Background & Aims: Genome-wide association studies in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually dimorphic complex autoimmune disease. Methods: We performed a chrX-wide association study, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals). Results: Single-marker association analyses found approximately 100 loci displaying P < 5 × 10–4, with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 × 10–6; odds ratio [OR], 1.39; 95% confidence interval [CI], 1.028–1.88; Japanese cohort). Although the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR, 1.17; 95% CI, 1.09–1.26; P = 9.93 × 10–8), the population-specific meta-analysis showed a genome-wide significant locus in East Asian individuals pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P = 6.2 × 10–9; OR, 1.33; 95% CI, 1.21–1.46). Indeed, rs7059064 tags a unique linkage disequilibrium block including 7 genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a superenhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is also predicted to target FOXP3, the main T-regulatory cell lineage specification factor. Consistently, OTUD5 and FOXP3 RNA levels were up-regulated in PBC case patients (1.75- and 1.64-fold, respectively). Conclusions: This work represents the first comprehensive study, to our knowledge, of the chrX contribution to the genetics of an autoimmune liver disease and shows a novel PBC-related genome-wide significant locus.

X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis / R. Asselta, E.M. Paraboschi, A. Gerussi, H.J. Cordell, G.F. Mells, R.N. Sandford, D.E. Jones, M. Nakamura, K. Ueno, Y. Hitomi, M. Kawashima, N. Nishida, K. Tokunaga, M. Nagasaki, A. Tanaka, R. Tang, Z. Li, Y. Shi, X. Liu, M. Xiong, G. Hirschfield, K.A. Siminovitch, E. Walker, G. Xie, A. Mason, R. Myers, K. Peltekian, C. Ghent, E. Atkinson, B. Juran, K. Lazaridis, Y. Lu, X. Gu, K. Jing, C. Amos, A. Affronti, M. Brunetto, B. Coco, G. Spinzi, G. Elia, C. Ferrari, A. Lleo, L. Muratori, P. Muratori, P. Portincasa, A. Colli, S. Bruno, G. Colloredo, F. Azzaroli, P. Andreone, M. Bragazzi, D. Alvaro, V. Cardinale, N. Cazzagon, C. Rigamonti, A. Floreani, F. Rosina, A. Ciaccio, L. Cristoferi, D. D'Amato, F. Malinverno, C. Mancuso, S. Massironi, C. Milani, S.E. O'Donnell, V. Ronca, D. Barisani, P. Lampertico, F. Donato, S. Fagiuoli, P.L. Almasio, E. Giannini, C. Cursaro, M. Colombo, L. Valenti, L. Miele, A. Andriulli, G.A. Niro, I. Grattagliano, L. Morini, G. Casella, M. Vinci, P.M. Battezzati, A. Crosignani, M. Zuin, A. Mattalia, V. Calvaruso, S. Colombo, A. Benedetti, M. Marzioni, A. Galli, F. Marra, M. Tarocchi, A. Picciotto, F. Morisco, L. Fabris, L.S. Croce, C. Tiribelli, P. Toniutto, M. Strazzabosco, C.L. Ch'ng, M. Rahman, T. Yapp, R. Sturgess, C. Healey, M. Czajkowski, A. Gunasekera, P. Gyawali, P. Premchand, K. Kapur, R. Marley, G. Foster, A. Watson, A. Dias, J. Subhani, R. Harvey, R. McCorry, D. Ramanaden, J. Gasem, R. Evans, T. Mathialahan, C. Shorrock, G. Lipscomb, P. Southern, J. Tibble, D. Gorard, A. Palegwala, S. Jones, M. Dawwas, G. Alexander, S. Dolwani, M. Prince, M. Foxton, D. Elphick, H. Mitchison, I. Gooding, M. Karmo, S. Saksena, M. Mendall, M. Patel, R. Ede, A. Austin, J. Sayer, L. Hankey, C. Hovell, N. Fisher, M. Carter, K. Koss, A. Piotrowicz, C. Grimley, D. Neal, G. Lim, S. Levi, A. Ala, A. Broad, A. Saeed, G. Wood, J. Brown, M. Wilkinson, H. Gordon, J. Ramage, J. Ridpath, T. Ngatchu, B. Grover, S. Shaukat, R. Shidrawi, G. Abouda, F. Ali, I. Rees, I. Salam, M. Narain, A. Brown, S. Taylor-Robinson, S. Williams, L. Grellier, P. Banim, D. Das, A. Chilton, M. Heneghan, H. Curtis, M. Gess, I. Drake, M. Aldersley, M. Davies, R. Jones, A. McNair, R. Srirajaskanthan, M. Pitcher, S. Sen, G. Bird, A. Barnardo, P. Kitchen, K. Yoong, O. Chirag, N. Sivaramakrishnan, G. MacFaul, D. Jones, A. Shah, C. Evans, S. Saha, K. Pollock, P. Bramley, A. Mukhopadhya, A. Fraser, P. Mills, C. Shallcross, S. Campbell, A. Bathgate, A. Shepherd, J. Dillon, S. Rushbrook, R. Przemioslo, C. Macdonald, J. Metcalf, U. Shmueli, A. Davis, A. Naqvi, T. Lee, S.D. Ryder, J. Collier, H. Klass, M. Ninkovic, M. Cramp, N. Sharer, R. Aspinall, P. Goggin, D. Ghosh, A. Douds, B. Hoeroldt, J. Booth, E. Williams, H. Hussaini, W. Stableforth, R. Ayres, D. Thorburn, E. Marshall, A. Burroughs, S. Mann, M. Lombard, P. Richardson, I. Patanwala, J. Maltby, M. Brookes, R. Mathew, S. Vyas, S. Singhal, D. Gleeson, S. Misra, J. Butterworth, K. George, T. Harding, A. Douglass, S. Panter, J. Shearman, G. Bray, G. Butcher, D. Forton, J. Mclindon, M. Cowan, G. Whatley, A. Mandal, H. Gupta, P. Sanghi, S. Jain, S. Pereira, G. Prasad, G. Watts, M. Wright, J. Neuberger, F. Gordon, E. Unitt, A. Grant, T. Delahooke, A. Higham, A. Brind, M. Cox, S. Ramakrishnan, A. King, C. Collins, S. Whalley, A. Li, J. Fraser, A. Bell, V.S. Wong, A. Singhal, I. Gee, Y. Ang, R. Ransford, J. Gotto, C. Millson, J. Bowles, C. Thomas, M. Harrison, R. Galaska, J. Kendall, J. Whiteman, C. Lawlor, C. Gray, K. Elliott, C. Mulvaney-Jones, L. Hobson, G. Van Duyvenvoorde, A. Loftus, K. Seward, R. Penn, J. Maiden, R. Damant, J. Hails, R. Cloudsdale, V. Silvestre, S. Glenn, E. Dungca, N. Wheatley, H. Doyle, M. Kent, C. Hamilton, D. Braim, H. Wooldridge, R. Abrahams, A. Paton, N. Lancaster, A. Gibbins, K. Hogben, P. Desousa, F. Muscariu, J. Musselwhite, A. McKay, L. Tan, C. Foale, J. Brighton, K. Flahive, E. Nambela, P. Townshend, C. Ford, S. Holder, C. Palmer, J. Featherstone, M. Nasseri, J. Sadeghian, B. Williams, C. Thomas, S.-. Rolls, A. Hynes, C. Duggan, S. Jones, M. Crossey, G. Stansfield, C. MacNicol, J. Wilkins, E. Wilhelmsen, P. Raymode, H.-. Lee, E. Durant, R. Bishop, N. Ncube, S. Tripoli, R. Casey, C. Cowley, R. Miller, K. Houghton, S. Ducker, F. Wright, B. Bird, G. Baxter, J. Keggans, M. Hughes, E. Grieve, K. Young, D. Williams, K. Ocker, F. Hines, K. Martin, C. Innes, T. Valliani, H. Fairlamb, S. Thornthwaite, A. Eastick, E. Tanqueray, J. Morrison, B. Holbrook, J. Browning, K. Walker, S. Congreave, J. Verheyden, S. Slininger, L. Stafford, D. O'Donnell, M. Ainsworth, S. Lord, L. Kent, L. March, C. Dickson, D. Simpson, B. Longhurst, M. Hayes, E. Shpuza, N. White, S. Besley, S. Pearson, A. Wright, L. Jones, E. Gunter, H. Dewhurst, A. Fouracres, L. Farrington, L. Graves, S. Marriott, M. Leoni, D. Tyrer, K. Martin, L. Dali-kemmery, V. Lambourne, M. Green, D. Sirdefield, K. Amor, J. Colley, B. Shinder, J. Jones, M. Mills, M. Carnahan, N. Taylor, K. Boulton, J. Tregonning, C. Brown, G. Clifford, E. Archer, M. Hamilton, J. Curtis, T. Shewan, S. Walsh, K. Warner, K. Netherton, M. Mupudzi, B. Gunson, J. Gitahi, D. Gocher, S. Batham, H. Pateman, S. Desmennu, J. Conder, D. Clement, S. Gallagher, J. Orpe, P. Chan, L. Currie, L. O'Donohoe, M. Oblak, L. Morgan, M. Quinn, I. Amey, Y. Baird, D. Cotterill, L. Cumlat, L. Winter, S. Greer, K. Spurdle, J. Allison, S. Dyer, H. Sweeting, J. Kordula, Y. Aiba, H. Nakamura, S. Abiru, S. Nagaoka, A. Komori, H. Yatsuhashi, H. Ishibashi, M. Ito, Y. Kawai, S.-. Kohn, O. Gervais, K. Migita, S. Katsushima, A. Naganuma, K. Sugi, T. Komatsu, T. Mannami, K. Matsushita, K. Yoshizawa, F. Makita, T. Nikami, H. Nishimura, H. Kouno, H. Kouno, H. Ota, T. Komura, Y. Nakamura, M. Shimada, N. Hirashima, T. Komeda, K. Ario, M. Nakamuta, T. Yamashita, K. Furuta, M. Kikuchi, N. Naeshiro, H. Takahashi, Y. Mano, S. Tsunematsu, I. Yabuuchi, Y. Shimada, K. Yamauchi, R. Sugimoto, H. Sakai, E. Mita, M. Koda, S. Tsuruta, H. Kamitsukasa, T. Sato, N. Masaki, T. Kobata, N. Fukushima, N. Higuchi, Y. Ohara, T. Muro, E. Takesaki, H. Takaki, T. Yamamoto, M. Kato, Y. Nagaoki, S. Hayashi, J. Ishida, Y. Watanabe, M. Kobayashi, M. Koga, T. Saoshiro, M. Yagura, K. Hirata, H. Takikawa, H. Ohira, M. Zeniya, M. Abe, M. Onji, S. Kaneko, M. Honda, K. Arai, T. Arinaga-Hino, E. Hashimoto, M. Taniai, T. Umemura, S. Joshita, K. Nakao, T. Ichikawa, H. Shibata, S. Yamagiwa, M. Seike, K. Honda, S. Sakisaka, Y. Takeyama, M. Harada, M. Senju, O. Yokosuka, T. Kanda, Y. Ueno, K. Kikuchi, H. Ebinuma, T. Himoto, M. Yasunami, K. Murata, M. Mizokami, S. Shimoda, Y. Miyake, A. Takaki, K. Yamamoto, K. Hirano, T. Ichida, A. Ido, H. Tsubouchi, K. Chayama, K. Harada, Y. Nakanuma, Y. Maehara, A. Taketomi, K. Shirabe, Y. Soejima, A. Mori, S. Yagi, S. Uemoto, T. Tanaka, N. Yamashiki, S. Tamura, Y. Sugawara, N. Kokudo, M. Carbone, G. Cardamone, S. Duga, M.E. Gershwin, M.F. Seldin, P. Invernizzi. - In: GASTROENTEROLOGY. - ISSN 0016-5085. - 160:7(2021 Jun), pp. 2483-2495.e26. [10.1053/j.gastro.2021.02.061]

X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis

P. Lampertico;L. Valenti
Membro del Collaboration Group
;
2021-06

Abstract

Background & Aims: Genome-wide association studies in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually dimorphic complex autoimmune disease. Methods: We performed a chrX-wide association study, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals). Results: Single-marker association analyses found approximately 100 loci displaying P < 5 × 10–4, with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 × 10–6; odds ratio [OR], 1.39; 95% confidence interval [CI], 1.028–1.88; Japanese cohort). Although the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR, 1.17; 95% CI, 1.09–1.26; P = 9.93 × 10–8), the population-specific meta-analysis showed a genome-wide significant locus in East Asian individuals pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P = 6.2 × 10–9; OR, 1.33; 95% CI, 1.21–1.46). Indeed, rs7059064 tags a unique linkage disequilibrium block including 7 genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a superenhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is also predicted to target FOXP3, the main T-regulatory cell lineage specification factor. Consistently, OTUD5 and FOXP3 RNA levels were up-regulated in PBC case patients (1.75- and 1.64-fold, respectively). Conclusions: This work represents the first comprehensive study, to our knowledge, of the chrX contribution to the genetics of an autoimmune liver disease and shows a novel PBC-related genome-wide significant locus.
Meta-analysis; Superenhancer; X-Wide Association Study
Settore MED/09 - Medicina Interna
4-mar-2021
https://www.sciencedirect.com/science/article/pii/S0016508521004662?via=ihub
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