelling, J., Franc, Y., Fournier, N., Pittet, V. E. H., Burnand, B., Egger, M., Golay, D., Marot, A., Musso, L., Rossel, J. -B., Seematter, V., Sommer, J., Vulliamy, R., Michetti, P., Maillard, M. H., Keller, C., Nydegger, A., Schoepfe, A., Archanioti, E., Ezri, J., Fraga, M., Schoepfer, A., Muller, C., Rogler, G., Biedermann, L., Blattmann, M., Burk, S., Dora, B., Fried, M., Misselwitz, B., Mullhaupt, B., Obialo, N., Pohl, D., Raschle, N., Scharl, M., Vavricka, S., Von Kanel, R., Zeitz, J., Abdelrahman, K., Ademi, G., Borovicka, J., Brand, S., Frei, R., Haarer, J., Knellwolf-Grieger, C., Krieger-Grubel, C., Kunzler, P., Meyenberger, C., Meyer, P., Rohrich, N., Sawatzki, M., Schelling, M., Semadeni, G. -M., Sulz, M., Zimmermann, D., Aepli, P., Criblez, D. H., Hess, C., Richterich, J. -P., Spalinger, J., Staudenmann, D., Stulz, A., Wohrle, S., Thomas, A., Anderegg, C., Kohler, H., Kusche, R., Antonino, A. -T., Arrigoni, E., Bengoa, J. M., Cunningham, S., de Saussure, P., Girard, L., de Jong, D. B., Basturk, P., Brunner, S., Degen, L., Hruz, P., Bakker, C. K. -D., Niess, J., Balsiger, B., Haldemann, J., Saner, G., Seibold, F., Bauerfeind, P., Becocci, A., Belli, D., Binek, J., Hengstler, P., Boehm, S., Boldanov, T., Buhr, P., Koller, R., Rueger, V., Senning, A., Burri, E., Buyse, S., Cao, D. -T., D'Angelo, F., Delarive, J., Doerig, C., Hessler, R., Preissler, C., Rentsch, R., Risti, B., Ritz, M. A., Steuerwald, M., Vogtlin, J., Sagmeister, M., Sauter, B., Schibli, S., Sokollik, C., Schlauri, H., Schnegg, J. -F., Seirafi, M., Spangenberger, H., Stadler, P., Staub, P., Stenz, V., Tempia-Caliera, M., Thorens, J., Truninger, K., Urfer, P., Viani, F., Vouillamoz, D., Zander, S., Wyli, T., Jostins, L., Kennedy, N. A., Ahmad, T., Lamb, C. A., Edwards, C., Hart, A., Hawkey, C., Mansfield, J. C., Mowat, C., Newman, W. G., Tremelling, M., Lee, J. C., Prescott, N. J., Mathew, C. G., Lees, C. W., Mcgovern, D. P. B., Targan, S. R., Botwin, G., Mengesha, E., Fleshner, P., Landers, C., Li, D., Rioux, J. D., Bitton, A., Cote-Daigneault, J., Daly, M. J., Xavier, R., Morris, K., Boucher, G., Cho, J. H., Abraham, C., Merad, M., Sands, B., Peter, I., Hao, K., Itan, Y., Duerr, R. H., Konnikova, L., Schwartz, M. B., Proksell, S., Johnston, E., Miladinova, V., Chen, W., Brant, S. R., Datta, L., Silverberg, M. S., Schumm, L. P., Birch, S., Giri, M., Gettler, K., Sharma, Y., Stevens, C., Lazarev, M., Haritunians, T., Snapper, S. B., Shah, N., Muise, A. M., Wilson, D. C., Uhlig, H. H., and Anderson, C. A.

Published
2022

13. Comparative performances of machine learning methods for classifying Crohn Disease patients using genome-wide genotyping data

Author

Romagnoni, A., Jegou, S., Van Steen, K., Wainrib, G., Hugot, J. -P., Peyrin-Biroulet, L., Chamaillard, M., Colombel, J. -F., Cottone, M., D'Amato, M., D'Inca, R., Halfvarson, J., Henderson, P., Karban, A., Kennedy, N. A., Khan, M. A., Lemann, M., Levine, A., Massey, D., Milla, M., S. M. E., Ng, Oikonomou, I., Peeters, H., Proctor, D. D., Rahier, J. -F., Rutgeerts, P., Seibold, F., Stronati, L., Taylor, K. M., Torkvist, L., Ublick, K., Van Limbergen, J., Van Gossum, A., Vatn, M. H., Zhang, H., Zhang, W., Andrews, J. M., Bampton, P. A., Barclay, M., Florin, T. H., Gearry, R., Krishnaprasad, K., Lawrance, I. C., Mahy, G., Montgomery, G. W., Radford-Smith, G., Roberts, R. L., Simms, L. A., Hanigan, K., Croft, A., Amininijad, L., Cleynen, I., Dewit, O., Franchimont, D., Georges, M., Laukens, D., Theatre, E., Vermeire, S., Aumais, G., Baidoo, L., Barrie, A. M., Beck, K., Bernard, E. -J., Binion, D. G., Bitton, A., Brant, S. R., Cho, J. H., Cohen, A., Croitoru, K., Daly, M. J., Datta, L. W., Deslandres, C., Duerr, R. H., Dutridge, D., Ferguson, J., Fultz, J., Goyette, P., Greenberg, G. R., Haritunians, T., Jobin, G., Katz, S., Lahaie, R. G., Mcgovern, D. P., Nelson, L., S. M., Ng, Ning, K., Pare, P., Regueiro, M. D., Rioux, J. D., Ruggiero, E., Schumm, L. P., Schwartz, M., Scott, R., Sharma, Y., Silverberg, M. S., Spears, D., Steinhart, A. H., Stempak, J. M., Swoger, J. M., Tsagarelis, C., Zhang, C., Zhao, H., Aerts, J., Ahmad, T., Arbury, H., Attwood, A., Auton, A., Ball, S. G., Balmforth, A. J., Barnes, C., Barrett, J. C., Barroso, I., Barton, A., Bennett, A. J., Bhaskar, S., Blaszczyk, K., Bowes, J., Brand, O. J., Braund, P. S., Bredin, F., Breen, G., Brown, M. J., Bruce, I. N., Bull, J., Burren, O. S., Burton, J., Byrnes, J., Caesar, S., Cardin, N., Clee, C. M., Coffey, A. J., MC Connell, J., Conrad, D. F., Cooper, J. D., Dominiczak, A. F., Downes, K., Drummond, H. E., Dudakia, D., Dunham, A., Ebbs, B., Eccles, D., Edkins, S., Edwards, C., Elliot, A., Emery, P., Evans, D. M., Evans, G., Eyre, S., Farmer, A., Ferrier, I. N., Flynn, E., Forbes, A., Forty, L., Franklyn, J. A., Frayling, T. M., Freathy, R. M., Giannoulatou, E., Gibbs, P., Gilbert, P., Gordon-Smith, K., Gray, E., Green, E., Groves, C. J., Grozeva, D., Gwilliam, R., Hall, A., Hammond, N., Hardy, M., Harrison, P., Hassanali, N., Hebaishi, H., Hines, S., Hinks, A., Hitman, G. A., Hocking, L., Holmes, C., Howard, E., Howard, P., Howson, J. M. M., Hughes, D., Hunt, S., Isaacs, J. D., Jain, M., Jewell, D. P., Johnson, T., Jolley, J. D., Jones, I. R., Jones, L. A., Kirov, G., Langford, C. F., Lango-Allen, H., Lathrop, G. M., Lee, J., Lee, K. L., Lees, C., Lewis, K., Lindgren, C. M., Maisuria-Armer, M., Maller, J., Mansfield, J., Marchini, J. L., Martin, P., Massey, D. C., Mcardle, W. L., Mcguffin, P., Mclay, K. E., Mcvean, G., Mentzer, A., Mimmack, M. L., Morgan, A. E., Morris, A. P., Mowat, C., Munroe, P. B., Myers, S., Newman, W., Nimmo, E. R., O'Donovan, M. C., Onipinla, A., Ovington, N. R., Owen, M. J., Palin, K., Palotie, A., Parnell, K., Pearson, R., Pernet, D., Perry, J. R., Phillips, A., Plagnol, V., Prescott, N. J., Prokopenko, I., Quail, M. A., Rafelt, S., Rayner, N. W., Reid, D. M., Renwick, A., Ring, S. M., Robertson, N., Robson, S., Russell, E., Clair, D. S., Sambrook, J. G., Sanderson, J. D., Sawcer, S. J., Schuilenburg, H., Scott, C. E., Seal, S., Shaw-Hawkins, S., Shields, B. M., Simmonds, M. J., Smyth, D. J., Somaskantharajah, E., Spanova, K., Steer, S., Stephens, J., Stevens, H. E., Stirrups, K., Stone, M. A., Strachan, D. P., Su, Z., Symmons, D. P. M., Thompson, J. R., Thomson, W., Tobin, M. D., Travers, M. E., Turnbull, C., Vukcevic, D., Wain, L. V., Walker, M., Walker, N. M., Wallace, C., Warren-Perry, M., Watkins, N. A., Webster, J., Weedon, M. N., Wilson, A. G., Woodburn, M., Wordsworth, B. P., Yau, C., Young, A. H., Zeggini, E., Brown, M. A., Burton, P. R., Caulfield, M. J., Compston, A., Farrall, M., Gough, S. C. L., Hall, A. S., Hattersley, A. T., Hill, A. V. S., Mathew, C. G., Pembrey, M., Satsangi, J., Stratton, M. R., Worthington, J., Hurles, M. E., Duncanson, A., Ouwehand, W. H., Parkes, M., Rahman, N., Todd, J. A., Samani, N. J., Kwiatkowski, D. P., Mccarthy, M. I., Craddock, N., Deloukas, P., Donnelly, P., Blackwell, J. M., Bramon, E., Casas, J. P., Corvin, A., Jankowski, J., Markus, H. S., Palmer, C. N., Plomin, R., Rautanen, A., Trembath, R. C., Viswanathan, A. C., Wood, N. W., Spencer, C. C. A., Band, G., Bellenguez, C., Freeman, C., Hellenthal, G., Pirinen, M., Strange, A., Blackburn, H., Bumpstead, S. J., Dronov, S., Gillman, M., Jayakumar, A., Mccann, O. T., Liddle, J., Potter, S. C., Ravindrarajah, R., Ricketts, M., Waller, M., Weston, P., Widaa, S., Whittaker, P., Romagnoni, A., Jegou, S., Van Steen, K., Wainrib, G., Hugot, J. -P., Peyrin-Biroulet, L., Chamaillard, M., Colombel, J. -F., Cottone, M., D'Amato, M., D'Inca, R., Halfvarson, J., Henderson, P., Karban, A., Kennedy, N. A., Khan, M. A., Lemann, M., Levine, A., Massey, D., Milla, M., Ng, S. M. E., Oikonomou, I., Peeters, H., Proctor, D. D., Rahier, J. -F., Rutgeerts, P., Seibold, F., Stronati, L., Taylor, K. M., Torkvist, L., Ublick, K., Van Limbergen, J., Van Gossum, A., Vatn, M. H., Zhang, H., Zhang, W., Andrews, J. M., Bampton, P. A., Barclay, M., Florin, T. H., Gearry, R., Krishnaprasad, K., Lawrance, I. C., Mahy, G., Montgomery, G. W., Radford-Smith, G., Roberts, R. L., Simms, L. A., Hanigan, K., Croft, A., Amininijad, L., Cleynen, I., Dewit, O., Franchimont, D., Georges, M., Laukens, D., Theatre, E., Vermeire, S., Aumais, G., Baidoo, L., Barrie, A. M., Beck, K., Bernard, E. -J., Binion, D. G., Bitton, A., Brant, S. R., Cho, J. H., Cohen, A., Croitoru, K., Daly, M. J., Datta, L. W., Deslandres, C., Duerr, R. H., Dutridge, D., Ferguson, J., Fultz, J., Goyette, P., Greenberg, G. R., Haritunians, T., Jobin, G., Katz, S., Lahaie, R. G., Mcgovern, D. P., Nelson, L., Ng, S. M., Ning, K., Pare, P., Regueiro, M. D., Rioux, J. D., Ruggiero, E., Schumm, L. P., Schwartz, M., Scott, R., Sharma, Y., Silverberg, M. S., Spears, D., Steinhart, A. H., Stempak, J. M., Swoger, J. M., Tsagarelis, C., Zhang, C., Zhao, H., Aerts, J., Ahmad, T., Arbury, H., Attwood, A., Auton, A., Ball, S. G., Balmforth, A. J., Barnes, C., Barrett, J. C., Barroso, I., Barton, A., Bennett, A. J., Bhaskar, S., Blaszczyk, K., Bowes, J., Brand, O. J., Braund, P. S., Bredin, F., Breen, G., Brown, M. J., Bruce, I. N., Bull, J., Burren, O. S., Burton, J., Byrnes, J., Caesar, S., Cardin, N., Clee, C. M., Coffey, A. J., MC Connell, J., Conrad, D. F., Cooper, J. D., Dominiczak, A. F., Downes, K., Drummond, H. E., Dudakia, D., Dunham, A., Ebbs, B., Eccles, D., Edkins, S., Edwards, C., Elliot, A., Emery, P., Evans, D. M., Evans, G., Eyre, S., Farmer, A., Ferrier, I. N., Flynn, E., Forbes, A., Forty, L., Franklyn, J. A., Frayling, T. M., Freathy, R. M., Giannoulatou, E., Gibbs, P., Gilbert, P., Gordon-Smith, K., Gray, E., Green, E., Groves, C. J., Grozeva, D., Gwilliam, R., Hall, A., Hammond, N., Hardy, M., Harrison, P., Hassanali, N., Hebaishi, H., Hines, S., Hinks, A., Hitman, G. A., Hocking, L., Holmes, C., Howard, E., Howard, P., Howson, J. M. M., Hughes, D., Hunt, S., Isaacs, J. D., Jain, M., Jewell, D. P., Johnson, T., Jolley, J. D., Jones, I. R., Jones, L. A., Kirov, G., Langford, C. F., Lango-Allen, H., Lathrop, G. M., Lee, J., Lee, K. L., Lees, C., Lewis, K., Lindgren, C. M., Maisuria-Armer, M., Maller, J., Mansfield, J., Marchini, J. L., Martin, P., Massey, D. C., Mcardle, W. L., Mcguffin, P., Mclay, K. E., Mcvean, G., Mentzer, A., Mimmack, M. L., Morgan, A. E., Morris, A. P., Mowat, C., Munroe, P. B., Myers, S., Newman, W., Nimmo, E. R., O'Donovan, M. C., Onipinla, A., Ovington, N. R., Owen, M. J., Palin, K., Palotie, A., Parnell, K., Pearson, R., Pernet, D., Perry, J. R., Phillips, A., Plagnol, V., Prescott, N. J., Prokopenko, I., Quail, M. A., Rafelt, S., Rayner, N. W., Reid, D. M., Renwick, A., Ring, S. M., Robertson, N., Robson, S., Russell, E., Clair, D. S., Sambrook, J. G., Sanderson, J. D., Sawcer, S. J., Schuilenburg, H., Scott, C. E., Seal, S., Shaw-Hawkins, S., Shields, B. M., Simmonds, M. J., Smyth, D. J., Somaskantharajah, E., Spanova, K., Steer, S., Stephens, J., Stevens, H. E., Stirrups, K., Stone, M. A., Strachan, D. P., Su, Z., Symmons, D. P. M., Thompson, J. R., Thomson, W., Tobin, M. D., Travers, M. E., Turnbull, C., Vukcevic, D., Wain, L. V., Walker, M., Walker, N. M., Wallace, C., Warren-Perry, M., Watkins, N. A., Webster, J., Weedon, M. N., Wilson, A. G., Woodburn, M., Wordsworth, B. P., Yau, C., Young, A. H., Zeggini, E., Brown, M. A., Burton, P. R., Caulfield, M. J., Compston, A., Farrall, M., Gough, S. C. L., Hall, A. S., Hattersley, A. T., Hill, A. V. S., Mathew, C. G., Pembrey, M., Satsangi, J., Stratton, M. R., Worthington, J., Hurles, M. E., Duncanson, A., Ouwehand, W. H., Parkes, M., Rahman, N., Todd, J. A., Samani, N. J., Kwiatkowski, D. P., Mccarthy, M. I., Craddock, N., Deloukas, P., Donnelly, P., Blackwell, J. M., Bramon, E., Casas, J. P., Corvin, A., Jankowski, J., Markus, H. S., Palmer, C. N., Plomin, R., Rautanen, A., Trembath, R. C., Viswanathan, A. C., Wood, N. W., Spencer, C. C. A., Band, G., Bellenguez, C., Freeman, C., Hellenthal, G., Pirinen, M., Strange, A., Blackburn, H., Bumpstead, S. J., Dronov, S., Gillman, M., Jayakumar, A., Mccann, O. T., Liddle, J., Potter, S. C., Ravindrarajah, R., Ricketts, M., Waller, M., Weston, P., Widaa, S., Whittaker, P., Daly, Mark J. [0000-0002-0949-8752], Apollo - University of Cambridge Repository, Hugot, Jean-Pierre [0000-0002-8446-6056], UCL - SSS/IREC/GAEN - Pôle d'Hépato-gastro-entérologie, UCL - (MGD) Service de gastro-entérologie, Romagnoni, A, Jegou, S, VAN STEEN, Kristel, Wainrib, G, Hugot, JP, Peyrin-Biroulet, L, Chamaillard, M, Colombel, JF, Cottone, M, D'Amato, M, D'Inca, R, Halfvarson, J, Henderson, P, Karban, A, Kennedy, NA, Khan, MA, Lemann, M, Levine, A, Massey, D, Milla, M, Ng, SME, Oikonomou, I, Peeters, H, Proctor, DD, Rahier, JF, Rutgeerts, P, Seibold, F, Stronati, L, Taylor, KM, Torkvist, L, Ublick, K, Van Limbergen, J, Van Gossum, A, Vatn, MH, Zhang, H, Zhang, W, Andrews, JM, Bampton, PA, Barclay, M, Florin, TH, Gearry, R, Krishnaprasad, K, Lawrance, IC, Mahy, G, Montgomery, GW, Radford-Smith, G, Roberts, RL, Simms, LA, Hanigan, K, Croft, A, Amininijad, L, Cleynen, I, Dewit, O, Franchimont, D, Georges, M, Laukens, D, Theatre, E, Vermeire, S, Aumais, G, Baidoo, L, Barrie, AM, 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, Ng, SM, Ning, K, Pare, P, Regueiro, MD, Rioux, JD, Ruggiero, E, Schumm, LP, Schwartz, M, Scott, R, Sharma, Y, Silverberg, MS, Spears, D, Steinhart, AH, Stempak, JM, Swoger, JM, Tsagarelis, C, Zhang, C, Zhao, HY, AERTS, Jan, 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, Mc Connell, J, 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, JMM, 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, DCO, 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, JRB, 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, DPM, 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, SCL, Hall, AS, Hattersley, AT, Hill, AVS, 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, CNA, Plomin, R, Rautanen, A, Trembath, RC, Viswanathan, AC, Wood, NW, Spencer, CCA, 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, and Kwiatkowski, D

Subjects
Male, 692/4020/1503/257/1402, Genotype, Genotyping Techniques, LOCI, 45/43, lcsh:Medicine, Polymorphism, Single Nucleotide, Crohn's disease, genetics, genome wide association, Article, Deep Learning, Crohn Disease, INDEL Mutation, Genetics research, Humans, genetics, Genetic Predisposition to Disease, 129, lcsh:Science, Alleles, Science & Technology, genome wide association, RISK PREDICTION, 45, Models, Genetic, lcsh:R, Decision Trees, 692/308/2056, ASSOCIATION, Multidisciplinary Sciences, Crohn's disease, Logistic Models, Nonlinear Dynamics, ROC Curve, Area Under Curve, Science & Technology - Other Topics, lcsh:Q, Female, Neural Networks, Computer, INFLAMMATORY-BOWEL-DISEASE, Genome-Wide Association Study
Abstract

Crohn Disease (CD) is a complex genetic disorder for which more than 140 genes have been identified using genome wide association studies (GWAS). However, the genetic architecture of the trait remains largely unknown. The recent development of machine learning (ML) approaches incited us to apply them to classify healthy and diseased people according to their genomic information. The Immunochip dataset containing 18,227 CD patients and 34,050 healthy controls enrolled and genotyped by the international Inflammatory Bowel Disease genetic consortium (IIBDGC) has been re-analyzed using a set of ML methods: penalized logistic regression (LR), gradient boosted trees (GBT) and artificial neural networks (NN). The main score used to compare the methods was the Area Under the ROC Curve (AUC) statistics. The impact of quality control (QC), imputing and coding methods on LR results showed that QC methods and imputation of missing genotypes may artificially increase the scores. At the opposite, neither the patient/control ratio nor marker preselection or coding strategies significantly affected the results. LR methods, including Lasso, Ridge and ElasticNet provided similar results with a maximum AUC of 0.80. GBT methods like XGBoost, LightGBM and CatBoost, together with dense NN with one or more hidden layers, provided similar AUC values, suggesting limited epistatic effects in the genetic architecture of the trait. ML methods detected near all the genetic variants previously identified by GWAS among the best predictors plus additional predictors with lower effects. The robustness and complementarity of the different methods are also studied. Compared to LR, non-linear models such as GBT or NN may provide robust complementary approaches to identify and classify genetic markers. Tis work was supported by Fondation pour la Recherche Médical (ref DEI20151234405) and Investissements d’Avenir programme ANR-11-IDEX-0005-02, Sorbonne Paris Cite, Laboratoire d’excellence INFLAMEX. Te authors thank the students that participated to the wisdom of the crowd exercise.

Published
2019

25. P575 Real-world effectiveness and safety of ustekinumab for the treatment of refractory Crohn’s disease: The Scottish ustekinumab cohort

Author

PLEVRIS, N, primary, Robertson, A, additional, Fulforth, J, additional, Hall, R, additional, Campbell, I, additional, Kane, C, additional, Veryan, J, additional, Lam, W, additional, Saunders, J, additional, Jenkinson, P, additional, Chuah, C, additional, Kelly, C, additional, Watts, D, additional, Gaya, D, additional, Macdonald, J, additional, Jafferbhoy, H, additional, Seenan, J P, additional, Mowat, C, additional, Sutherland, D, additional, Naismith, G, additional, Bain, G, additional, Arnott, I, additional, Jones, G, additional, and Lees, C, additional

Published
2020
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26. NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease

Author

Schwerd, T., Bryant, R. V., Pandey, S., Capitani, M., Meran, L., Cazier, J. -B., Jung, J., Mondal, K., Parkes, M., Mathew, C. G., Fiedler, K., McCarthy, D. J., Sullivan, P. B., Rodrigues, A., Travis, S. P. L., Moore, C., Sambrook, J., Ouwehand, W. H., Roberts, D. J., Danesh, J., Russell, R. K., Wilson, D. C., Kelsen, J. R., Cornall, R., Denson, L. A., Kugathasan, S., Knaus, U. G., Serra, E. G., Anderson, C. A., Duerr, R. H., McGovern, D. P. B., Cho, J., Powrie, Fiona, Li, V. S. W., Muise, A. M., Uhlig, H. H., Donnelly, P., Bell, J., Bentley, D., McVean, G., Ratcliffe, P., Taylor, J., Wilkie, A. O. M., Broxholme, J., Buck, D., Gregory, L., Gregory, J., Lunter, G., Tomlinson, I., Allan, C., Attar, M., Green, A., Humphray, S., Kingsbury, Z., Lamble, S., Lonie, L., Pagnamenta, A., Piazza, P., Polanco, G., Trebes, A., Copley, R., Fiddy, S., Grocock, R., Hatton, E., Holmes, C., Hughes, L., Humburg, P., Kanapin, A., Lise, S., Martin, H., Murray, L., McCarthy, D., Rimmer, A., Sahgal, N., Wright, B., Yau, C., Arancibia, Carolina, Bailey, Adam, Barnes, Ellie, Bird-Lieberman, Beth, Brain, Oliver, Braden, Barbara, Collier, Jane, East, James, Geremia, Alessandra, Howarth, Lucy, Keshav, Satish, Klenerman, Paul, Leedham, Simon, Palmer, Rebecca, Rodrigues, Astor, Simmons, Alison, Sullivan, Peter B, Travis, Simon P L, Uhlig, Holm H, Heuschkel, Rob, Zilbauer, Matthias, Auth, Marcus K. H., Shah, Neil, Kammermeier, Jochen, Croft, Nick, Barakat, Farah, Russell, Richard K., Wilson, David C., Henderson, Paul, Braegger, Christian P., Posovszky, Carsten, Fyderek, Krzysztof, Wedrychowicz, Andrzej, Zurek, Marlen, Strisciuglio, Caterina, Elawad, Mamoun, Lo, Bernice, Parkes, Miles, Satsangi, Jack, Anderson, Carl A., Jostins, L., Kennedy, N. A., Lamb, C. A., Ahmad, T., Edwards, C., Hart, A., Hawkey, C., Mansfield, J. C., Mowat, C., Newman, W. G., Satsangi, J., Simmons, A., Tremelling, M., Lee, J. C., Prescott, N. J., Lees, C. W., Barrett, J. C., UK IBD Genetics Consortium, COLORS in IBD, Oxford IBD cohort study investigators, WGS500 Consortium, INTERVAL Study, Schwerd, T., Bryant, R. V., Pandey, S., Capitani, M., Meran, L., Cazier, J. -B., Jung, J., Mondal, K., Parkes, M., Mathew, C. G., Fiedler, K., Mccarthy, D. J., Sullivan, P. B., Rodrigues, A., Travis, S. P. L., Moore, C., Sambrook, J., Ouwehand, W. H., Roberts, D. J., Danesh, J., Russell, R. K., Wilson, D. C., Kelsen, J. R., Cornall, R., Denson, L. A., Kugathasan, S., Knaus, U. G., Serra, E. G., Anderson, C. A., Duerr, R. H., Mcgovern, D. P. B., Cho, J., Powrie, Fiona, Li, V. S. W., Muise, A. M., Uhlig, H. H., Donnelly, P., Bell, J., Bentley, D., Mcvean, G., Ratcliffe, P., Taylor, J., Wilkie, A. O. M., Broxholme, J., Buck, D., Gregory, L., Gregory, J., Lunter, G., Tomlinson, I., Allan, C., Attar, M., Green, A., Humphray, S., Kingsbury, Z., Lamble, S., Lonie, L., Pagnamenta, A., Piazza, P., Polanco, G., Trebes, A., Copley, R., Fiddy, S., Grocock, R., Hatton, E., Holmes, C., Hughes, L., Humburg, P., Kanapin, A., Lise, S., Martin, H., Murray, L., Mccarthy, D., Rimmer, A., Sahgal, N., Wright, B., Yau, C., Arancibia, Carolina, Bailey, Adam, Barnes, Ellie, Bird-Lieberman, Beth, Brain, Oliver, Braden, Barbara, Collier, Jane, East, Jame, Geremia, Alessandra, Howarth, Lucy, Keshav, Satish, Klenerman, Paul, Leedham, Simon, Palmer, Rebecca, Rodrigues, Astor, Simmons, Alison, Sullivan, Peter B, Travis, Simon P L, Uhlig, Holm H, Heuschkel, Rob, Zilbauer, Matthia, Auth, Marcus K. H., Shah, Neil, Kammermeier, Jochen, Croft, Nick, Barakat, Farah, Russell, Richard K., Wilson, David C., Henderson, Paul, Braegger, Christian P., Posovszky, Carsten, Fyderek, Krzysztof, Wedrychowicz, Andrzej, Zurek, Marlen, Strisciuglio, Caterina, Elawad, Mamoun, Lo, Bernice, Parkes, Mile, Satsangi, Jack, Anderson, Carl A., Jostins, L., Kennedy, N. A., Lamb, C. A., Ahmad, T., Edwards, C., Hart, A., Hawkey, C., Mansfield, J. C., Mowat, C., Newman, W. G., Satsangi, J., Simmons, A., Tremelling, M., Lee, J. C., Prescott, N. J., Lees, C. W., Barrett, J. C., UK IBD Genetics, Consortium, COLORS in, Ibd, Oxford IBD cohort study, Investigator, Wgs500, Consortium, and Interval, Study

Subjects
Male, Genotype, Colon, Immunology, Mutation, Missense, Genetic Association Studie, Polymorphism, Single Nucleotide, Article, Mice, Animals, Humans, Immunology and Allergy, Genetic Predisposition to Disease, Child, Genetic Association Studies, Genes, Modifier, Genome, Animal, Inflammatory Bowel Disease, High-Throughput Nucleotide Sequencing, Inflammatory Bowel Diseases, digestive system diseases, Host-Pathogen Interaction, Mice, Inbred C57BL, Child, Preschool, Host-Pathogen Interactions, NADPH Oxidase 1, Reactive Oxygen Species, Reactive Oxygen Specie, Human
Abstract

Genetic defects that affect intestinal epithelial barrier function can present with very early-onset inflammatory bowel disease (VEOIBD). Using whole-genome sequencing, a novel hemizygous defect in NOX1 encoding NAPDH oxidase 1 was identified in a patient with ulcerative colitis-like VEOIBD. Exome screening of 1,878 pediatric patients identified further seven male inflammatory bowel disease (IBD) patients with rare NOX1 mutations. Loss-of-function was validated in p.N122H and p.T497A, and to a lesser degree in p.Y470H, p.R287Q, p.I67M, p.Q293R as well as the previously described p.P330S, and the common NOX1 SNP p.D360N (rs34688635) variant. The missense mutation p.N122H abrogated reactive oxygen species (ROS) production in cell lines, ex vivo colonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.D360N and IBD. Our data suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context-specific modifier. Our results implicate that variants in NOX1 change brush border ROS within colonic crypts at the interface between the epithelium and luminal microbes.

Published
2018

27. IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes

Author

Momozawa, Y, Dmitrieva, J, Theatre, E, Deffontaine, V, Rahmouni, S, Charloteaux, B, Crins, F, Docampo, E, Elansary, M, Gori, AS, Lecut, C, Mariman, R, Mni, M, Oury, C, Altukhov, I, Alexeev, D, Aulchenko, Y, Amininejad, L, Bouma, G, Hoentjen, F, Lowenberg, M, Oldenburg, B, Pierik, MJ, de Jong, AE, van der Woude, C.J., Visschedijk, MC, Lathrop, M, Hugot, JP, Weersma, RK, Vos, M, Franchimont, D, Vermeire, S, Kubo, M, Louis, E, Georges, M, Abraham, C, Achkar, JP, Ahmad, T, Ananthakrishnan, AN, Andersen, V, Anderson, CA, Andrews, JM, Annese, V, Aumais, G, Baidoo, L, Baldassano, RN, Bampton, PA, Barclay, M, Barrett, JC, Bayless, TM, Bethge, J, Bitton, A, Boucher, G, Brand, S, Brandt, B, Brant, SR, Buning, C, Chew, A, Cho, JH, Cleynen, I, Cohain, A, Croft, A, Daly, MJ, D'Amato, M, Danese, S, Jong, D, Denapiene, G, Denson, LA, Devaney, KL, Dewit, O, D'Inca, R, Dubinsky, M, Duerr, RH, Edwards, C, Ellinghaus, D, Essers, J, Ferguson, LR, Festen, EA, Fleshner, P, Florin, T, Franke, A, Fransen, K, Gearry, R, Gieger, C, Glas, J, Goyette, P, Green, T, Griffiths, AM, Guthery, SL, Hakonarson, H, Halfvarson, J, Hanigan, K, Haritunians, T, de Hart, A, Hawkey, C, Hayward, NK, Hedl, M, Henderson, P, Hu, XH, Huang, HL, Hui, KY, Imielinski, M, Ippoliti, A, Jonaitis, L, Jostins, L, Karlsen, TH, Kennedy, NA, Khan, MA, Kiudelis, G, Krishnaprasad, K, Kugathasan, S, Kupcinskas, L, Latiano, A, Laukens, D, Lawrance, IC, Lee, JC, Lees, CW, Leja, M, van Limbergen, J, Lionetti, P, Liu, JZ, Mahy, G, Mansfield, J, Massey, D, Mathew, CG, McGovern, DPB, Milgrom, R, Mitrovic, M, Montgomery, GW, Mowat, C, Newman, W, Ng, A, Ng, SC, Ng, SME, Nikolaus, S, Ning, K, Nothen, M, Oikonomou, I, Palmieri, O, Parkes, M, Phillips, A, Ponsioen, CY, Potocnik, U, Prescott, NJ, Proctor, DD, Radford-Smith, G, Rahier, JF, Raychaudhuri, S, Regueiro, M, Rieder, F, Rioux, JD, Ripke, S, Roberts, R, Russell, RK, Sanderson, JD, Sans, M, Satsangi, J, Schadt, EE, Schreiber, S, Schulte, D, Schumm, LP, Scott, R, Seielstad, M, Sharma, Y, Silverberg, MS, Simms, LA, Skieceviciene, J, Spain, SL, Steinhart, AH, Stempak, JM, Stronati, L, Sventoraityte, J, Targan, SR, Taylor, KM, Velde, A, Torkvist, L, Tremelling, M, van Sommeren, S, Vasiliauskas, E, Verspaget, HW, Walters, T, Wang, K, Wang, MH, Wei, Z, Whiteman, D, Wijmenga, C, Wilson, DC, Winkelmann, J, Xavier, RJ, Zhang, B, Zhang, CK, Zhang, H, Zhang, W, Zhao, HY, Zhao, ZZ, Momozawa, Y, Dmitrieva, J, Theatre, E, Deffontaine, V, Rahmouni, S, Charloteaux, B, Crins, F, Docampo, E, Elansary, M, Gori, A, Lecut, C, Mariman, R, Mni, M, Oury, C, Altukhov, I, Alexeev, D, Aulchenko, Y, Amininejad, L, Bouma, G, Hoentjen, F, Lowenberg, M, Oldenburg, B, Pierik, Mj, vander Meulen-de Jong, Ae, van der Woude, Cj, Visschedijk, Mc, Lathrop, M, Hugot, Jp, Weersma, Rk, De Vos, M, Franchimont, D, Vermeire, S, Kubo, M, Louis, E, Georges, M, Abraham, C, Achkar, Jp, Ahmad, T, Ananthakrishnan, An, Andersen, V, Anderson, Ca, Andrews, Jm, Annese, V, Aumais, G, Baidoo, L, Baldassano, Rn, Bampton, Pa, Barclay, M, Barrett, Jc, Bayless, Tm, Bethge, J, Bitton, A, Boucher, G, Brand, S, Brandt, B, Brant, Sr, Buning, C, Chew, A, Cho, Jh, Cleynen, I, Cohain, A, Croft, A, Daly, Mj, D'Amato, M, Danese, S, De Jong, D, Denapiene, G, Denson, La, Devaney, Kl, Dewit, O, D'Inca, R, Dubinsky, M, Duerr, Rh, Edwards, C, Ellinghaus, D, Essers, J, Ferguson, Lr, Festen, Ea, Fleshner, P, Florin, T, Franke, A, Fransen, K, Gearry, R, Gieger, C, Glas, J, Goyette, P, Green, T, Griffiths, Am, Guthery, Sl, Hakonarson, H, Halfvarson, J, Hanigan, K, Haritunians, T, Hart, A, Hawkey, C, Hayward, Nk, Hedl, M, Henderson, P, Hu, Xh, Huang, Hl, Hui, Ky, Imielinski, M, Ippoliti, A, Jonaitis, L, Jostins, L, Karlsen, Th, Kennedy, Na, Khan, Ma, Kiudelis, G, Krishnaprasad, K, Kugathasan, S, Kupcinskas, L, Latiano, A, Laukens, D, Lawrance, Ic, Lee, Jc, Lees, Cw, Leja, M, Van Limbergen, J, Lionetti, P, Liu, Jz, Mahy, G, Mansfield, J, Massey, D, Mathew, Cg, Mcgovern, Dpb, Milgrom, R, Mitrovic, M, Montgomery, Gw, Mowat, C, Newman, W, Ng, A, Ng, Sc, Ng, Sme, Nikolaus, S, Ning, K, Nothen, M, Oikonomou, I, Palmieri, O, Parkes, M, Phillips, A, Ponsioen, Cy, Potocnik, U, Prescott, Nj, Proctor, Dd, Radford-Smith, G, Rahier, Jf, Raychaudhuri, S, Regueiro, M, Rieder, F, Rioux, Jd, Ripke, S, Roberts, R, Russell, Rk, Sanderson, Jd, Sans, M, Satsangi, J, Schadt, Ee, Schreiber, S, Schulte, D, Schumm, Lp, Scott, R, Seielstad, M, Sharma, Y, Silverberg, M, Simms, La, Skieceviciene, J, Spain, Sl, Steinhart, Ah, Stempak, Jm, Stronati, L, Sventoraityte, J, Targan, Sr, Taylor, Km, ter Velde, A, Torkvist, L, Tremelling, M, van Sommeren, S, Vasiliauskas, E, Verspaget, Hw, Walters, T, Wang, K, Wang, Mh, Wei, Z, Whiteman, D, Wijmenga, C, Wilson, Dc, Winkelmann, J, Xavier, Rj, Zhang, B, Zhang, Ck, Zhang, H, Zhang, W, Zhao, Hy, Zhao, Zz, Gastroenterology & Hepatology, UCL - SSS/IREC/GAEN - Pôle d'Hépato-gastro-entérologie, and UCL - (MGD) Service de gastro-entérologie

Subjects
Adult, Male, Multifactorial Inheritance, QUANTITATIVE TRAIT LOCUS, Genotype, SEQUENCING DATA, Quantitative Trait Loci, SUSCEPTIBILITY, Polymorphism, Single Nucleotide, Article, Cohort Studies, CODING VARIANTS, Crohn Disease, 80 and over, Journal Article, Medicine and Health Sciences, LOCUS, Humans, Genetic Predisposition to Disease, Polymorphism, GENOME-WIDE ASSOCIATION, Genetic Association Studies, Aged, Aged, 80 and over, Science & Technology, Female, Gene Expression Profiling, Inflammatory Bowel Diseases, Middle Aged, Sequence Analysis, DNA, COMPLEX TRAITS, Biology and Life Sciences, Single Nucleotide, DNA, CROHNS-DISEASE, Multidisciplinary Sciences, QUANTITATIVE TRAIT, RARE VARIANTS, Science & Technology - Other Topics, LOW-FREQUENCY, Sequence Analysis, INFLAMMATORY-BOWEL-DISEASE
Abstract

GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach., Most of the more than 200 known genetic risk loci for inflammatory bowel disease (IBD) reside in regulatory regions. Here, the authors provide eQTL datasets for six circulating immune cell types and ileal, colonic and rectal biopsies to map regulatory modules and identify potential causative genes for IBD.

Published
2018

29. Follow‐up of small and diminutive colonic polyps—How to balance the risks in the COVID‐19 era.

Author

MacLeod, C, Mowat, C, Winter, J, Todd, J, Ray, C, Maxwell, F, McKinley, A, Noble, C, Collins, P, Wilson, L, Cruikshank, N, Hendry, P, Leggett, G, Fletcher, J, Weber, B, Moug, S, and Watson, AJM

Subjects
*POLYPS, *COLON polyps, *COVID-19, *OLDER patients, *VIRTUAL colonoscopy, *COVID-19 pandemic
Abstract

Follow-up of small and diminutive colonic polyps - How to balance the risks in the COVID-19 era Polypectomy for diminutive polyps in elderly patients is similarly difficult to justify given the low risk of the polyps progressing within the patients' lifetime. Clinicians may feel uncomfortable about leaving diminutive polyps in younger patients who are at least 5 years from the bowel screening age given the risk of progression in the longer term. [Extracted from the article]

Published
2021
Full Text
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30. Association of Genetic Variants in NUDT15 With Thiopurine-Induced Myelosuppression in Patients With Inflammatory Bowel Disease

Author

Walker, GJ, Harrison, JW, Heap, GA, Voskuil, MD, Andersen, V, Anderson, CA, Ananthakrishnan, AN, Barrett, JC, Beaugerie, L, Bewshea, CM, Cole, AT, Cummings, FR, Daly, MJ, Ellul, P, Fedorak, RN, Festen, EAM, Florin, TH, Gaya, DR, Halfvarson, J, Hart, AL, Heerasing, NM, Hendy, P, Irving, PM, Jones, SE, Koskela, J, Lindsay, JO, Mansfield, JC, McGovern, D, Parkes, M, Pollok, RCG, Ramakrishnan, S, Rampton, DS, Rivas, MA, Russell, RK, Schultz, M, Sebastian, S, Seksik, P, Singh, A, So, K, Sokol, H, Subramaniam, K, Todd, A, Annese, V, Weersma, RK, Xavier, R, Ward, R, Weedon, MN, Goodhand, JR, Kennedy, NA, Ahmad, T, Holden, AL, Andrews, J, Auth, M, Babu, S, Bampton, P, Banim, P, Barnes, T, Basude, D, Beckly, J, Bell, A, Bell, S, Bhandari, P, Bloom, S, Border, D, Bredin, F, Brookes, MJ, Brown, M, Calvert, C, Campbell, D, Chanchlani, N, Chaudhary, B, Chaudhary, R, Chung-Faye, G, Colleypriest, B, Connor, S, Cooney, R, Cooper, S, Creed, TJ, Croft, N, Cullen, S, D'Amato, M, Dalal, H, Daneshmend, TK, Das, D, Delaney, M, Desilva, S, Dhar, A, Dharmasiri, S, Direkze, N, Dunckley, P, Elphick, D, Everett, SM, Feeney, M, Fell, J, Foley, S, Franke, A, Gavin, D, Gee, I, Ghosh, D, Goldsmith, C, Gorard, D, Gordon, JN, Gore, S, Green, J, Grimes, D, Hamill, G, Harbord, M, Hart, J, Hawkey, C, Iqbal, T, Ireland, A, Johnson, M, Jones, C, Kanegasundaram, S, Karban, A, Katsanos, KH, Kiparissi, F, Kirkham, S, Lal, S, Langlands, S, Lawrance, IC, Lees, CW, Lev-Tzion, R, Levison, S, Lewis, SJ, Li, A, Limdi, J, Lin, S, Lobo, A, Lockett, M, Loehry, J, MacDonald, C, MacFaul, G, Mahmood, T, Mann, S, Mawdsley, J, Mazhar, Z, McGovern, JF, McNair, A, Modi, A, Monahan, K, Moran, A, Morris, M-A, Mortimore, M, Mowat, C, Muhammed, R, Murray, CDR, Olivier, H, Orchard, TR, Panter, S, Patel, V, Phillips, R, Prasad, N, Preston, C, Radford-Smith, G, Rajasekhar, P, Roy, D, Saich, R, Satsangi, J, Schreiber, S, Sen, S, Shah, N, Shenderay, R, Shenoy, A, Shutt, J, Silverberg, M, Simmons, A, Simmons, J, Singh, S, Smith, M, Snook, JA, Sonwalker, S, Stevens, CR, Sturniolo, G, Subramanian, S, Thomas, A, Tighe, M, Torrente, F, Tremelling, M, Tsianos, E, Vani, D, Walsh, A, Watermeyer, G, Watts, D, Watts, G, Weaver, S, Wesley, E, Willmott, A, Yearsley, K, Zambar, V, Zeissig, S, University of Helsinki, Broad Institute, University of Helsinki, Complex Disease Genetics, Institute for Molecular Medicine Finland, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Simmons, A

Subjects
Male, PREDICTOR, AZATHIOPRINE, Azathioprine, Genome-wide association study, CHILDREN, S-METHYLTRANSFERASE, SUSCEPTIBILITY, Gastroenterology, THERAPY, Leukocyte Count, 0302 clinical medicine, Crohn Disease, Interquartile range, Medicine, Exome, Pyrophosphatases, 11 Medical and Health Sciences, 0303 health sciences, Thiopurine methyltransferase, biology, IBD Pharmacogenetics Study Group, General Medicine, 3. Good health, Editorial Commentary, Cohort, 030211 gastroenterology & hepatology, Female, Life Sciences & Biomedicine, medicine.drug, Adult, medicine.medical_specialty, Adolescent, MERCAPTOPURINE INTOLERANCE, European Continental Ancestry Group, 3121 Internal medicine, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, Young Adult, Medicine, General & Internal, Internal medicine, General & Internal Medicine, MANAGEMENT, Humans, POLYMORPHISMS, 030304 developmental biology, ACUTE LYMPHOBLASTIC-LEUKEMIA, Science & Technology, business.industry, Case-control study, Odds ratio, Methyltransferases, Sequence Analysis, DNA, Haplotypes, 3121 General medicine, internal medicine and other clinical medicine, Case-Control Studies, biology.protein, Colitis, Ulcerative, business, Pharmacogenetics, Genome-Wide Association Study
Abstract

Funding Information: reported serving as a consultant for AbbVie UK; receiving honoraria from Falk and AbbVie UK; receiving grants from Crohn’s & Colitis UK and Tillott’s Pharmaceuticals; having a fellowship from the UK National Institute for Health Research; and receiving travel reimbursement from Merck Sharp & Dohme and Norgine. Dr Heap reported receiving travel reimbursement from AbbVie; and being a current employee of AbbVie and owning stock in the company. Dr Andersen reported receiving personal fees from Merck Sharp & Dohme and Janssen. Dr Ananthakrishnan reported receiving a grant from Pfizer; and receiving personal fees from Takeda. Dr Beaugerie reported receiving advisory board fees from Allergan, Janssen, and Pfizer; receiving a grant from Hospira; and receiving grants and honoraria from AbbVie, Merck Sharp & Dohme, Ferring, Takeda, and Tillott’s Pharmaceuticals. Dr Cummings reported receiving personal fees from AbbVie, Takeda, Biogen, Janssen, Merck Sharp & Dohme, Amgen, Hakim Pharmaceuticals, and Pfizer/Hospira; and receiving grants from Takeda, Biogen, AstraZeneca, and Pfizer/Hospira. Dr Halfvarson reported receiving personal fees from AbbVie, Hospira, Janssen, Medivir, Merck Sharp & Dohme, Pfizer, RenapharmaVifor, Takeda, Tillott’s Pharmaceuticals, Celgene, Sandoz, and Shire; and receiving grants from Janssen, Merck Sharp & Dohme, and Takeda. Dr Hart reported receiving advisory board fees from AbbVie, Atlantic, Bristol-Myers Squibb, Celltrion, Janssen, Merck Sharp & Dohme, Pfizer, Shire, and Takeda; receiving honoraria from Falk and Ferring; and receiving a grant from Takeda. Dr Irving reported receiving personal fees from Janssen, AbbVie, Takeda, Ferring, Pfizer, Lilly, Merck Sharp & Dohme, Samsung, and Sandoz; and receiving grants from Takeda and Merck Sharp & Dohme. Dr Lindsay reported receiving advisory board fees from Atlantic Health, AbbVie UK/global, Merck Sharp & Dohme, Shire UK, Vifor Pharma, Ferring International, Celltrion, Takeda, Napp, Pfizer, and Janssen; serving as a consultant for AbbVie UK/global, Takeda, and Pfizer; receiving grants from Shire UK, AbbVie UK/global, Warner Chilcott, Funding Information: Takeda, Hospira, Ferring International, and Merck Sharp & Dohme; receiving honoraria from Takeda, Cornerstones US, Tillott’s Pharmaceuticals, Napp, Shire International, Janssen, AbbVie, and Pfizer; and receiving travel reimbursement from AbbVie UK, Merck Sharp & Dohme, Warner Chilcott, Takeda, and Shire International. Dr McGovern reported receiving grants from the National Institutes of Health, Helmsley Charitable Trust, and Janssen; and serving as a consultant for Pfizer, Q Biologics, Cidara, Gilead, and Janssen. Dr Seksik reported receiving advisory board fees from Astellas; receiving honoraria from Takeda, AbbVie, and Ferring; and receiving grants from Merck Sharp & Dohme and Biocodex. Dr Sokol reported receiving grants from Biocodex, Danone, and BiomX; serving as a consultant for Enterome, Takeda, AbbVie, Roche, Amgen, Danone, BiomX, Ferring, Bristol-Myers Squibb, Astellas, Merck Sharp & Dohme, Novartis, Tillott’s Pharmaceuticals, and Biose; and being the co-founder of Nextbiotix. Dr Annese reported receiving advisory board fees from Takeda, AbbVie, and Medtronic; and receiving honoraria from Janssen, Takeda, AbbVie, and Medtronic. Dr Weersma reported receiving grants from Takeda, Ferring, and Tramedico; and receiving personal fees from AbbVie. Dr Goodhand reported receiving honoraria from Falk, AbbVie, and Shield Therapeutics. Dr Kennedy reported serving as a consultant for Falk; receiving honoraria from Falk, Allergan, Pharmacosmos, and Takeda; and being a deputy editor of Alimentary Pharmacology & Therapeutics. Dr Ahmad reported receiving unrestricted grants, advisory board fees, speaker honoraria, and support to attend international meetings from AbbVie, Merck Sharp & Dohme, Janssen, Takeda, Ferring, Tillott’s Pharmaceuticals, Ferring, Pfizer, Napp, Celltrion, and Hospira. No other disclosures were reported. Funding Information: Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California), Alistair McNair, PhD (Queen Elizabeth Hospital, London, UK), Anita Modi, MD (Luton and Dunstable University Hospital, Luton, UK), Kevin Monahan, PhD (West Middlesex University Hospital, Middlesex, UK), Alex Moran, MD (Northern Devon Healthcare Trust, Barnstaple, UK), Mary-Anne Morris, MD (Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK), Marianne Mortimore, MBBS (Mater Research Institute, University of Queensland, South Brisbane, Australia), Craig Mowat, MD (Ninewells Hospital, NHS Tayside, Dundee, UK), Rafeeq Muhammed, MD (Birmingham Children's Hospital, Birmingham, UK), Charles D. R. Murray, PhD (Royal Free Hospital, Royal Free London NHS Foundation Trust, London, UK), Hanlie Olivier (IBD Pharmacogenetics Group, University of Exeter, Exeter, UK), Timothy R. Orchard, DM (Imperial College Healthcare NHS Trust, London, UK), Simon Panter, MD (South Tyneside District Hospital, South Tyneside, UK), Vinod Patel, MBBS (Tameside and Glossop Integrated Care NHS Foundation Trust, Ashton-under-Lyne, UK), Rosemary Phillips, MD (Princess Alexandra Hospital, Essex, UK), Neeraj Prasad, MSc (Wrightington Hospital, Wrightington, UK), Cathryn Preston, MBChB (Bradford Royal Infirmary, Bradford, UK), Graham Radford-Smith, PhD (Royal Brisbane and Women’s Hospital, Brisbane, Australia), Praveen Rajasekhar, MD (Northumbria NHS Trust, Tyne and Wear, UK), Dipak Roy, PhD (Tameside and Glossop Integrated Care NHS Foundation Trust, Ashton-under-Lyne, UK), Rebecca Saich, PhD (Basingstoke and North Hampshire Hospital, Basingstoke, UK), Jack Satsangi, PhD (Western General Hospital, NHS Lothian, Edinburgh, UK), Stefan Schreiber, PhD (Kiel University, Kiel, Germany), Sandip Sen, MD (Royal Stoke University Hospital, Stoke-on-Trent, UK), Neil Shah, MD (Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK), Richard Shenderay, MBBS (Airedale NHS Foundation Trust, Keighley, UK), Acuth Shenoy, MD (Colchester Hospital University NHS Foundation Trust, Colchester, UK), James Shutt, DM (Dorset County Hospital NHS Foundation Trust, Dorchester, UK), Mark Silverberg, PhD (Mount Sinai Hospital, Toronto, Ontario, Canada), Alison Simmons, PhD (Oxford University Hospitals, Oxford, UK), Jonathan Simmons, DM (Royal Berkshire Hospital, Royal Berkshire NHS Foundation Trust, Reading, UK), Salil Singh, PhD (Bolton NHS Foundation Trust, Bolton, UK), Malcolm Smith, MBChB (Aberdeen Royal Infirmary, Aberdeen, UK), Mark Smith, MD (Shrewsbury and Telford Hospital NHS Trust, Shrewsbury, UK), Melissa Smith, MB (Royal Sussex County Hospital, Brighton, UK), Jonathon A. Snook, DPhil (Poole Hospital NHS Foundation Trust, Poole, UK), Sunil Sonwalker, MD (Calderdale Royal Hospital, Halifax, UK), Christine R. Stevens, PhD (Broad Institute, Harvard University, Cambridge, Massachusetts), Giacomo Sturniolo, PhD (Univerita di Padova, Padova, Italy), Sreedhar Subramanian, MD (Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK), Amanda Thomas, MBBS (Department of Gastroenterology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, UK), Mark Tighe, BM (Poole Hospital NHS Foundation Trust, Poole, UK), Franco Torrente, MD (Department of Gastroenterology, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK), Mark Tremelling, MD (Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK), Epameinondas Tsianos, PhD (University Hospital of Ioannina, Ioannina, Greece), Deven Vani, MD (Mid Yorkshire Hospitals NHS Trust, Wakefield, UK), Alissa Walsh, MBBS (St Vincent’s Hospital, Sydney, Australia), Gillian Watermeyer, MBChB (Groote Schuur Hospital, Cape Town, South Africa), David Watts, MBChB (Forth Valley Royal Hospital, Larbert, UK), Gill Watts, MD (Wythenshawe Hospital, South Manchester, UK), Sean Weaver, PhD (Royal Bournemouth General Hospital, Bournemouth, UK), Emma Wesley, MBBS (Musgrove Park Hospital, Taunton and Somerset NHS Hospitals, Taunton, UK), Anne Willmott, MBChB (Leicester Royal Infirmary-Paediatric, Leicester, UK), Karen Yearsley, BM (Nevill Hall Hospital, Abergavenny, UK), Veena Zambar, MBBS (Leeds General Infirmary, Leeds, UK), and Sebastian Zeissig, MD (University Medical Center Schleswig-Hostein, Kiel, Germany). These individuals identified and recruited patient s to the study and provided comments on a draft of the manuscript. Funding Information: Adverse Events Consortium funded the sample collection and genotyping at the Broad Institute. The UK National Institute for Health Research provided research nurse support to facilitate recruitment at all UK research sites. Crohn’s & Colitis UK and forCrohns provided funding support and publicized this study to their members. The Exeter National Institute for Health Research Clinical Research Facility provided DNA storage and management. Institutional strategic support award WT097835MF from Wellcome Trust supported the management of the study. Samples from Cedars-Sinai were collected and processed through the MIRIAD biobank that was funded by grant P01DK046763 from the National Institutes of Health. Publisher Copyright: © 2019 American Medical Association. All rights reserved. IMPORTANCE Use of thiopurines may be limited by myelosuppression. TPMT pharmacogenetic testing identifies only 25% of at-risk patients of European ancestry. Among patients of East Asian ancestry, NUDT15 variants are associated with thiopurine-induced myelosuppression (TIM). OBJECTIVE To identify genetic variants associated with TIM among patients of European ancestry with inflammatory bowel disease (IBD). DESIGN, SETTING, AND PARTICIPANTS Case-control study of 491 patients affected by TIM and 679 thiopurine-tolerant unaffected patients who were recruited from 89 international sites between March 2012 and November 2015. Genome-wide association studies (GWAS) and exome-wide association studies (EWAS) were conducted in patients of European ancestry. The replication cohort comprised 73 patients affected by TIM and 840 thiopurine-tolerant unaffected patients. EXPOSURES Genetic variants associated with TIM. MAIN OUTCOMES AND MEASURES Thiopurine-induced myelosuppression, defined as a decline in absolute white blood cell count to 2.5 x 10(9)/L or less or a decline in absolute neutrophil cell count to 1.0 x 10(9)/L or less leading to a dose reduction or drug withdrawal. RESULTS Among 1077 patients (398 affected and 679 unaffected; median age at IBD diagnosis, 31.0 years [interquartile range, 21.2 to 44.1 years]; 540 [50%] women; 602 [56%] diagnosed as having Crohn disease), 919 (311 affected and 608 unaffected) were included in the GWAS analysis and 961 (328 affected and 633 unaffected) in the EWAS analysis. The GWAS analysis confirmed association of TPMT (chromosome 6, rs11969064) with TIM (30.5% [95/311] affected vs 16.4% [100/608] unaffected patients; odds ratio [OR], 2.3 [95% CI, 1.7 to 3.1], P = 5.2 x 10(-9)). The EWAS analysis demonstrated an association with an in-frame deletion in NUDT15 (chromosome 13, rs746071566) and TIM (5.8% [19/328] affected vs 0.2% [1/633] unaffected patients; OR, 38.2 [95% CI, 5.1 to 286.1], P = 1.3 x 10(-8)), which was replicated in a different cohort (2.7% [2/73] affected vs 0.2% [2/840] unaffected patients; OR, 11.8 [95% CI, 1.6 to 85.0], P = .03). Carriage of any of 3 coding NUDT15 variants was associated with an increased risk (OR, 27.3 [95% CI, 9.3 to 116.7], P = 1.1 x 10(-7)) of TIM, independent of TPMT genotype and thiopurine dose. CONCLUSIONS AND RELEVANCE Among patients of European ancestry with IBD, variants in NUDT15 were associated with increased risk of TIM. These findings suggest that NUDT15 genotyping may be considered prior to initiation of thiopurine therapy; however, further study including additional validation in independent cohorts is required.

Published
2019

32. Golimumab induction and maintenance for moderate to severe ulcerative colitis: results from GO-COLITIS (Golimumab: a Phase 4, UK, open label, single arm study on its utilization and impact in ulcerative Colitis)

Author

Probert, CSJ, Sebastian, S, Gaya, DR, Hamlin, PJ, Gillespie, G, Rose, A, Tate, H, Wheeler, C, Irving, PM, Probert, C, Gaya, D, Hart, A, Irving, P, Ahmad, T, Pollok, R, Orchard, T, Arasaradnam, R, Iqbal, T, Johnson, M, Kaser, A, Allen, P, Gordon, J, Preston, C, Shenderey, R, Hoque, S, Bloom, S, Ansari, A, Mowat, C, Hamlin, J, Arnott, I, Shaw, I, Steed, H, Butterworth, J, Robinson, A, Mawdsley, J, Creed, T, Cummings, F, and GO-COLITIS Study Grp

Abstract

Objective GO-COLITIS aimed to measure the effectiveness of subcutaneous golimumab in tumour necrosis factor-α antagonist–naive patients with moderate to severe ulcerative colitis (UC) despite conventional treatment.\ud \ud Design GO-COLITIS was an open label, single arm, phase 4 study with a pragmatic design which reflected UK clinical practice. Adult patients were eligible if diagnosed with UC ≥3 months, partial Mayo score (PMS) 4–9. Patients received subcutaneous golimumab induction (200 mg initially and 100 mg at week 2) followed at week 6 by 50 mg or 100 mg (depending on weight) every 4 weeks until week 54 with a 12-week follow-up. Efficacy was measured by PMS at baseline, week 6, 30, 54 and 66. Health-related quality of life (HRQoL; Inflammatory Bowel Disease Questionnaire (IBDQ) and EuroQol Group 5 Dimensions Health Questionnaire (EQ-5D)) was assessed at baseline, week 6 and week 54. All safety adverse events (AEs) were recorded.\ud \ud Results 207 patients were enrolled and 205 received golimumab (full analysis set (FAS)205). At week 6, 68.8% (95% CI 62.0% to 75.1%) and 38.5% (95% CI 31.8% to 45.6%) of patients were in response and remission, respectively, using PMS. At the end of the induction phase, 140/141 patients in clinical response continued into the maintenance phase (Maintenance FAS). Sustained clinical response through week 54 was achieved in 51/205 (24.9%) of the FAS205 population and 51/140 (36.4%) of the Maintenance FAS population. Statistically significant improvements from baseline to week 6 were observed for the IBDQ total score and for each IBDQ domain score (bowel symptoms, emotional function, systemic symptoms and social function), as well as the EQ-5D index score and associated visual analogue scale score (p

Published
2018

36. IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes

Author

Momozawa, Y., Dmitrieva, J., Theatre, E., Deffontaine, V., Rahmouni, S., Charloteaux, B., Crins, F., Docampo, E., Elansary, M., Gori, A.S., Lecut, C., Mariman, R., Mni, M., Oury, C., Altukhov, I., Alexeev, D., Aulchenko, Y., Amininejad, L., Bouma, G., Hoentjen, F., Lowenberg, M., Oldenburg, B., Pierik, M.J., vander Meulen-de Jong, A.E., Woude, C.J. van der, Visschedijk, M.C., Lathrop, M., Hugot, J.P., Weersma, R.K., Vos, M. de, Franchimont, D., Vermeire, S., Kubo, M., Louis, E., Georges, M., Abraham, C., Achkar, J.P., Ahmad, T., Ananthakrishnan, A.N., Andersen, V., Anderson, C.A., Andrews, J.M., Annese, V., Aumais, G., Baidoo, L., Baldassano, R.N., Bampton, P.A., Barclay, M., Barrett, J.C., Bayless, T.M., Bethge, J., Bitton, A., Boucher, G., Brand, S., Brandt, B., Brant, S.R., Buning, C., Chew, A., Cho, J.H., Cleynen, I., Cohain, A., Croft, A., Daly, M.J., D'Amato, M., Danese, S., Jong, D. de, Denapiene, G., Denson, L.A., Devaney, K.L., Dewit, O., D'Inca, R., Dubinsky, M., Duerr, R.H., Edwards, C., Ellinghaus, D., Essers, J., Ferguson, L.R., Festen, E.A., Fleshner, P., Florin, T., Franke, A., Fransen, K., Gearry, R., Gieger, C., Glas, J., Goyette, P., Green, T., Griffiths, A.M., Guthery, S.L., Hakonarson, H., Halfvarson, J., Hanigan, K., Haritunians, T., Hart, A., Hawkey, C., Hayward, N.K., Hedl, M., Henderson, P., Hu, X.H., Huang, H.L., Hui, K.Y., Imielinski, M., Ippoliti, A., Jonaitis, L., Jostins, L., Karlsen, T.H., Kennedy, N.A., Khan, M.A., Kiudelis, G., Krishnaprasad, K., Kugathasan, S., Kupcinskas, L., Latiano, A., Laukens, D., Lawrance, I.C., Lee, J.C., Lees, C.W., Leja, M., Limbergen, J. van, Lionetti, P., Liu, J.Z., Mahy, G., Mansfield, J., Massey, D., Mathew, C.G., McGovern, D.P.B., Milgrom, R., Mitrovic, M., Montgomery, G.W., Mowat, C., Newman, W., Ng, A., Ng, S.C., Ng, S.M.E., Nikolaus, S., Ning, K., Nothen, M., Oikonomou, I., Palmieri, O., Parkes, M., Phillips, A., Ponsioen, C.Y., Potocnik, U., Prescott, N.J., Proctor, D.D., Radford-Smith, G., Rahier, J.F., Raychaudhuri, S., Regueiro, M., Rieder, F., Rioux, J.D., Ripke, S., Roberts, R., Russell, R.K., Sanderson, J.D., Sans, M., Satsangi, J., Schadt, E.E., Schreiber, S., Schulte, D., Schumm, L.P., Scott, R., Seielstad, M., Sharma, Y., Silverberg, M.S., Simms, L.A., Skieceviciene, J., Spain, S.L., Steinhart, A.H., Stempak, J.M., Stronati, L., Sventoraityte, J., Targan, S.R., Taylor, K.M., Velde, A. ter, Torkvist, L., Tremelling, M., Sommeren, S. van, Vasiliauskas, E., Verspaget, H.W., Walters, T., Wang, K., Wang, M.H., Wei, Z., Whiteman, D., Wijmenga, C., Wilson, D.C., Winkelmann, J., Xavier, R.J., Zhang, B., Zhang, C.K., Zhang, H., Zhang, W., Zhao, H.Y., Zhao, Z.Z., and Int IBD Genetics Consortium

Published
2018

38. Real-world Effectiveness and Safety of Vedolizumab for the Treatment of Inflammatory Bowel Disease: The Scottish Vedolizumab Cohort

Author

Plevris, N, primary, Chuah, C S, additional, Allen, R M, additional, Arnott, I D, additional, Brennan, P N, additional, Chaudhary, S, additional, Churchhouse, A M D, additional, Din, S, additional, Donoghue, E, additional, Gaya, D R, additional, Groome, M, additional, Jafferbhoy, H M, additional, Jenkinson, P W, additional, Lam, W L, additional, Lyons, M, additional, Macdonald, J C, additional, MacMaster, M, additional, Mowat, C, additional, Naismith, G D, additional, Potts, L F, additional, Saffouri, E, additional, Seenan, J P, additional, Sengupta, A, additional, Shasi, P, additional, Sutherland, D I, additional, Todd, J A, additional, Veryan, J, additional, Watson, A J M, additional, Watts, D A, additional, Jones, G R, additional, and Lees, C W, additional

Published
2019
Full Text
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39. IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes

Author

Momozawa, Y. (Yukihide), Dmitrieva, J. (Julia), Théâtre, E. (Emilie), Deffontaine, V. (Valérie), Rahmouni, S. (Souad), Charloteaux, B. (Benoît), Crins, F. (François), Docampo, E. (Elisa), Elansary, M. (Mahmoud), Gori, A.-S. (Ann-Stephan), Lecut, C. (Christelle), Mariman, R. (Rob), Mni, M. (Myriam), Oury, C. (Cécile), Altukhov, I. (Ilya), Alexeev, D. (Dmitry), Aulchenko, Y.S. (Yurii), Amininejad, L. (Leila), Bouma, G. (Gerd), Hoentjen, F., Löwenberg, M., Oldenburg, B. (Bas), Pierik, M. (Marieke), Vander Meulen-De Jong, A.E. (Andrea E.), Woude, C.J. (Janneke) van der, Visschedijk, M. (Marijn), Lathrop, M. (Mark), Hugot, J.P. (J.), Weersma, R.K. (Rinse), De Vos, M. (Martine), Franchimont, D. (Denis), Vermeire, S. (Séverine), Kubo, M. (Michiaki), Louis, E. (Edouard), Georges, M. (Michel), Abraham, C. (Clara), Achkar, J.-P. (Jean-Paul), Ahmad, T. (Tariq), Ananthakrishnan, A.N. (Ashwin N.), Andersen, V. (Vibeke), Anderson, C.A. (Carl A.), Andrews, J.M. (Jane M.), Annese, V. (Vito), Aumais, G. (Guy), Baidoo, L. (Leonard), Baldassano, R.N. (Robert), Bampton, P.A. (Peter A.), Barclay, M. (Murray), Barrett, J.C. (Jeffrey), Bayless, T.M. (Theodore M.), Bethge, J. (Johannes), Bitton, A., Boucher, G. (Gabrielle), Brand, S. (Stephan), Brandt, B. (Berenice), Brant, S.R. (Steven R.), Büning, C. (Carsten), Chew, A. (Angela), Cho, J.H. (Judy H.), Cleynen, I. (Isabelle), Cohain, A. (Ariella), Croft, A. (Anthony), Daly, M.J. (Mark J.), D'Amato, M. (Mauro), Danese, S. (Silvio), De Jong, D.J. (Dirk J.), Denapiene, G. (Goda), Denson, L.A. (Lee A.), Devaney, K.L. (Kathy L.), Dewit, O. (Olivier), D'Inca, R. (Renata), Dubinsky, M. (Marla), Duerr, R.H. (Richard), Edwards, C. (Cathryn), Ellinghaus, D. (David), Essers, J.B. (Jonah), Ferguson, L.R. (Lynnette R.), Festen, E.A.M. (Eleonora), Fleshner, P. (Philip), Florin, T. (Tim), Franke, A. (Andre), Fransen, K. (Karin), Gearry, R. (Richard), Gieger, C. (Christian), Glas, J. (Jürgen), Goyette, P. (Philippe), Green, T. (Todd), Griffiths, A.M. (Anne), Guthery, S.L. (Stephen L.), Hakonarson, H. (Hakon), Halfvarson, J. (Jonas), Hanigan, K. (Katherine), Haritunians, T. (Talin), Hart, A. (Ailsa), Hawkey, S., Hayward, N.K. (Nicholas K.), Hedl, M. (Matija), Henderson, P. (Paul), Hu, X. (Xinli), Huang, H. (Hailiang), Hui, K.Y. (Ken Y.), Imielinski, M. (Marcin), Ippoliti, A. (Andrew), Jonaitis, L. (Laimas), Jostins, L. (Luke), Karlsen, T.H. (Tom), Kennedy, N.A. (Nicholas A.), Khan, M.A. (Mohammed Azam), Kiudelis, G. (Gediminas), Krishnaprasad, K. (Krupa), Kugathasan, S. (Subra), Kupcinskas, L. (Limas), Latiano, A. (Anna), Laukens, D. (Debby), Lawrance, I.C. (Ian C.), Lee, J.C. (James C.), Lees, C.W. (Charlie), Leja, M. (Marcis), Van Limbergen, J. (Johan), Lionetti, P. (Paolo), Liu, J.Z. (Jimmy Z.), Mahy, G. (Gillian), Mansfield, J. (John), Massey, D. (Dunecan), Mathew, J. (Joseph), McGovern, D.P.B. (Dermot P.B.), Milgrom, R. (Raquel), Mitrovic, M. (Mitja), Montgomery, G.W. (Grant W.), Mowat, C. (Craig), Newman, W.G. (William G.), Ng, A. (Aylwin), Ng, S.C. (Siew C.), Ng, S.M.E. (Sok Meng Evelyn), Nikolaus, S. (Susanna), Ning, K. (Kaida), Nöthen, M.M. (Markus), Oikonomou, I. (Ioannis), Palmieri, O. (Orazio), Parkes, M. (Miles), Phillips, A. (Anne), Ponsioen, C.Y. (Cyril), Potocnik, U. (Uros), Prescott, N.J. (Natalie J.), Proctor, D.D. (Deborah D.), Radford-Smith, G. (Graham), Rahier, J.F. (J.), Raychaudhuri, S. (Soumya), Regueiro, M. (Miguel), Rieder, F. (Florian), Rioux, J.D. (John), Ripke, S. (Stephan), Roberts, R. (Rebecca), Russell, R.K. (Richard), Sanderson, J.D. (Jeremy), Sans, S. (Susana), Satsangi, J. (Jack), Schadt, E.E. (Eric), Schreiber, S. (Stefan), Schulte, D. (Dominik), Schumm, L.P. (L. Philip), Scott, R. (Regan), Seielstad, M. (Mark), Sharma, Y. (Yashoda), Silverberg, M. (Mark), Simms, L.A. (Lisa A.), Skieceviciene, J. (Jurgita), Spain, S.L. (Sarah L.), Steinhart, A.H. (A. Hillary), Stempak, J.M. (Joanne M.), Stronati, L. (Laura), Sventoraityte, J. (Jurgita), Targan, S.R. (Stephan R.), Taylor, K.M. (Kirstin M.), Ter Velde, A. (Anje), Torkvist, L. (Leif), Tremelling, M. (Mark), Van Sommeren, S. (Suzanne), Vasiliauskas, E. (Eric), Verspaget, H.W., Walters, T. (Thomas), Wang, K. (Kai), Wang, M.-H. (Ming-Hsi), Wei, Z. (Zhi), Whiteman, D.C. (David C.), Wijmenga, C. (Cisca), Wilson, D.C. (David C.), Winkelmann, B., Xavier, R.J. (Ramnik J.), Zhang, B. (Bin), Zhang, C.K. (Clarence K.), Zhang, H. (Hu), Zhang, W. (Wei), Zhao, H. (Hongyu), Zhao, Z.Z. (Zhen Z.), Momozawa, Y. (Yukihide), Dmitrieva, J. (Julia), Théâtre, E. (Emilie), Deffontaine, V. (Valérie), Rahmouni, S. (Souad), Charloteaux, B. (Benoît), Crins, F. (François), Docampo, E. (Elisa), Elansary, M. (Mahmoud), Gori, A.-S. (Ann-Stephan), Lecut, C. (Christelle), Mariman, R. (Rob), Mni, M. (Myriam), Oury, C. (Cécile), Altukhov, I. (Ilya), Alexeev, D. (Dmitry), Aulchenko, Y.S. (Yurii), Amininejad, L. (Leila), Bouma, G. (Gerd), Hoentjen, F., Löwenberg, M., Oldenburg, B. (Bas), Pierik, M. (Marieke), Vander Meulen-De Jong, A.E. (Andrea E.), Woude, C.J. (Janneke) van der, Visschedijk, M. (Marijn), Lathrop, M. (Mark), Hugot, J.P. (J.), Weersma, R.K. (Rinse), De Vos, M. (Martine), Franchimont, D. (Denis), Vermeire, S. (Séverine), Kubo, M. (Michiaki), Louis, E. (Edouard), Georges, M. (Michel), Abraham, C. (Clara), Achkar, J.-P. (Jean-Paul), Ahmad, T. (Tariq), Ananthakrishnan, A.N. (Ashwin N.), Andersen, V. (Vibeke), Anderson, C.A. (Carl A.), Andrews, J.M. (Jane M.), Annese, V. (Vito), Aumais, G. (Guy), Baidoo, L. (Leonard), Baldassano, R.N. (Robert), Bampton, P.A. (Peter A.), Barclay, M. (Murray), Barrett, J.C. (Jeffrey), Bayless, T.M. (Theodore M.), Bethge, J. (Johannes), Bitton, A., Boucher, G. (Gabrielle), Brand, S. (Stephan), Brandt, B. (Berenice), Brant, S.R. (Steven R.), Büning, C. (Carsten), Chew, A. (Angela), Cho, J.H. (Judy H.), Cleynen, I. (Isabelle), Cohain, A. (Ariella), Croft, A. (Anthony), Daly, M.J. (Mark J.), D'Amato, M. (Mauro), Danese, S. (Silvio), De Jong, D.J. (Dirk J.), Denapiene, G. (Goda), Denson, L.A. (Lee A.), Devaney, K.L. (Kathy L.), Dewit, O. (Olivier), D'Inca, R. (Renata), Dubinsky, M. (Marla), Duerr, R.H. (Richard), Edwards, C. (Cathryn), Ellinghaus, D. (David), Essers, J.B. (Jonah), Ferguson, L.R. (Lynnette R.), Festen, E.A.M. (Eleonora), Fleshner, P. (Philip), Florin, T. (Tim), Franke, A. (Andre), Fransen, K. (Karin), Gearry, R. (Richard), Gieger, C. (Christian), Glas, J. (Jürgen), Goyette, P. (Philippe), Green, T. (Todd), Griffiths, A.M. (Anne), Guthery, S.L. (Stephen L.), Hakonarson, H. (Hakon), Halfvarson, J. (Jonas), Hanigan, K. (Katherine), Haritunians, T. (Talin), Hart, A. (Ailsa), Hawkey, S., Hayward, N.K. (Nicholas K.), Hedl, M. (Matija), Henderson, P. (Paul), Hu, X. (Xinli), Huang, H. (Hailiang), Hui, K.Y. (Ken Y.), Imielinski, M. (Marcin), Ippoliti, A. (Andrew), Jonaitis, L. (Laimas), Jostins, L. (Luke), Karlsen, T.H. (Tom), Kennedy, N.A. (Nicholas A.), Khan, M.A. (Mohammed Azam), Kiudelis, G. (Gediminas), Krishnaprasad, K. (Krupa), Kugathasan, S. (Subra), Kupcinskas, L. (Limas), Latiano, A. (Anna), Laukens, D. (Debby), Lawrance, I.C. (Ian C.), Lee, J.C. (James C.), Lees, C.W. (Charlie), Leja, M. (Marcis), Van Limbergen, J. (Johan), Lionetti, P. (Paolo), Liu, J.Z. (Jimmy Z.), Mahy, G. (Gillian), Mansfield, J. (John), Massey, D. (Dunecan), Mathew, J. (Joseph), McGovern, D.P.B. (Dermot P.B.), Milgrom, R. (Raquel), Mitrovic, M. (Mitja), Montgomery, G.W. (Grant W.), Mowat, C. (Craig), Newman, W.G. (William G.), Ng, A. (Aylwin), Ng, S.C. (Siew C.), Ng, S.M.E. (Sok Meng Evelyn), Nikolaus, S. (Susanna), Ning, K. (Kaida), Nöthen, M.M. (Markus), Oikonomou, I. (Ioannis), Palmieri, O. (Orazio), Parkes, M. (Miles), Phillips, A. (Anne), Ponsioen, C.Y. (Cyril), Potocnik, U. (Uros), Prescott, N.J. (Natalie J.), Proctor, D.D. (Deborah D.), Radford-Smith, G. (Graham), Rahier, J.F. (J.), Raychaudhuri, S. (Soumya), Regueiro, M. (Miguel), Rieder, F. (Florian), Rioux, J.D. (John), Ripke, S. (Stephan), Roberts, R. (Rebecca), Russell, R.K. (Richard), Sanderson, J.D. (Jeremy), Sans, S. (Susana), Satsangi, J. (Jack), Schadt, E.E. (Eric), Schreiber, S. (Stefan), Schulte, D. (Dominik), Schumm, L.P. (L. Philip), Scott, R. (Regan), Seielstad, M. (Mark), Sharma, Y. (Yashoda), Silverberg, M. (Mark), Simms, L.A. (Lisa A.), Skieceviciene, J. (Jurgita), Spain, S.L. (Sarah L.), Steinhart, A.H. (A. Hillary), Stempak, J.M. (Joanne M.), Stronati, L. (Laura), Sventoraityte, J. (Jurgita), Targan, S.R. (Stephan R.), Taylor, K.M. (Kirstin M.), Ter Velde, A. (Anje), Torkvist, L. (Leif), Tremelling, M. (Mark), Van Sommeren, S. (Suzanne), Vasiliauskas, E. (Eric), Verspaget, H.W., Walters, T. (Thomas), Wang, K. (Kai), Wang, M.-H. (Ming-Hsi), Wei, Z. (Zhi), Whiteman, D.C. (David C.), Wijmenga, C. (Cisca), Wilson, D.C. (David C.), Winkelmann, B., Xavier, R.J. (Ramnik J.), Zhang, B. (Bin), Zhang, C.K. (Clarence K.), Zhang, H. (Hu), Zhang, W. (Wei), Zhao, H. (Hongyu), and Zhao, Z.Z. (Zhen Z.)

Abstract

GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach.

Published
2018
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40. Mercaptopurine versus placebo to prevent recurrence of Crohn's disease after surgical resection (TOPPIC): a multicentre, double-blind, randomised controlled trial

Author

Mowat, C, Arnott, I, Cahill, A, Smith, M, Ahmad, T, Subramanian, S, Travis, S, Morris, J, Hamlin, J, Dhar, A, Nwokolo, C, Edwards, C, Creed, T, Bloom, S, Yousif, M, Thomas, L, Campbell, S, Lewis, SJ, Sebastian, S, Sen, S, Lal, S, Hawkey, C, Murray, C, Cummings, F, Goh, J, Lindsay, JO, Arebi, N, Potts, L, McKinley, AJ, Thomson, JM, Todd, JA, Collie, M, Dunlop, MG, Mowat, A, Gaya, DR, Winter, J, Naismith, GD, Ennis, H, Keerie, C, Lewis, S, Prescott, RJ, Kennedy, NA, Satsangi, J, and TOPPIC Study Group

Abstract

BACKGROUND: Up to 60% of patients with Crohn's disease need intestinal resection within the first 10 years of diagnosis, and postoperative recurrence is common. We investigated whether mercaptopurine can prevent or delay postoperative clinical recurrence of Crohn's disease. METHODS: We did a randomised, placebo-controlled, double-blind trial at 29 UK secondary and tertiary hospitals of patients (aged >16 years in Scotland or >18 years in England and Wales) who had a confirmed diagnosis of Crohn's disease and had undergone intestinal resection. Patients were randomly assigned (1:1) by a computer-generated web-based randomisation system to oral daily mercaptopurine at a dose of 1 mg/kg bodyweight rounded to the nearest 25 mg or placebo; patients with low thiopurine methyltransferase activity received half the normal dose. Patients and their carers and physicians were masked to the treatment allocation. Patients were followed up for 3 years. The primary endpoint was clinical recurrence of Crohn's disease (Crohn's Disease Activity Index >150 plus 100-point increase in score) and the need for anti-inflammatory rescue treatment or primary surgical intervention. Primary and safety analyses were by intention to treat. Subgroup analyses by smoking status, previous thiopurines, previous infliximab or methotrexate, previous surgery, duration of disease, or age at diagnosis were also done. This trial is registered with the International Standard Randomised Controlled Trial Register (ISRCTN89489788) and the European Clinical Trials Database (EudraCT number 2006-005800-15). FINDINGS: Between June 6, 2008, and April 23, 2012, 240 patients with Crohn's disease were randomly assigned: 128 to mercaptopurine and 112 to placebo. All patients received at least one dose of study drug, and no randomly assigned patients were excluded from the analysis. 16 (13%) of patients in the mercaptopurine group versus 26 (23%) patients in the placebo group had a clinical recurrence of Crohn's disease and needed anti-inflammatory rescue treatment or primary surgical intervention (adjusted hazard ratio [HR] 0·54, 95% CI 0·27-1·06; p=0·07; unadjusted HR 0·53, 95% CI 0·28-0·99; p=0·046). In a subgroup analysis, three (10%) of 29 smokers in the mercaptopurine group and 12 (46%) of 26 in the placebo group had a clinical recurrence that needed treatment (HR 0·13, 95% CI 0·04-0·46), compared with 13 (13%) of 99 non-smokers in the mercaptopurine group and 14 (16%) of 86 in the placebo group (0·90, 0·42-1·94; pinteraction=0·018). The effect of mercaptopurine did not significantly differ from placebo for any of the other planned subgroup analyses (previous thiopurines, previous infliximab or methotrexate, previous surgery, duration of disease, or age at diagnosis). The incidence and types of adverse events were similar in the mercaptopurine and placebo groups. One patient on placebo died of ischaemic heart disease. Adverse events caused discontinuation of treatment in 39 (30%) of 128 patients in the mercaptopurine group versus 41 (37%) of 112 in the placebo group. INTERPRETATION: Mercaptopurine is effective in preventing postoperative clinical recurrence of Crohn's disease, but only in patients who are smokers. Thus, in smokers, thiopurine treatment seems to be justified in the postoperative period, although smoking cessation should be strongly encouraged given that smoking increases the risk of recurrence.

Published
2017

41. Exploring the genetic architecture of inflammatory bowel disease by whole-genome sequencing identifies association at $\textit{ADCY7}$

Author

Luo, Y, de Lange, KM, Jostins, L, Moutsianas, L, Randall, J, Kennedy, NA, Lamb, CA, McCarthy, S, Ahmad, T, Edwards, C, Serra, EG, Hart, A, Hawkey, C, Mansfield, JC, Mowat, C, Newman, WG, Nichols, S, Pollard, M, Satsangi, J, Simmons, A, Tremelling, M, Uhlig, H, Wilson, DC, Lee, JC, Prescott, NJ, Lees, CW, Mathew, CG, Parkes, M, Barrett, JC, Anderson, CA, McCarthy, Shane [0000-0002-2715-4187], Lee, James [0000-0001-5711-9385], Parkes, Miles [0000-0002-6467-0631], and Apollo - University of Cambridge Repository

Subjects
inflammatory bowel disease, genetic association study, DNA sequencing
Abstract

To further resolve the genetic architecture of the inflammatory bowel diseases ulcerative colitis and Crohn’s disease, we sequenced the whole genomes of 4,280 patients at low coverage and compared them to 3,652 previously sequenced population controls across 73.5 million variants. We then imputed from these sequences into new and existing genome-wide association study cohorts and tested for association at ~12 million variants in a total of 16,432 cases and 18,843 controls. We discovered a 0.6% frequency missense variant in $\textit{ADCY7}$ that doubles the risk of ulcerative colitis. Despite good statistical power, we did not identify any other new low-frequency risk variants and found that such variants explained little heritability. We detected a burden of very rare, damaging missense variants in known Crohn’s disease risk genes, suggesting that more comprehensive sequencing studies will continue to improve understanding of the biology of complex diseases.

Published
2017
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42. Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease

Author

De Lange, KM, Moutsianas, L, Lee, JC, Lamb, CA, Luo, Y, Kennedy, NA, Jostins, L, Rice, DL, Gutierrez-Achury, J, Ji, S-G, Heap, G, Nimmo, ER, Edwards, C, Henderson, P, Mowat, C, Sanderson, J, Satsangi, J, Simmons, A, Wilson, DC, Tremelling, M, Hart, A, Mathew, CG, Newman, WG, Parkes, M, Lees, CW, Uhlig, H, Hawkey, C, Prescott, NJ, Ahmad, T, Mansfield, JC, Anderson, CA, and Barrett, JC

Subjects
Inflammation, Integrins, Quantitative Trait Loci, Humans, Genetic Predisposition to Disease, Inflammatory Bowel Diseases, Polymorphism, Single Nucleotide, Alleles, Genome-Wide Association Study
Abstract

Genetic association studies have identified 215 risk loci for inflammatory bowel disease, thereby uncovering fundamental aspects of its molecular biology. We performed a genome-wide association study of 25,305 individuals and conducted a meta-analysis with published summary statistics, yielding a total sample size of 59,957 subjects. We identified 25 new susceptibility loci, 3 of which contain integrin genes that encode proteins in pathways that have been identified as important therapeutic targets in inflammatory bowel disease. The associated variants are correlated with expression changes in response to immune stimulus at two of these genes ($\textit{ITGA4 }$ and $\textit{ITGB8}$) and at previously implicated loci ($\textit{ITGAL }$and $\textit{ICAM1}$). In all four cases, the expression-increasing allele also increases disease risk. We also identified likely causal missense variants in a gene implicated in primary immune deficiency, $\textit{PLCG2}$, and a negative regulator of inflammation, $\textit{SLAMF8}$. Our results demonstrate that new associations at common variants continue to identify genes relevant to therapeutic target identification and prioritization.

Published
2017
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43. P399 Vedolizumab therapy results in reduced hospitalisation and steroid use over 1-year: Results from the Scottish vedolizumab consortium

Author

Plevris, N, primary, Chuah, C S, additional, Allen, R, additional, Baker, P, additional, Brennan, P, additional, Churchhouse, A, additional, Donoghue, E, additional, Gaya, D, additional, Jafferbhoy, H, additional, Jenkinson, P, additional, Jones, G, additional, Macdonald, J, additional, MacMaster, M, additional, Mowat, C, additional, Naismith, G, additional, Potts, L, additional, Saffouri, E, additional, Seenan, J P, additional, Sengupta, A, additional, Shasi, P, additional, Todd, J, additional, Veryan, J, additional, Watson, A, additional, Watts, D, additional, Arnott, I, additional, Lees, C, additional, and Groome, M, additional

Published
2018
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44. The JCMT Gould Belt Survey: A First Look at the Auriga–California Molecular Cloud with SCUBA-2

Author

Broekhoven-Fiene, H., primary, Matthews, B. C., additional, Harvey, P., additional, Kirk, H., additional, Chen, M., additional, Currie, M. J., additional, Pattle, K., additional, Lane, J., additional, Buckle, J., additional, Francesco, J. Di, additional, Drabek-Maunder, E., additional, Johnstone, D., additional, Berry, D. S., additional, Fich, M., additional, Hatchell, J., additional, Jenness, T., additional, Mottram, J. C., additional, Nutter, D., additional, Pineda, J. E., additional, Quinn, C., additional, Salji, C., additional, Tisi, S., additional, Hogerheijde, M. R., additional, Ward-Thompson, D., additional, Bastien, P., additional, Bresnahan, D., additional, Butner, H., additional, Chrysostomou, A., additional, Coude, S., additional, Davis, C. J., additional, Duarte-Cabral, A., additional, Fiege, J., additional, Friberg, P., additional, Friesen, R., additional, Fuller, G. A., additional, Graves, S., additional, Greaves, J., additional, Gregson, J., additional, Holland, W., additional, Joncas, G., additional, Kirk, J. M., additional, Knee, L. B. G., additional, Mairs, S., additional, Marsh, K., additional, Moriarty-Schieven, G., additional, Mowat, C., additional, Rawlings, J., additional, Richer, J., additional, Robertson, D., additional, Rosolowsky, E., additional, Rumble, D., additional, Sadavoy, S., additional, Thomas, H., additional, Tothill, N., additional, Viti, S., additional, White, G. J., additional, Wilson, C. D., additional, Wouterloot, J., additional, Yates, J., additional, and Zhu, M., additional

Published
2018
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45. The JCMT Gould Belt Survey: A First Look at SCUBA-2 Observations of the Lupus I Molecular Cloud

Author

Mowat, C., Hatchell, J., Rumble, D., Kirk, H., Buckle, J., Berry, D.S., Broekhoven-Fiene, H., Currie, M.J., Jenness, T., Johnstone, D., Mottram, J.C., Pattle, K., Tisi, S., Francesco, J. Di, Hogerheijde, M.R., Ward-Thompson, Derek, Bastien, P., Bresnahan, D., Butner, H., Chen, M., Chrysostomou, A., Coudé, S., Davis, C.J., Drabek-Maunder, E., Duarte-Cabral, A., Fich, M., Fiege, J., Friberg, P., Friesen, R., Fuller, G.A., Graves, S., Greaves, J., Holland, W., Joncas, G., Kirk, Jason Matthew, Knee, L.B.G., Mairs, S., Marsh, K., Matthews, B.C., Moriarty-Schieven, G., Rawlings, J., Retter, B., Richer, J., Robertson, D., Rosolowsky, E., Sadavoy, S., Thomas, H., Tothill, N., Viti, S., White, G.J., Wouterloot, J., Yates, J., Zhu, M., Mowat, C., Hatchell, J., Rumble, D., Kirk, H., Buckle, J., Berry, D.S., Broekhoven-Fiene, H., Currie, M.J., Jenness, T., Johnstone, D., Mottram, J.C., Pattle, K., Tisi, S., Francesco, J. Di, Hogerheijde, M.R., Ward-Thompson, Derek, Bastien, P., Bresnahan, D., Butner, H., Chen, M., Chrysostomou, A., Coudé, S., Davis, C.J., Drabek-Maunder, E., Duarte-Cabral, A., Fich, M., Fiege, J., Friberg, P., Friesen, R., Fuller, G.A., Graves, S., Greaves, J., Holland, W., Joncas, G., Kirk, Jason Matthew, Knee, L.B.G., Mairs, S., Marsh, K., Matthews, B.C., Moriarty-Schieven, G., Rawlings, J., Retter, B., Richer, J., Robertson, D., Rosolowsky, E., Sadavoy, S., Thomas, H., Tothill, N., Viti, S., White, G.J., Wouterloot, J., Yates, J., and Zhu, M.

Abstract

This paper presents observations of the Lupus I molecular cloud at 450 and 850 μm with Submillimetre Common User Bolometer Array (SCUBA-2) as part of the James Clerk Maxwell Telescope Gould Belt Survey (JCMT GBS). Nine compact sources, assumed to be the discs of young stellar objects (YSOs), 12 extended protostellar, pre-stellar and starless cores, and one isolated, low-luminosity protostar, are detected in the region. Spectral energy distributions, including submillimetre fluxes, are produced for 15 YSOs, and each is fitted with the models of Robitaille et al. The proportion of Class 0/I protostars is higher than that seen in other Gould Belt regions such as Ophiuchus and Serpens. Circumstellar disc masses are calculated for more evolved sources, while protostellar envelope masses are calculated for protostars. Up to four very low luminosity objects are found; a large fraction when compared to other Spitzer c2d regions. One YSO has a disc mass greater than the minimum mass solar nebula. 12 starless/protostellar cores are detected by SCUBA-2 and their masses are calculated. The stability of these cores is examined using both the thermal Jeans mass and a turbulent virial mass when possible. Two cores in Lupus I are super-Jeans and contain no known YSOs. One of these cores has a virial parameter of 1.1 ± 0.4, and could therefore be pre-stellar. The high ratio of Class 0/I to Class III YSOs (1:1), and the presence of a pre-stellar core candidate, provides support for the hypothesis that a shock recently triggered star formation in Lupus I.

Published
2017

47. The Idea of An English School

Author

Sidney, Philip, Johnson, Samuel, Wordsworth, William, Keats, John, Bysshe, Percy, Arnold, Matthew, Eliot, T. S., BUTT, JOHN, LEECH, CLIFFORD, KINSLEY, JAMES, and MOWAT, C. L.

Published
1963

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