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

Nature Genetics

Volumn 49, Issue 2, 2017, Pages 256-261

  De Lange, Katrina M ^a   Moutsianas, Loukas ^a   Lee, James C ^b   Lamb, Christopher A ^c   Luo, Yang ^a,d,e   Kennedy, Nicholas A ^f,g   Jostins, Luke ^h,i   Rice, Daniel L ^a   Gutierrez Achury, Javier ^a   Ji, Sun Gou ^a   Heap, Graham ^f,g   Nimmo, Elaine R ^j   Edwards, Cathryn ^k   Henderson, Paul ^j,l   Mowat, Craig ^m   Sanderson, Jeremy ⁿ   Satsangi, Jack ^j   Simmons, Alison ^o,p   Wilson, David C ^j,l   Tremelling, Mark ^q   Hart, Ailsa ^r   Mathew, Christopher G ^s,t   Newman, William G ^u,v   Parkes, Miles ^b   Lees, Charlie W ^j   Uhlig, Holm ^o,w   Hawkey, Chris ^x   Prescott, Natalie J ^s   Ahmad, Tariq ^f,g   Mansfield, John C ^y   Anderson, Carl A ^a   Barrett, Jeffrey C ^a   more..

^a WELLCOME TRUST SANGER INSTITUTE   (United Kingdom)

^b ADDENBROOKE S HOSPITAL   (United Kingdom)

^c NEWCASTLE UNIVERSITY   (United Kingdom)

^d BRIGHAM AND WOMEN S HOSPITAL   (United States)

^e BROAD INSTITUTE OF MIT AND HARVARD   (United States)

^f UNIVERSITY OF EXETER   (United Kingdom)

^g ROYAL DEVON AND EXETER NHS FOUNDATION TRUST   (United Kingdom)

^h UNIVERSITY OF OXFORD   (United Kingdom)

ⁱ CHRIST CHURCH   (United Kingdom)

^j UNIVERSITY OF EDINBURGH   (United Kingdom)

^k TORBAY HOSPITAL   (United Kingdom)

^l ROYAL HOSPITAL FOR SICK CHILDREN   (United Kingdom)

^m UNIVERSITY OF DUNDEE   (United Kingdom)

ⁿ ST THOMAS HOSPITAL   (United Kingdom)

^o UNIVERSITY OF OXFORD   (United Kingdom)

^p UNIVERSITY OF OXFORD   (United Kingdom)

^q NORFOLK AND NORWICH UNIVERSITY HOSPITAL   (United Kingdom)

^r ST MARK S HOSPITAL   (United Kingdom)

^s GUY S HOSPITAL   (United Kingdom)

^t UNIVERSITY OF THE WITWATERSRAND   (South Africa)

^u UNIVERSITY OF MANCHESTER   (United Kingdom)

^v UNIVERSITY OF MANCHESTER   (United Kingdom)

^w UNIVERSITY OF OXFORD   (United Kingdom)

^x QUEEN S MEDICAL CENTRE   (United Kingdom)

^y NEWCASTLE UNIVERSITY   (United Kingdom)

more..

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA4 INTEGRIN; ALPHA5 INTEGRIN; ANTISENSE OLIGONUCLEOTIDE; BETA7 INTEGRIN; BETA8 INTEGRIN; EFALIZUMAB; ETROLIZUMAB; INTEGRIN; INTERCELLULAR ADHESION MOLECULE 1; PHOSPHOLIPASE C GAMMA2; REACTIVE OXYGEN METABOLITE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE; RETINOID RELATED ORPHAN RECEPTOR GAMMA; UNCLASSIFIED DRUG; VEDOLIZUMAB;

ANTISENSE THERAPY; ARTICLE; CROHN DISEASE; GENE EXPRESSION; GENE LINKAGE DISEQUILIBRIUM; GENE LOCUS; GENETIC SUSCEPTIBILITY; GENETIC VARIABILITY; GENOME-WIDE ASSOCIATION STUDY; HUMAN; ILEITIS; IMMUNE DEFICIENCY; INFLAMMATION; INFLAMMATORY BOWEL DISEASE; MAJOR CLINICAL STUDY; MISSENSE MUTATION; PRIORITY JOURNAL; QUANTITATIVE TRAIT LOCUS; ULCERATIVE COLITIS; ALLELE; GENETIC PREDISPOSITION; GENETICS; META ANALYSIS; PROCEDURES; SINGLE NUCLEOTIDE POLYMORPHISM;

ALLELES; GENETIC PREDISPOSITION TO DISEASE; GENOME-WIDE ASSOCIATION STUDY; HUMANS; INFLAMMATION; INFLAMMATORY BOWEL DISEASES; INTEGRINS; POLYMORPHISM, SINGLE NUCLEOTIDE; QUANTITATIVE TRAIT LOCI;

EID: 85008712412     PISSN: 10614036     EISSN: 15461718     Source Type: Journal    
DOI: 10.1038/ng.3760     Document Type: Article

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57. Liu, J.Z., et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat. Genet. 47, 979-986 (2015).
58. Parkes, M., et al. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility. Nat. Genet. 39, 830-832 (2007).
59. Yamazaki, K., et al. A genome-wide association study identifies 2 susceptibility loci for Crohn's disease in a Japanese population. Gastroenterology 144, 781-788 (2013).
60. Anderson, C.A., et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat. Genet. 43, 246-252 (2011).
61. Kenny, E.E., et al. A genome-wide scan of Ashkenazi Jewish Crohn's disease suggests novel susceptibility loci. PLoS Genet. 8, e1002559 (2012).
62. Julià, A., et al. A genome-wide association study identifies a novel locus at 6q22.1 associated with ulcerative colitis. Hum. Mol. Genet. 23, 6927-6934 (2014).
63. Yang, S.-K., et al. Genome-wide association study of Crohn's disease in Koreans revealed three new susceptibility loci and common attributes of genetic susceptibility across ethnic populations. Gut 63, 80-87 (2014).
64. Ellinghaus, D., et al. Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci. Nat. Genet. 48, 510-518 (2016).
65. Luo, Y., et al. Exploring the genetic architecture of inflammatory bowel disease by whole-genome sequencing identifies association at ADCY7. Nat. Genet. http://dx.doi.org/10.1038/ng.3761 (2017).
66. Walter, K., et al. The UK10K project identifies rare variants in health and disease. Nature 526, 82-90 (2015).
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68. Huang, H., et al. Association mapping of inflammatory bowel disease loci to single variant resolution. Preprint at bioRxiv http://dx.doi.org/10.1101/028688 (2015).
69. Ivanov, I.I., et al. The orphan nuclear receptor ROR?t directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121-1133 (2006).
70. Wang, G., et al. Migration of myeloid cells during inflammation is differentially regulated by the cell surface receptors Slamf1 and Slamf8. PLoS One 10, e0121968 (2015).
71. Wang, G., et al. Cutting edge: Slamf8 is a negative regulator of Nox2 activity in macrophages. J. Immunol. 188, 5829-5832 (2012).
72. Kircher, M., et al. A general framework for estimating the relative pathogenicity of human genetic variants. Nat. Genet. 46, 310-315 (2014).
73. Luci, C., et al. Influence of the transcription factor ROR?t on the development of NKp46+ cell populations in gut and skin. Nat. Immunol. 10, 75-82 (2009).
74. Yang, Y., et al. Focused specificity of intestinal TH17 cells towards commensal bacterial antigens. Nature 510, 152-156 (2014).
75. Sawa, S., et al. ROR?t+ innate lymphoid cells regulate intestinal homeostasis by integrating negative signals from the symbiotic microbiota. Nat. Immunol. 12, 320-326 (2011).
76. Gevers, D., et al. The treatment-naive microbiome in new-onset Crohn's disease. Cell Host Microbe 15, 382-392 (2014).
77. Withers, D.R., et al. Transient inhibition of ROR-?t therapeutically limits intestinal inflammation by reducing TH17 cells and preserving group 3 innate lymphoid cells. Nat. Med. 22, 319-323 (2016).
78. Fu, G., Chen, Y., Schuman, J., Wang, D., Wen, R. Phospholipase C?2 plays a role in TCR signal transduction and T cell selection. J. Immunol. 189, 2326-2332 (2012).
79. Ombrello, M.J., et al. Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions. N. Engl. J. Med. 366, 330-338 (2012).
80. Zhou, Q., et al. A hypermorphic missense mutation in PLCG2, encoding phospholipase C?2, causes a dominantly inherited autoinflammatory disease with immunodeficiency. Am. J. Hum. Genet. 91, 713-720 (2012).
81. Jostins, L., et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119-124 (2012).
82. Matute, J.D., et al. A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40phox and selective defects in neutrophil NADPH oxidase activity. Blood 114, 3309-3315 (2009).
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93. Carson, K.R., et al. Monoclonal antibody-associated progressive multifocal leucoencephalopathy in patients treated with rituximab, natalizumab, and efalizumab: a Review from the Research on Adverse Drug Events and Reports (RADAR) Project. Lancet Oncol. 10, 816-824 (2009).
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97. Monteleone, G., et al. Mongersen, an oral SMAD7 antisense oligonucleotide, and Crohn's disease. N. Engl. J. Med. 372, 1104-1113 (2015).
98. Miceli-Richard, C., et al. CARD15 mutations in Blau syndrome. Nat. Genet. 29, 19-20 (2001).
99. Shah, T.S., et al. optiCall: a robust genotype-calling algorithm for rare, low-frequency and common variants. Bioinformatics 28, 1598-1603 (2012).
100. Durbin, R. Efficient haplotype matching and storage using the positional Burrows-Wheeler transform (PBWT). Bioinformatics 30, 1266-1272 (2014).
101. Bulik-Sullivan, B.K., et al. LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat. Genet. 47, 291-295 (2015).
102. Wakefield, J. Bayes factors for genome-wide association studies: comparison with P-values. Genet. Epidemiol. 33, 79-86 (2009).
103. Maller, J.B., et al. Bayesian refinement of association signals for 14 loci in 3 common diseases. Nat. Genet. 44, 1294-1301 (2012).
104. Zhernakova, D., et al. Identification of context-dependent expression quantitative trait loci in whole blood. Nat. Genet. http://dx.doi.org/10.1038/ng.3737 (2017).
105. Battle, A., et al. Characterizing the genetic basis of transcriptome diversity through RNA-sequencing of 922 individuals. Genome Res. 24, 14-24 (2014).
106. Monlong, J., Calvo, M., Ferreira, P.G., Guigó, R. Identification of genetic variants associated with alternative splicing using sQTLseekeR. Nat. Commun. 5, 4698 (2014).
107. Ongen, H., Buil, A., Brown, A.A., Dermitzakis, E.T., Delaneau, O. Fast and efficient QTL mapper for thousands of molecular phenotypes. Bioinformatics 32, 1479-1485 (2016).
108. Giambartolomei, C., et al. Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. PLoS Genet. 10, e1004383 (2014).
109. Sandborn, W.J., et al. Ustekinumab induction and maintenance therapy in refractory Crohn's disease. N. Engl. J. Med. 367, 1519-1528 (2012).
110. Hanauer, S.B., et al. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet 359, 1541-1549 (2002).
111. Colombel, J.-F., et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. Gastroenterology 132, 52-65 (2007).
112. Schaefer, C.F., et al. PID: the Pathway Interaction Database. Nucleic Acids Res. 37, D674-D679 (2009).