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1. Multi-ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis

Author

Ishigaki, Kazuyoshi, Sakaue, Saori, Terao, Chikashi, Luo, Yang, Sonehara, Kyuto, Yamaguchi, Kensuke, Amariuta, Tiffany, Too, Chun Lai, Laufer, Vincent A., Scott, Ian C., Viatte, Sebastien, Takahashi, Meiko, Ohmura, Koichiro, Murasawa, Akira, Hashimoto, Motomu, Ito, Hiromu, Hammoudeh, Mohammed, Emadi, Samar Al, Masri, Basel K., Halabi, Hussein, Badsha, Humeira, Uthman, Imad W., Wu, Xin, Lin, Li, Li, Ting, Plant, Darren, Barton, Anne, Orozco, Gisela, Verstappen, Suzanne M. M., Bowes, John, MacGregor, Alexander J., Honda, Suguru, Koido, Masaru, Tomizuka, Kohei, Kamatani, Yoichiro, Tanaka, Hiroaki, Tanaka, Eiichi, Suzuki, Akari, Maeda, Yuichi, Yamamoto, Kenichi, Miyawaki, Satoru, Xie, Gang, Zhang, Jinyi, Amos, Christopher I., Keystone, Edward, Wolbink, Gertjan, van der Horst-Bruinsma, Irene, Cui, Jing, Liao, Katherine P., Carroll, Robert J., Lee, Hye-Soon, Bang, So-Young, Siminovitch, Katherine A., de Vries, Niek, Alfredsson, Lars, Rantapää-Dahlqvist, Solbritt, Karlson, Elizabeth W., Bae, Sang-Cheol, Kimberly, Robert P., Edberg, Jeffrey C., Mariette, Xavier, Huizinga, Tom, Dieudé, Philippe, Schneider, Matthias, Kerick, Martin, Denny, Joshua C., Matsuda, Koichi, Matsuo, Keitaro, Mimori, Tsuneyo, Matsuda, Fumihiko, Fujio, Keishi, Tanaka, Yoshiya, Kumanogoh, Atsushi, Traylor, Matthew, Lewis, Cathryn M., Eyre, Stephen, Xu, Huji, Saxena, Richa, Arayssi, Thurayya, Kochi, Yuta, Ikari, Katsunori, Harigai, Masayoshi, Gregersen, Peter K., Yamamoto, Kazuhiko, Louis Bridges, S., Padyukov, Leonid, Martin, Javier, Klareskog, Lars, Okada, Yukinori, Raychaudhuri, Soumya, Ishigaki, Kazuyoshi, Sakaue, Saori, Terao, Chikashi, Luo, Yang, Sonehara, Kyuto, Yamaguchi, Kensuke, Amariuta, Tiffany, Too, Chun Lai, Laufer, Vincent A., Scott, Ian C., Viatte, Sebastien, Takahashi, Meiko, Ohmura, Koichiro, Murasawa, Akira, Hashimoto, Motomu, Ito, Hiromu, Hammoudeh, Mohammed, Emadi, Samar Al, Masri, Basel K., Halabi, Hussein, Badsha, Humeira, Uthman, Imad W., Wu, Xin, Lin, Li, Li, Ting, Plant, Darren, Barton, Anne, Orozco, Gisela, Verstappen, Suzanne M. M., Bowes, John, MacGregor, Alexander J., Honda, Suguru, Koido, Masaru, Tomizuka, Kohei, Kamatani, Yoichiro, Tanaka, Hiroaki, Tanaka, Eiichi, Suzuki, Akari, Maeda, Yuichi, Yamamoto, Kenichi, Miyawaki, Satoru, Xie, Gang, Zhang, Jinyi, Amos, Christopher I., Keystone, Edward, Wolbink, Gertjan, van der Horst-Bruinsma, Irene, Cui, Jing, Liao, Katherine P., Carroll, Robert J., Lee, Hye-Soon, Bang, So-Young, Siminovitch, Katherine A., de Vries, Niek, Alfredsson, Lars, Rantapää-Dahlqvist, Solbritt, Karlson, Elizabeth W., Bae, Sang-Cheol, Kimberly, Robert P., Edberg, Jeffrey C., Mariette, Xavier, Huizinga, Tom, Dieudé, Philippe, Schneider, Matthias, Kerick, Martin, Denny, Joshua C., Matsuda, Koichi, Matsuo, Keitaro, Mimori, Tsuneyo, Matsuda, Fumihiko, Fujio, Keishi, Tanaka, Yoshiya, Kumanogoh, Atsushi, Traylor, Matthew, Lewis, Cathryn M., Eyre, Stephen, Xu, Huji, Saxena, Richa, Arayssi, Thurayya, Kochi, Yuta, Ikari, Katsunori, Harigai, Masayoshi, Gregersen, Peter K., Yamamoto, Kazuhiko, Louis Bridges, S., Padyukov, Leonid, Martin, Javier, Klareskog, Lars, Okada, Yukinori, and Raychaudhuri, Soumya

Abstract

Rheumatoid arthritis (RA) is a highly heritable complex disease with unknown etiology. Multi-ancestry genetic research of RA promises to improve power to detect genetic signals, fine-mapping resolution and performances of polygenic risk scores (PRS). Here, we present a large-scale genome-wide association study (GWAS) of RA, which includes 276,020 samples from five ancestral groups. We conducted a multi-ancestry meta-analysis and identified 124 loci (P < 5 × 10−8), of which 34 are novel. Candidate genes at the novel loci suggest essential roles of the immune system (for example, TNIP2 and TNFRSF11A) and joint tissues (for example, WISP1) in RA etiology. Multi-ancestry fine-mapping identified putatively causal variants with biological insights (for example, LEF1). Moreover, PRS based on multi-ancestry GWAS outperformed PRS based on single-ancestry GWAS and had comparable performance between populations of European and East Asian ancestries. Our study provides several insights into the etiology of RA and improves the genetic predictability of RA.

Published
2022
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2. Biological insights into systemic lupus erythematosus through an immune cell-specific transcriptome-wide association study

Author

Yin, Xianyong, Kim, Kwangwoo, Suetsugu, Hiroyuki, Bang, So-Young, Wen, Leilei, Koido, Masaru, Ha, Eunji, Liu, Lu, Sakamoto, Yuma, Jo, Sungsin, Leng, Rui-Xue, Otomo, Nao, Kwon, Young-Chang, Sheng, Yujun, Sugano, Nobuhiko, Hwang, Mi Yeong, Li, Weiran, Mukai, Masaya, Yoon, Kyungheon, Cai, Minglong, Ishigaki, Kazuyoshi, Chung, Won Tae, Huang, He, Takahashi, Daisuke, Lee, Shin-Seok, Wang, Mengwei, Karino, Kohei, Shim, Seung-Cheol, Zheng, Xiaodong, Miyamura, Tomoya, Kang, Young Mo, Ye, Dongqing, Nakamura, Junichi, Suh, Chang-Hee, Tang, Yuanjia, Motomura, Goro, Park, Yong-Beom, Ding, Huihua, Kuroda, Takeshi, Choe, Jung-Yoon, Li, Chengxu, Niiro, Hiroaki, Park, Youngho, Shen, Changbing, Miyamoto, Takeshi, Ahn, Ga-Young, Fei, Wenmin, Takeuchi, Tsutomu, Shin, Jung-Min, Li, Keke, Kawaguchi, Yasushi, Lee, Yeon-Kyung, Wang, Yong-Fei, Amano, Koichi, Park, Dae Jin, Yang, Wanling, Tada, Yoshifumi, Lau, Yu Lung, Yamaji, Ken, Zhu, Zhengwei, Shimizu, Masato, Atsumi, Takashi, Suzuki, Akari, Sumida, Takayuki, Okada, Yukinori, Matsuda, Koichi, Matsuo, Keitaro, Kochi, Yuta, Yamamoto, Kazuhiko, Ohmura, Koichiro, Kim, Tae-Hwan, Yang, Sen, Yamamoto, Takuaki, Kim, Bong-Jo, Shen, Nan, Ikegawa, Shiro, Lee, Hye-Soon, Zhang, Xuejun, Terao, Chikashi, Cui, Yong, Bae, Sang-Cheol, Japanese Research Committee on Idiopathic Osteonecrosis of the Femoral Head, Yin, Xianyong, Kim, Kwangwoo, Suetsugu, Hiroyuki, Bang, So-Young, Wen, Leilei, Koido, Masaru, Ha, Eunji, Liu, Lu, Sakamoto, Yuma, Jo, Sungsin, Leng, Rui-Xue, Otomo, Nao, Kwon, Young-Chang, Sheng, Yujun, Sugano, Nobuhiko, Hwang, Mi Yeong, Li, Weiran, Mukai, Masaya, Yoon, Kyungheon, Cai, Minglong, Ishigaki, Kazuyoshi, Chung, Won Tae, Huang, He, Takahashi, Daisuke, Lee, Shin-Seok, Wang, Mengwei, Karino, Kohei, Shim, Seung-Cheol, Zheng, Xiaodong, Miyamura, Tomoya, Kang, Young Mo, Ye, Dongqing, Nakamura, Junichi, Suh, Chang-Hee, Tang, Yuanjia, Motomura, Goro, Park, Yong-Beom, Ding, Huihua, Kuroda, Takeshi, Choe, Jung-Yoon, Li, Chengxu, Niiro, Hiroaki, Park, Youngho, Shen, Changbing, Miyamoto, Takeshi, Ahn, Ga-Young, Fei, Wenmin, Takeuchi, Tsutomu, Shin, Jung-Min, Li, Keke, Kawaguchi, Yasushi, Lee, Yeon-Kyung, Wang, Yong-Fei, Amano, Koichi, Park, Dae Jin, Yang, Wanling, Tada, Yoshifumi, Lau, Yu Lung, Yamaji, Ken, Zhu, Zhengwei, Shimizu, Masato, Atsumi, Takashi, Suzuki, Akari, Sumida, Takayuki, Okada, Yukinori, Matsuda, Koichi, Matsuo, Keitaro, Kochi, Yuta, Yamamoto, Kazuhiko, Ohmura, Koichiro, Kim, Tae-Hwan, Yang, Sen, Yamamoto, Takuaki, Kim, Bong-Jo, Shen, Nan, Ikegawa, Shiro, Lee, Hye-Soon, Zhang, Xuejun, Terao, Chikashi, Cui, Yong, Bae, Sang-Cheol, and Japanese Research Committee on Idiopathic Osteonecrosis of the Femoral Head

Abstract

Objective Genome-wide association studies (GWAS) have identified >100 risk loci for systemic lupus erythematosus (SLE), but the disease genes at most loci remain unclear, hampering translation of these genetic discoveries. We aimed to prioritise genes underlying the 110 SLE loci that were identified in the latest East Asian GWAS meta-analysis. Methods We built gene expression predictive models in blood B cells, CD4(+) and CD8(+) T cells, monocytes, natural killer cells and peripheral blood cells of 105 Japanese individuals. We performed a transcriptome-wide association study (TWAS) using data from the latest genome-wide association meta-analysis of 208 370 East Asians and searched for candidate genes using TWAS and three data-driven computational approaches. Results TWAS identified 171 genes for SLE (p<1.0x10(-5)); 114 (66.7%) showed significance only in a single cell type; 127 (74.3%) were in SLE GWAS loci. TWAS identified a strong association between CD83 and SLE (p<7.7x10(-8)). Meta-analysis of genetic associations in the existing 208 370 East Asian and additional 1498 cases and 3330 controls found a novel single-variant association at rs72836542 (OR=1.11, p=4.5x10(-9)) around CD83. For the 110 SLE loci, we identified 276 gene candidates, including 104 genes at recently-identified SLE novel loci. We demonstrated in vitro that putative causal variant rs61759532 exhibited an allele-specific regulatory effect on ACAP1, and that presence of the SLE risk allele decreased ACAP1 expression. Conclusions Cell-level TWAS in six types of immune cells complemented SLE gene discovery and guided the identification of novel genetic associations. The gene findings shed biological insights into SLE genetic associations.

Published
2022

3. Amino acid signatures of HLA Class-I and II molecules are strongly associated with SLE susceptibility and autoantibody production in Eastern Asians

Author

50626637, Molineros, Julio E., Looger, Loren L., Kim, Kwangwoo, Okada, Yukinori, Terao, Chikashi, Sun, Celi, Zhou, Xu-jie, Raj, Prithvi, Kochi, Yuta, Suzuki, Akari, Akizuki, Shuji, Nakabo, Shuichiro, Bang, So-Young, Lee, Hye-Soon, Kang, Young Mo, Suh, Chang-Hee, Chung, Won Tae, Park, Yong-Beom, Choe, Jung-Yoon, Shim, Seung-Cheol, Lee, Shin-Seok, Zuo, Xiaoxia, Yamamoto, Kazuhiko, Li, Quan-Zhen, Shen, Nan, Porter, Lauren L., Harley, John B., Chua, Kek Heng, Zhang, Hong, Wakeland, Edward K., Tsao, Betty P., Bae, Sang-Cheol, Nath, Swapan K., 50626637, Molineros, Julio E., Looger, Loren L., Kim, Kwangwoo, Okada, Yukinori, Terao, Chikashi, Sun, Celi, Zhou, Xu-jie, Raj, Prithvi, Kochi, Yuta, Suzuki, Akari, Akizuki, Shuji, Nakabo, Shuichiro, Bang, So-Young, Lee, Hye-Soon, Kang, Young Mo, Suh, Chang-Hee, Chung, Won Tae, Park, Yong-Beom, Choe, Jung-Yoon, Shim, Seung-Cheol, Lee, Shin-Seok, Zuo, Xiaoxia, Yamamoto, Kazuhiko, Li, Quan-Zhen, Shen, Nan, Porter, Lauren L., Harley, John B., Chua, Kek Heng, Zhang, Hong, Wakeland, Edward K., Tsao, Betty P., Bae, Sang-Cheol, and Nath, Swapan K.

Abstract

Human leukocyte antigen (HLA) is a key genetic factor conferring risk of systemic lupus erythematosus (SLE), but precise independent localization of HLA effects is extremely challenging. As a result, the contribution of specific HLA alleles and amino-acid residues to the overall risk of SLE and to risk of specific autoantibodies are far from completely understood. Here, we dissected (a) overall SLE association signals across HLA, (b) HLA-peptide interaction, and (c) residue-autoantibody association. Classical alleles, SNPs, and amino-acid residues of eight HLA genes were imputed across 4, 915 SLE cases and 13, 513 controls from Eastern Asia. We performed association followed by conditional analysis across HLA, assessing both overall SLE risk and risk of autoantibody production. DR15 alleles HLA-DRB1*15:01 (P = 1.4x10-27, odds ratio (OR) = 1.57) and HLA-DQB1*06:02 (P = 7.4x10-23, OR = 1.55) formed the most significant haplotype (OR = 2.33). Conditioned protein-residue signals were stronger than allele signals and mapped predominantly to HLA-DRB1 residue 13 (P = 2.2x10-75) and its proxy position 11 (P = 1.1x10-67), followed by HLA-DRB1-37 (P = 4.5x10-24). After conditioning on HLA-DRB1, novel associations at HLA-A-70 (P = 1.4x10-8), HLA-DPB1-35 (P = 9.0x10-16), HLA-DQB1-37 (P = 2.7x10-14), and HLA-B-9 (P = 6.5x10-15) emerged. Together, these seven residues increased the proportion of explained heritability due to HLA to 2.6%. Risk residues for both overall disease and hallmark autoantibodies (i.e., nRNP: DRB1-11, P = 2.0x10-14; DRB1-13, P = 2.9x10-13; DRB1-30, P = 3.9x10-14) localized to the peptide-binding groove of HLA-DRB1. Enrichment for specific amino-acid characteristics in the peptide-binding groove correlated with overall SLE risk and with autoantibody presence. Risk residues were in primarily negatively charged side-chains, in contrast with rheumatoid arthritis. We identified novel SLE signals in HLA Class I loci (HLA-A, HLA-B), and localized primary Class II

Published
2019

4. A missense variant in NCF1 is associated with susceptibility to multiple autoimmune diseases.

Author

Zhao, Jian, Zhao, Jian, Ma, Jianyang, Deng, Yun, Kelly, Jennifer A, Kim, Kwangwoo, Bang, So-Young, Lee, Hye-Soon, Li, Quan-Zhen, Wakeland, Edward K, Qiu, Rong, Liu, Mengru, Guo, Jianping, Li, Zhanguo, Tan, Wenfeng, Rasmussen, Astrid, Lessard, Christopher J, Sivils, Kathy L, Hahn, Bevra H, Grossman, Jennifer M, Kamen, Diane L, Gilkeson, Gary S, Bae, Sang-Cheol, Gaffney, Patrick M, Shen, Nan, Tsao, Betty P, Zhao, Jian, Zhao, Jian, Ma, Jianyang, Deng, Yun, Kelly, Jennifer A, Kim, Kwangwoo, Bang, So-Young, Lee, Hye-Soon, Li, Quan-Zhen, Wakeland, Edward K, Qiu, Rong, Liu, Mengru, Guo, Jianping, Li, Zhanguo, Tan, Wenfeng, Rasmussen, Astrid, Lessard, Christopher J, Sivils, Kathy L, Hahn, Bevra H, Grossman, Jennifer M, Kamen, Diane L, Gilkeson, Gary S, Bae, Sang-Cheol, Gaffney, Patrick M, Shen, Nan, and Tsao, Betty P

Abstract

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with a strong genetic component characterized by autoantibody production and a type I interferon signature. Here we report a missense variant (g.74779296G>A; p.Arg90His) in NCF1, encoding the p47phox subunit of the phagocyte NADPH oxidase (NOX2), as the putative underlying causal variant that drives a strong SLE-associated signal detected by the Immunochip in the GTF2IRD1-GTF2I region at 7q11.23 with a complex genomic structure. We show that the p.Arg90His substitution, which is reported to cause reduced reactive oxygen species (ROS) production, predisposes to SLE (odds ratio (OR) = 3.47 in Asians (Pmeta = 3.1 × 10-104), OR = 2.61 in European Americans, OR = 2.02 in African Americans) and other autoimmune diseases, including primary Sjögren's syndrome (OR = 2.45 in Chinese, OR = 2.35 in European Americans) and rheumatoid arthritis (OR = 1.65 in Koreans). Additionally, decreased and increased copy numbers of NCF1 predispose to and protect against SLE, respectively. Our data highlight the pathogenic role of reduced NOX2-derived ROS levels in autoimmune diseases.

Published
2017

5. High-density genotyping of immune loci in Koreans and Europeans identifies eight new rheumatoid arthritis risk loci

Author

Kim, Kwangwoo, Bang, So-Young, Lee, Hye-Soon, Cho, Soo-Kyung, Choi, Chan-Bum, Sung, Yoon-Kyoung, Kim, Tae-Hwan, Jun, Jae-Bum, Yoo, Dae Hyun, Kang, Young Mo, Kim, Seong-Kyu, Suh, Chang-Hee, Shim, Seung-Cheol, Lee, Shin-Seok, Lee, Jisoo, Chung, Won Tae, Choe, Jung-Yoon, Shin, Hyoung Doo, Lee, Jong-Young, Han, Bok-Ghee, Nath, Swapan K., Eyre, Steve, Bowes, John, Pappas, Dimitrios A., Kremer, Joel M., Gonzalez-Gay, Miguel A., Rodriguez-Rodriguez, Luis, Ärlestig, Lisbeth, Okada, Yukinori, Diogo, Dorothee, Liao, Katherine P., Karlson, Elizabeth W., Raychaudhuri, Soumya, Rantapää-Dahlqvist, Solbritt, Martin, Javier, Klareskog, Lars, Padyukov, Leonid, Gregersen, Peter K., Worthington, Jane, Greenberg, Jeffrey D., Plenge, Robert M., Bae, Sang-Cheol, Kim, Kwangwoo, Bang, So-Young, Lee, Hye-Soon, Cho, Soo-Kyung, Choi, Chan-Bum, Sung, Yoon-Kyoung, Kim, Tae-Hwan, Jun, Jae-Bum, Yoo, Dae Hyun, Kang, Young Mo, Kim, Seong-Kyu, Suh, Chang-Hee, Shim, Seung-Cheol, Lee, Shin-Seok, Lee, Jisoo, Chung, Won Tae, Choe, Jung-Yoon, Shin, Hyoung Doo, Lee, Jong-Young, Han, Bok-Ghee, Nath, Swapan K., Eyre, Steve, Bowes, John, Pappas, Dimitrios A., Kremer, Joel M., Gonzalez-Gay, Miguel A., Rodriguez-Rodriguez, Luis, Ärlestig, Lisbeth, Okada, Yukinori, Diogo, Dorothee, Liao, Katherine P., Karlson, Elizabeth W., Raychaudhuri, Soumya, Rantapää-Dahlqvist, Solbritt, Martin, Javier, Klareskog, Lars, Padyukov, Leonid, Gregersen, Peter K., Worthington, Jane, Greenberg, Jeffrey D., Plenge, Robert M., and Bae, Sang-Cheol

Abstract

Objective A highly polygenic aetiology and high degree of allele-sharing between ancestries have been well elucidated in genetic studies of rheumatoid arthritis. Recently, the high-density genotyping array Immunochip for immune disease loci identified 14 new rheumatoid arthritis risk loci among individuals of European ancestry. Here, we aimed to identify new rheumatoid arthritis risk loci using Korean-specific Immunochip data. Methods We analysed Korean rheumatoid arthritis case-control samples using the Immunochip and genome-wide association studies (GWAS) array to search for new risk alleles of rheumatoid arthritis with anticitrullinated peptide antibodies. To increase power, we performed a meta-analysis of Korean data with previously published European Immunochip and GWAS data for a total sample size of 9299 Korean and 45 790 European case-control samples. Results We identified eight new rheumatoid arthritis susceptibility loci (TNFSF4, LBH, EOMES, ETS1-FLI1, COG6, RAD51B, UBASH3A and SYNGR1) that passed a genome-wide significance threshold (p<5x10(-8)), with evidence for three independent risk alleles at 1q25/TNFSF4. The risk alleles from the seven new loci except for the TNFSF4 locus (monomorphic in Koreans), together with risk alleles from previously established RA risk loci, exhibited a high correlation of effect sizes between ancestries. Further, we refined the number of single nucleotide polymorphisms (SNPs) that represent potentially causal variants through a trans-ethnic comparison of densely genotyped SNPs. Conclusions This study demonstrates the advantage of dense-mapping and trans-ancestral analysis for identification of potentially causal SNPs. In addition, our findings support the importance of T cells in the pathogenesis and the fact of frequent overlap of risk loci among diverse autoimmune diseases.

Published
2015
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6. Genetics of rheumatoid arthritis contributes to biology and drug discovery

Author

Okada, Yukinori, Wu, Di, Trynka, Gosia, Raj, Towfique, Terao, Chikashi, Ikari, Katsunori, Kochi, Yuta, Ohmura, Koichiro, Suzuki, Akari, Yoshida, Shinji, Graham, Robert R, Manoharan, Arun, Ortmann, Ward, Bhangale, Tushar, Denny, Joshua C, Carroll, Robert J, Eyler, Anne E, Greenberg, Jeffrey D, Kremer, Joel M, Pappas, Dimitrios A, Jiang, Lei, Yin, Jian, Ye, Lingying, Su, Ding-Feng, Yang, Jian, Xie, Gang, Keystone, Ed, Westra, Harm-Jan, Esko, Tonu, Metspalu, Andres, Zhou, Xuezhong, Gupta, Namrata, Mirel, Daniel, Stahl, Eli A, Diogo, Dorothee, Cui, Jing, Liao, Katherine, Guo, Michael H, Myouzen, Keiko, Kawaguchi, Takahisa, Coenen, Marieke JH, van Riel, Piet LCM, van de laar, Mart AFJ, Guchelaar, Henk-Jan, Huizinga, Tom WJ, Dieude, Philippe, Mariette, Xavier, Bridges, S Louis, Jr., Zhernakova, Alexandra, Toes, Rene EM, Tak, Paul P, Miceli-Richard, Corinne, Bang, So-Young, Lee, Hye-Soon, Martin, Javier, Gonzalez-Gay, Miguel A, Rodriguez-Rodriguez, Luis, Rantapää-Dahlqvist, Solbritt, Ärlestig, Lisbeth, Choi, Hyon K, Kamatani, Yoichiro, Galan, Pilar, Lathrop, Mark, Eyre, Steve, Bowes, John, Barton, Anne, de Vries, Niek, Moreland, Larry W, Criswell, Lindsey A, Karlson, Elizabeth W, Taniguchi, Atsuo, Yamada, Ryo, Kubo, Michiaki, Liu, Jun S, Bae, Sang-Cheol, Worthington, Jane, Padyukov, Leonid, Klareskog, Lars, Gregersen, Peter K, Raychaudhuri, Soumya, Stranger, Barbara E, De Jager, Philip L, Franke, Lude, Visscher, Peter M, Brown, Matthew A, Yamanaka, Hisashi, Mimori, Tsuneyo, Takahashi, Atsushi, Xu, Huji, Behrens, Timothy W, Siminovitch, Katherine A, Momohara, Shigeki, Matsuda, Fumihiko, Yamamoto, Kazuhiko, Plenge, Robert M, Okada, Yukinori, Wu, Di, Trynka, Gosia, Raj, Towfique, Terao, Chikashi, Ikari, Katsunori, Kochi, Yuta, Ohmura, Koichiro, Suzuki, Akari, Yoshida, Shinji, Graham, Robert R, Manoharan, Arun, Ortmann, Ward, Bhangale, Tushar, Denny, Joshua C, Carroll, Robert J, Eyler, Anne E, Greenberg, Jeffrey D, Kremer, Joel M, Pappas, Dimitrios A, Jiang, Lei, Yin, Jian, Ye, Lingying, Su, Ding-Feng, Yang, Jian, Xie, Gang, Keystone, Ed, Westra, Harm-Jan, Esko, Tonu, Metspalu, Andres, Zhou, Xuezhong, Gupta, Namrata, Mirel, Daniel, Stahl, Eli A, Diogo, Dorothee, Cui, Jing, Liao, Katherine, Guo, Michael H, Myouzen, Keiko, Kawaguchi, Takahisa, Coenen, Marieke JH, van Riel, Piet LCM, van de laar, Mart AFJ, Guchelaar, Henk-Jan, Huizinga, Tom WJ, Dieude, Philippe, Mariette, Xavier, Bridges, S Louis, Jr., Zhernakova, Alexandra, Toes, Rene EM, Tak, Paul P, Miceli-Richard, Corinne, Bang, So-Young, Lee, Hye-Soon, Martin, Javier, Gonzalez-Gay, Miguel A, Rodriguez-Rodriguez, Luis, Rantapää-Dahlqvist, Solbritt, Ärlestig, Lisbeth, Choi, Hyon K, Kamatani, Yoichiro, Galan, Pilar, Lathrop, Mark, Eyre, Steve, Bowes, John, Barton, Anne, de Vries, Niek, Moreland, Larry W, Criswell, Lindsey A, Karlson, Elizabeth W, Taniguchi, Atsuo, Yamada, Ryo, Kubo, Michiaki, Liu, Jun S, Bae, Sang-Cheol, Worthington, Jane, Padyukov, Leonid, Klareskog, Lars, Gregersen, Peter K, Raychaudhuri, Soumya, Stranger, Barbara E, De Jager, Philip L, Franke, Lude, Visscher, Peter M, Brown, Matthew A, Yamanaka, Hisashi, Mimori, Tsuneyo, Takahashi, Atsushi, Xu, Huji, Behrens, Timothy W, Siminovitch, Katherine A, Momohara, Shigeki, Matsuda, Fumihiko, Yamamoto, Kazuhiko, and Plenge, Robert M

Abstract

A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)(1). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating similar to 10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2-4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation(5), cis-acting expression quantitative trait loci(6) and pathway analyses(7-9)-as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes-to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.

Published
2014
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7. Two functional lupus-associated BLK promoter variants control cell-type- and developmental-stage-specific transcription.

Author

Guthridge, Joel M, Guthridge, Joel M, Lu, Rufei, Sun, Harry, Sun, Celi, Wiley, Graham B, Dominguez, Nicolas, Macwana, Susan R, Lessard, Christopher J, Kim-Howard, Xana, Cobb, Beth L, Kaufman, Kenneth M, Kelly, Jennifer A, Langefeld, Carl D, Adler, Adam J, Harley, Isaac TW, Merrill, Joan T, Gilkeson, Gary S, Kamen, Diane L, Niewold, Timothy B, Brown, Elizabeth E, Edberg, Jeffery C, Petri, Michelle A, Ramsey-Goldman, Rosalind, Reveille, John D, Vilá, Luis M, Kimberly, Robert P, Freedman, Barry I, Stevens, Anne M, Boackle, Susan A, Criswell, Lindsey A, Vyse, Tim J, Behrens, Timothy W, Jacob, Chaim O, Alarcón-Riquelme, Marta E, Sivils, Kathy L, Choi, Jiyoung, Joo, Young Bin, Bang, So-Young, Lee, Hye-Soon, Bae, Sang-Cheol, Shen, Nan, Qian, Xiaoxia, Tsao, Betty P, Scofield, R Hal, Harley, John B, Webb, Carol F, Wakeland, Edward K, James, Judith A, Nath, Swapan K, Graham, Robert R, Gaffney, Patrick M, Guthridge, Joel M, Guthridge, Joel M, Lu, Rufei, Sun, Harry, Sun, Celi, Wiley, Graham B, Dominguez, Nicolas, Macwana, Susan R, Lessard, Christopher J, Kim-Howard, Xana, Cobb, Beth L, Kaufman, Kenneth M, Kelly, Jennifer A, Langefeld, Carl D, Adler, Adam J, Harley, Isaac TW, Merrill, Joan T, Gilkeson, Gary S, Kamen, Diane L, Niewold, Timothy B, Brown, Elizabeth E, Edberg, Jeffery C, Petri, Michelle A, Ramsey-Goldman, Rosalind, Reveille, John D, Vilá, Luis M, Kimberly, Robert P, Freedman, Barry I, Stevens, Anne M, Boackle, Susan A, Criswell, Lindsey A, Vyse, Tim J, Behrens, Timothy W, Jacob, Chaim O, Alarcón-Riquelme, Marta E, Sivils, Kathy L, Choi, Jiyoung, Joo, Young Bin, Bang, So-Young, Lee, Hye-Soon, Bae, Sang-Cheol, Shen, Nan, Qian, Xiaoxia, Tsao, Betty P, Scofield, R Hal, Harley, John B, Webb, Carol F, Wakeland, Edward K, James, Judith A, Nath, Swapan K, Graham, Robert R, and Gaffney, Patrick M

Abstract

Efforts to identify lupus-associated causal variants in the FAM167A/BLK locus on 8p21 are hampered by highly associated noncausal variants. In this report, we used a trans-population mapping and sequencing strategy to identify a common variant (rs922483) in the proximal BLK promoter and a tri-allelic variant (rs1382568) in the upstream alternative BLK promoter as putative causal variants for association with systemic lupus erythematosus. The risk allele (T) at rs922483 reduced proximal promoter activity and modulated alternative promoter usage. Allelic differences at rs1382568 resulted in altered promoter activity in B progenitor cell lines. Thus, our results demonstrated that both lupus-associated functional variants contribute to the autoimmune disease association by modulating transcription of BLK in B cells and thus potentially altering immune responses.

Published
2014

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