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

X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis

Alvaro D.;
2021

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.
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