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1. Genetic legacy of ancient hunter-gatherer Jomon in Japanese populations

Author

Kenichi Yamamoto, Shinichi Namba, Kyuto Sonehara, Ken Suzuki, Saori Sakaue, Niall P. Cooke, Shinichi Higashiue, Shuzo Kobayashi, Hisaaki Afuso, Kosho Matsuura, Yojiro Mitsumoto, Yasuhiko Fujita, Torao Tokuda, the Biobank Japan Project, Koichi Matsuda, Takashi Gakuhari, Toshimasa Yamauchi, Takashi Kadowaki, Shigeki Nakagome, and Yukinori Okada

Subjects
Science
Abstract

Abstract The tripartite ancestral structure is a recently proposed model for the genetic origin of modern Japanese, comprising indigenous Jomon hunter-gatherers and two additional continental ancestors from Northeast Asia and East Asia. To investigate the impact of the tripartite structure on genetic and phenotypic variation today, we conducted biobank-scale analyses by merging Biobank Japan (BBJ; n = 171,287) with ancient Japanese and Eurasian genomes (n = 22). We demonstrate the applicability of the tripartite model to Japanese populations throughout the archipelago, with an extremely strong correlation between Jomon ancestry and genomic variation among individuals. We also find that the genetic legacy of Jomon ancestry underlies an elevated body mass index (BMI). Genome-wide association analysis with rigorous adjustments for geographical and ancestral substructures identifies 132 variants that are informative for predicting individual Jomon ancestry. This prediction model is validated using independent Japanese cohorts (Nagahama cohort, n = 2993; the second cohort of BBJ, n = 72,695). We further confirm the phenotypic association between Jomon ancestry and BMI using East Asian individuals from UK Biobank (n = 2286). Our extensive analysis of ancient and modern genomes, involving over 250,000 participants, provides valuable insights into the genetic legacy of ancient hunter-gatherers in contemporary populations.

Published
2024
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2. The influence of HLA genetic variation on plasma protein expression

Author

Chirag Krishna, Joshua Chiou, Saori Sakaue, Joyce B. Kang, Stephen M. Christensen, Isac Lee, Melis Atalar Aksit, Hye In Kim, David von Schack, Soumya Raychaudhuri, Daniel Ziemek, and Xinli Hu

Subjects
Science
Abstract

Abstract Genetic variation in the human leukocyte antigen (HLA) loci is associated with risk of immune-mediated diseases, but the molecular effects of HLA polymorphism are unclear. Here we examined the effects of HLA genetic variation on the expression of 2940 plasma proteins across 45,330 Europeans in the UK Biobank, with replication analyses across multiple ancestry groups. We detected 504 proteins affected by HLA variants (HLA-pQTL), including widespread trans effects by autoimmune disease risk alleles. More than 80% of the HLA-pQTL fine-mapped to amino acid positions in the peptide binding groove. HLA-I and II affected proteins expressed in similar cell types but in different pathways of both adaptive and innate immunity. Finally, we investigated potential HLA-pQTL effects on disease by integrating HLA-pQTL with fine-mapped HLA-disease signals in the UK Biobank. Our data reveal the diverse effects of HLA genetic variation and aid the interpretation of associations between HLA alleles and immune-mediated diseases.

Published
2024
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3. Clonal associations between lymphocyte subsets and functional states in rheumatoid arthritis synovium

Author

Garrett Dunlap, Aaron Wagner, Nida Meednu, Ruoqiao Wang, Fan Zhang, Jabea Cyril Ekabe, Anna Helena Jonsson, Kevin Wei, Saori Sakaue, Aparna Nathan, Accelerating Medicines Partnership Program: Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Network, Vivian P. Bykerk, Laura T. Donlin, Susan M. Goodman, Gary S. Firestein, David L. Boyle, V. Michael Holers, Larry W. Moreland, Darren Tabechian, Costantino Pitzalis, Andrew Filer, Soumya Raychaudhuri, Michael B. Brenner, Juilee Thakar, Andrew McDavid, Deepak A. Rao, and Jennifer H. Anolik

Subjects
Science
Abstract

Abstract Rheumatoid arthritis (RA) is an autoimmune disease involving antigen-specific T and B cells. Here, we perform single-cell RNA and repertoire sequencing on paired synovial tissue and blood samples from 12 seropositive RA patients. We identify clonally expanded CD4 + T cells, including CCL5+ cells and T peripheral helper (Tph) cells, which show a prominent transcriptomic signature of recent activation and effector function. CD8 + T cells show higher oligoclonality than CD4 + T cells, with the largest synovial clones enriched in GZMK+ cells. CD8 + T cells with possibly virus-reactive TCRs are distributed across transcriptomic clusters. In the B cell compartment, NR4A1+ activated B cells, and plasma cells are enriched in the synovium and demonstrate substantial clonal expansion. We identify synovial plasma cells that share BCRs with synovial ABC, memory, and activated B cells. Receptor-ligand analysis predicted IFNG and TNFRSF members as mediators of synovial Tph-B cell interactions. Together, these results reveal clonal relationships between functionally distinct lymphocyte populations that infiltrate the synovium of patients with RA.

Published
2024
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4. The chromatin landscape of pathogenic transcriptional cell states in rheumatoid arthritis

Author

Kathryn Weinand, Saori Sakaue, Aparna Nathan, Anna Helena Jonsson, Fan Zhang, Gerald F. M. Watts, Majd Al Suqri, Zhu Zhu, Accelerating Medicines Partnership Program: Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Network, Deepak A. Rao, Jennifer H. Anolik, Michael B. Brenner, Laura T. Donlin, Kevin Wei, and Soumya Raychaudhuri

Subjects
Science
Abstract

Abstract Synovial tissue inflammation is a hallmark of rheumatoid arthritis (RA). Recent work has identified prominent pathogenic cell states in inflamed RA synovial tissue, such as T peripheral helper cells; however, the epigenetic regulation of these states has yet to be defined. Here, we examine genome-wide open chromatin at single-cell resolution in 30 synovial tissue samples, including 12 samples with transcriptional data in multimodal experiments. We identify 24 chromatin classes and predict their associated transcription factors, including a CD8 + GZMK+ class associated with EOMES and a lining fibroblast class associated with AP-1. By integrating with an RA tissue transcriptional atlas, we propose that these chromatin classes represent ‘superstates’ corresponding to multiple transcriptional cell states. Finally, we demonstrate the utility of this RA tissue chromatin atlas through the associations between disease phenotypes and chromatin class abundance, as well as the nomination of classes mediating the effects of putatively causal RA genetic variants.

Published
2024
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5. 1009 In-depth analysis of myeloid cell subsets in lupus nephritis kidneys provides insights into disease mechanisms: lessons from the accelerating medicines partnership (AMP) in RA/SLE consortium

Author

Richard Furie, Joel M Guthridge, Judith A James, Maria Dall’Era, Michelle A Petri, Chaim Putterman, Jill P Buyon, Diane L Kamen, Betty Diamond, David Wofsy, Soumya Raychaudhuri, Thomas Tuschl, Jennifer Grossman, Peter M Izmirly, Qian Xiao, Nir Hacohen, Kenneth C Kalunian, Michael B Brenner, Mariko Ishimori, H Michael Belmont, Robert Clancy, ANNE DAVIDSON, Matthias Kretzler, Michael Weisman, Celine C Berthier, Andrea Fava, Jennifer L Barnas, Jennifer H Anolik, Paul J Hoover, Deepak A Rao, Arnon Arazi, William Apruzzese, Fernanda Payan-Schober, Joseph Mears, Saori Sakaue, James Lederer, Michael Peters, Tony Jones, Thomas M Eisenhaure, Siddarth Gurajala, Derek Fine, David A Hildeman, Steve Woodle, Maureen A McMahon, and Jeffery Hodgin

Subjects
Immunologic diseases. Allergy, RC581-607
Published
2024
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6. Genome-wide association study reveals BET1L associated with survival time in the 137,693 Japanese individuals

Author

Masato Akiyama, Saori Sakaue, Atsushi Takahashi, Kazuyoshi Ishigaki, Makoto Hirata, Koichi Matsuda, Yukihide Momozawa, Yukinori Okada, Toshiharu Ninomiya, The Biobank Japan project, Chikashi Terao, Yoshinori Murakami, Michiaki Kubo, and Yoichiro Kamatani

Subjects
Biology (General), QH301-705.5
Abstract

A genome-wide association study in the BioBank Japan cohort reveals new locus, BET1L, which is associated with survival time in a Japanese population.

Published
2023
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7. Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Author

Stavroula Kanoni, Sarah E. Graham, Yuxuan Wang, Ida Surakka, Shweta Ramdas, Xiang Zhu, Shoa L. Clarke, Konain Fatima Bhatti, Sailaja Vedantam, Thomas W. Winkler, Adam E. Locke, Eirini Marouli, Greg J. M. Zajac, Kuan-Han H. Wu, Ioanna Ntalla, Qin Hui, Derek Klarin, Austin T. Hilliard, Zeyuan Wang, Chao Xue, Gudmar Thorleifsson, Anna Helgadottir, Daniel F. Gudbjartsson, Hilma Holm, Isleifur Olafsson, Mi Yeong Hwang, Sohee Han, Masato Akiyama, Saori Sakaue, Chikashi Terao, Masahiro Kanai, Wei Zhou, Ben M. Brumpton, Humaira Rasheed, Aki S. Havulinna, Yogasudha Veturi, Jennifer Allen Pacheco, Elisabeth A. Rosenthal, Todd Lingren, QiPing Feng, Iftikhar J. Kullo, Akira Narita, Jun Takayama, Hilary C. Martin, Karen A. Hunt, Bhavi Trivedi, Jeffrey Haessler, Franco Giulianini, Yuki Bradford, Jason E. Miller, Archie Campbell, Kuang Lin, Iona Y. Millwood, Asif Rasheed, George Hindy, Jessica D. Faul, Wei Zhao, David R. Weir, Constance Turman, Hongyan Huang, Mariaelisa Graff, Ananyo Choudhury, Dhriti Sengupta, Anubha Mahajan, Michael R. Brown, Weihua Zhang, Ketian Yu, Ellen M. Schmidt, Anita Pandit, Stefan Gustafsson, Xianyong Yin, Jian’an Luan, Jing-Hua Zhao, Fumihiko Matsuda, Hye-Mi Jang, Kyungheon Yoon, Carolina Medina-Gomez, Achilleas Pitsillides, Jouke Jan Hottenga, Andrew R. Wood, Yingji Ji, Zishan Gao, Simon Haworth, Noha A. Yousri, Ruth E. Mitchell, Jin Fang Chai, Mette Aadahl, Anne A. Bjerregaard, Jie Yao, Ani Manichaikul, Chii-Min Hwu, Yi-Jen Hung, Helen R. Warren, Julia Ramirez, Jette Bork-Jensen, Line L. Kårhus, Anuj Goel, Maria Sabater-Lleal, Raymond Noordam, Pala Mauro, Floris Matteo, Aaron F. McDaid, Pedro Marques-Vidal, Matthias Wielscher, Stella Trompet, Naveed Sattar, Line T. Møllehave, Matthias Munz, Lingyao Zeng, Jianfeng Huang, Bin Yang, Alaitz Poveda, Azra Kurbasic, Claudia Lamina, Lukas Forer, Markus Scholz, Tessel E. Galesloot, Jonathan P. Bradfield, Sanni E. Ruotsalainen, EWarwick Daw, Joseph M. Zmuda, Jonathan S. Mitchell, Christian Fuchsberger, Henry Christensen, Jennifer A. Brody, Miguel Vazquez-Moreno, Mary F. Feitosa, Mary K. Wojczynski, Zhe Wang, Michael H. Preuss, Massimo Mangino, Paraskevi Christofidou, Niek Verweij, Jan W. Benjamins, Jorgen Engmann, Noah L. Tsao, Anurag Verma, Roderick C. Slieker, Ken Sin Lo, Nuno R. Zilhao, Phuong Le, Marcus E. Kleber, Graciela E. Delgado, Shaofeng Huo, Daisuke D. Ikeda, Hiroyuki Iha, Jian Yang, Jun Liu, Ayşe Demirkan, Hampton L. Leonard, Jonathan Marten, Mirjam Frank, Börge Schmidt, Laura J. Smyth, Marisa Cañadas-Garre, Chaolong Wang, Masahiro Nakatochi, Andrew Wong, Nina Hutri-Kähönen, Xueling Sim, Rui Xia, Alicia Huerta-Chagoya, Juan Carlos Fernandez-Lopez, Valeriya Lyssenko, Suraj S. Nongmaithem, Swati Bayyana, Heather M. Stringham, Marguerite R. Irvin, Christopher Oldmeadow, Han-Na Kim, Seungho Ryu, Paul R. H. J. Timmers, Liubov Arbeeva, Rajkumar Dorajoo, Leslie A. Lange, Gauri Prasad, Laura Lorés-Motta, Marc Pauper, Jirong Long, Xiaohui Li, Elizabeth Theusch, Fumihiko Takeuchi, Cassandra N. Spracklen, Anu Loukola, Sailalitha Bollepalli, Sophie C. Warner, Ya Xing Wang, Wen B. Wei, Teresa Nutile, Daniela Ruggiero, Yun Ju Sung, Shufeng Chen, Fangchao Liu, Jingyun Yang, Katherine A. Kentistou, Bernhard Banas, Giuseppe Giovanni Nardone, Karina Meidtner, Lawrence F. Bielak, Jennifer A. Smith, Prashantha Hebbar, Aliki-Eleni Farmaki, Edith Hofer, Maoxuan Lin, Maria Pina Concas, Simona Vaccargiu, Peter J. van der Most, Niina Pitkänen, Brian E. Cade, Sander W. van der Laan, Kumaraswamy Naidu Chitrala, Stefan Weiss, Amy R. Bentley, Ayo P. Doumatey, Adebowale A. Adeyemo, Jong Young Lee, Eva R. B. Petersen, Aneta A. Nielsen, Hyeok Sun Choi, Maria Nethander, Sandra Freitag-Wolf, Lorraine Southam, Nigel W. Rayner, Carol A. Wang, Shih-Yi Lin, Jun-Sing Wang, Christian Couture, Leo-Pekka Lyytikäinen, Kjell Nikus, Gabriel Cuellar-Partida, Henrik Vestergaard, Bertha Hidalgo, Olga Giannakopoulou, Qiuyin Cai, Morgan O. Obura, Jessica van Setten, Xiaoyin Li, Jingjing Liang, Hua Tang, Natalie Terzikhan, Jae Hun Shin, Rebecca D. Jackson, Alexander P. Reiner, Lisa Warsinger Martin, Zhengming Chen, Liming Li, Takahisa Kawaguchi, Joachim Thiery, Joshua C. Bis, Lenore J. Launer, Huaixing Li, Mike A. Nalls, Olli T. Raitakari, Sahoko Ichihara, Sarah H. Wild, Christopher P. Nelson, Harry Campbell, Susanne Jäger, Toru Nabika, Fahd Al-Mulla, Harri Niinikoski, Peter S. Braund, Ivana Kolcic, Peter Kovacs, Tota Giardoglou, Tomohiro Katsuya, Dominique de Kleijn, Gert J. de Borst, Eung Kweon Kim, Hieab H. H. Adams, M. Arfan Ikram, Xiaofeng Zhu, Folkert W. Asselbergs, Adriaan O. Kraaijeveld, Joline W. J. Beulens, Xiao-Ou Shu, Loukianos S. Rallidis, Oluf Pedersen, Torben Hansen, Paul Mitchell, Alex W. Hewitt, Mika Kähönen, Louis Pérusse, Claude Bouchard, Anke Tönjes, Yii-Der Ida Chen, Craig E. Pennell, Trevor A. Mori, Wolfgang Lieb, Andre Franke, Claes Ohlsson, Dan Mellström, Yoon Shin Cho, Hyejin Lee, Jian-Min Yuan, Woon-Puay Koh, Sang Youl Rhee, Jeong-Taek Woo, Iris M. Heid, Klaus J. Stark, Martina E. Zimmermann, Henry Völzke, Georg Homuth, Michele K. Evans, Alan B. Zonderman, Ozren Polasek, Gerard Pasterkamp, Imo E. Hoefer, Susan Redline, Katja Pahkala, Albertine J. Oldehinkel, Harold Snieder, Ginevra Biino, Reinhold Schmidt, Helena Schmidt, Stefania Bandinelli, George Dedoussis, Thangavel Alphonse Thanaraj, Sharon L. R. Kardia, Patricia A. Peyser, Norihiro Kato, Matthias B. Schulze, Giorgia Girotto, Carsten A. Böger, Bettina Jung, Peter K. Joshi, David A. Bennett, Philip L. De Jager, Xiangfeng Lu, Vasiliki Mamakou, Morris Brown, Mark J. Caulfield, Patricia B. Munroe, Xiuqing Guo, Marina Ciullo, Jost B. Jonas, Nilesh J. Samani, Jaakko Kaprio, Päivi Pajukanta, Teresa Tusié-Luna, Carlos A. Aguilar-Salinas, Linda S. Adair, Sonny Augustin Bechayda, H. Janaka de Silva, Ananda R. Wickremasinghe, Ronald M. Krauss, Jer-Yuarn Wu, Wei Zheng, Anneke Iden Hollander, Dwaipayan Bharadwaj, Adolfo Correa, James G. Wilson, Lars Lind, Chew-Kiat Heng, Amanda E. Nelson, Yvonne M. Golightly, James F. Wilson, Brenda Penninx, Hyung-Lae Kim, John Attia, Rodney J. Scott, D. C. Rao, Donna K. Arnett, Steven C. Hunt, Mark Walker, Heikki A. Koistinen, Giriraj R. Chandak, Josep M. Mercader, Maria C. Costanzo, Dongkeun Jang, Noël P. Burtt, Clicerio Gonzalez Villalpando, Lorena Orozco, Myriam Fornage, EShyong Tai, Rob M. van Dam, Terho Lehtimäki, Nish Chaturvedi, Mitsuhiro Yokota, Jianjun Liu, Dermot F. Reilly, Amy Jayne McKnight, Frank Kee, Karl-Heinz Jöckel, Mark I. McCarthy, Colin N. A. Palmer, Veronique Vitart, Caroline Hayward, Eleanor Simonsick, Cornelia M. van Duijn, Zi-Bing Jin, Jia Qu, Haretsugu Hishigaki, Xu Lin, Winfried März, Vilmundur Gudnason, Jean-Claude Tardif, Guillaume Lettre, Leen M.‘t Hart, Petra J. M. Elders, Scott M. Damrauer, Meena Kumari, Mika Kivimaki, Pim van der Harst, Tim D. Spector, Ruth J. F. Loos, Michael A. Province, Esteban J. Parra, Miguel Cruz, Bruce M. Psaty, Ivan Brandslund, Peter P. Pramstaller, Charles N. Rotimi, Kaare Christensen, Samuli Ripatti, Elisabeth Widén, Hakon Hakonarson, Struan F. A. Grant, Lambertus A. L. M. Kiemeney, Jacqueline de Graaf, Markus Loeffler, Florian Kronenberg, Dongfeng Gu, Jeanette Erdmann, Heribert Schunkert, Paul W. Franks, Allan Linneberg, J. Wouter Jukema, Amit V. Khera, Minna Männikkö, Marjo-Riitta Jarvelin, Zoltan Kutalik, Cucca Francesco, Dennis O. Mook-Kanamori, Ko Willems van Dijk, Hugh Watkins, David P. Strachan, Niels Grarup, Peter Sever, Neil Poulter, Lee-Ming Chuang, Jerome I. Rotter, Thomas M. Dantoft, Fredrik Karpe, Matt J. Neville, Nicholas J. Timpson, Ching-Yu Cheng, Tien-Yin Wong, Chiea Chuen Khor, Hengtong Li, Charumathi Sabanayagam, Annette Peters, Christian Gieger, Andrew T. Hattersley, Nancy L. Pedersen, Patrik K. E. Magnusson, Dorret I. Boomsma, Allegonda H. M. Willemsen, LAdrienne Cupples, Joyce B. J. van Meurs, Mohsen Ghanbari, Penny Gordon-Larsen, Wei Huang, Young Jin Kim, Yasuharu Tabara, Nicholas J. Wareham, Claudia Langenberg, Eleftheria Zeggini, Johanna Kuusisto, Markku Laakso, Erik Ingelsson, Goncalo Abecasis, John C. Chambers, Jaspal S. Kooner, Paul S. de Vries, Alanna C. Morrison, Scott Hazelhurst, Michèle Ramsay, Kari E. North, Martha Daviglus, Peter Kraft, Nicholas G. Martin, John B. Whitfield, Shahid Abbas, Danish Saleheen, Robin G. Walters, Michael V. Holmes, Corri Black, Blair H. Smith, Aris Baras, Anne E. Justice, Julie E. Buring, Paul M. Ridker, Daniel I. Chasman, Charles Kooperberg, Gen Tamiya, Masayuki Yamamoto, David A. van Heel, Richard C. Trembath, Wei-Qi Wei, Gail P. Jarvik, Bahram Namjou, M. Geoffrey Hayes, Marylyn D. Ritchie, Pekka Jousilahti, Veikko Salomaa, Kristian Hveem, Bjørn Olav Åsvold, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada, Yoshinori Murakami, Bong-Jo Kim, Unnur Thorsteinsdottir, Kari Stefansson, Jifeng Zhang, YEugene Chen, Yuk-Lam Ho, Julie A. Lynch, Daniel J. Rader, Philip S. Tsao, Kyong-Mi Chang, Kelly Cho, Christopher J. O’Donnell, John M. Gaziano, Peter W. F. Wilson, Timothy M. Frayling, Joel N. Hirschhorn, Sekar Kathiresan, Karen L. Mohlke, Yan V. Sun, Andrew P. Morris, Michael Boehnke, Christopher D. Brown, Pradeep Natarajan, Panos Deloukas, Cristen J. Willer, Themistocles L. Assimes, and Gina M. Peloso

Subjects
Cholesterol, Lipids, Genetics, Genome-wide association study, GWAS, Biology (General), QH301-705.5, QH426-470
Abstract

Abstract Background Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.

Published
2022
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8. 1107 Immune cell heterogeneity in lupus nephritis kidneys and its relation to histopathological features: lessons from the accelerating medicines partnership (AMP) in SLE Consortium

Author

Richard Furie, Joel M Guthridge, Judith A James, Maria Dall’Era, Michelle A Petri, Chaim Putterman, Jill P Buyon, Diane L Kamen, Betty Diamond, David Wofsy, Soumya Raychaudhuri, Thomas Tuschl, Jennifer Grossman, Peter M Izmirly, Qian Xiao, Nir Hacohen, Kenneth C Kalunian, Michael B Brenner, Mariko Ishimori, H Michael Belmont, Robert Clancy, ANNE DAVIDSON, Matthias Kretzler, Michael Weisman, Celine C Berthier, Andrea Fava, Jennifer L Barnas, Jennifer H Anolik, Paul J Hoover, Deepak A Rao, Arnon Arazi, William Apruzzese, Fernanda Payan-Schober, Saori Sakaue, James Lederer, Michael Peters, Tony Jones, Jospeh Mears, Thomas M Eisenhaure, Siddarth Gurajala, Derek Fine, David A Hildeman, Steve Woodle, Maureen A McMahon, and Jeffery Hodgin

Subjects
Immunologic diseases. Allergy, RC581-607
Published
2022
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9. Genetic determinants of risk in autoimmune pulmonary alveolar proteinosis

Author

Saori Sakaue, Etsuro Yamaguchi, Yoshikazu Inoue, Meiko Takahashi, Jun Hirata, Ken Suzuki, Satoru Ito, Toru Arai, Masaki Hirose, Yoshinori Tanino, Takefumi Nikaido, Toshio Ichiwata, Shinya Ohkouchi, Taizou Hirano, Toshinori Takada, Satoru Miyawaki, Shogo Dofuku, Yuichi Maeda, Takuro Nii, Toshihiro Kishikawa, Kotaro Ogawa, Tatsuo Masuda, Kenichi Yamamoto, Kyuto Sonehara, Ryushi Tazawa, Konosuke Morimoto, Masahiro Takaki, Satoshi Konno, Masaru Suzuki, Keisuke Tomii, Atsushi Nakagawa, Tomohiro Handa, Kiminobu Tanizawa, Haruyuki Ishii, Manabu Ishida, Toshiyuki Kato, Naoya Takeda, Koshi Yokomura, Takashi Matsui, Masaki Watanabe, Hiromasa Inoue, Kazuyoshi Imaizumi, Yasuhiro Goto, Hiroshi Kida, Tomoyuki Fujisawa, Takafumi Suda, Takashi Yamada, Yasuomi Satake, Hidenori Ibata, Nobuyuki Hizawa, Hideki Mochizuki, Atsushi Kumanogoh, Fumihiko Matsuda, Koh Nakata, Tomomitsu Hirota, Mayumi Tamari, and Yukinori Okada

Subjects
Science
Abstract

Autoimmune pulmonary alveolar proteinosis (aPAP) is a complex lung disease caused by abnormal surfactant homeostasis. Here, the authors carry out a genome-wide association study of aPAP in a Japanese cohort, finding variants in the MHC and suggesting predisposition to abnormal antibody production.

Published
2021
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10. Cerebral small vessel disease genomics and its implications across the lifespan

Author

Muralidharan Sargurupremraj, Hideaki Suzuki, Xueqiu Jian, Chloé Sarnowski, Tavia E. Evans, Joshua C. Bis, Gudny Eiriksdottir, Saori Sakaue, Natalie Terzikhan, Mohamad Habes, Wei Zhao, Nicola J. Armstrong, Edith Hofer, Lisa R. Yanek, Saskia P. Hagenaars, Rajan B. Kumar, Erik B. van den Akker, Rebekah E. McWhirter, Stella Trompet, Aniket Mishra, Yasaman Saba, Claudia L. Satizabal, Gregory Beaudet, Laurent Petit, Ami Tsuchida, Laure Zago, Sabrina Schilling, Sigurdur Sigurdsson, Rebecca F. Gottesman, Cora E. Lewis, Neelum T. Aggarwal, Oscar L. Lopez, Jennifer A. Smith, Maria C. Valdés Hernández, Jeroen van der Grond, Margaret J. Wright, Maria J. Knol, Marcus Dörr, Russell J. Thomson, Constance Bordes, Quentin Le Grand, Marie-Gabrielle Duperron, Albert V. Smith, David S. Knopman, Pamela J. Schreiner, Denis A. Evans, Jerome I. Rotter, Alexa S. Beiser, Susana Muñoz Maniega, Marian Beekman, Julian Trollor, David J. Stott, Meike W. Vernooij, Katharina Wittfeld, Wiro J. Niessen, Aicha Soumaré, Eric Boerwinkle, Stephen Sidney, Stephen T. Turner, Gail Davies, Anbupalam Thalamuthu, Uwe Völker, Mark A. van Buchem, R. Nick Bryan, Josée Dupuis, Mark E. Bastin, David Ames, Alexander Teumer, Philippe Amouyel, John B. Kwok, Robin Bülow, Ian J. Deary, Peter R. Schofield, Henry Brodaty, Jiyang Jiang, Yasuharu Tabara, Kazuya Setoh, Susumu Miyamoto, Kazumichi Yoshida, Manabu Nagata, Yoichiro Kamatani, Fumihiko Matsuda, Bruce M. Psaty, David A. Bennett, Philip L. De Jager, Thomas H. Mosley, Perminder S. Sachdev, Reinhold Schmidt, Helen R. Warren, Evangelos Evangelou, David-Alexandre Trégouët, International Network against Thrombosis (INVENT) Consortium, International Headache Genomics Consortium (IHGC), Mohammad A. Ikram, Wei Wen, Charles DeCarli, Velandai K. Srikanth, J. Wouter Jukema, Eline P. Slagboom, Sharon L. R. Kardia, Yukinori Okada, Bernard Mazoyer, Joanna M. Wardlaw, Paul A. Nyquist, Karen A. Mather, Hans J. Grabe, Helena Schmidt, Cornelia M. Van Duijn, Vilmundur Gudnason, William T. Longstreth, Lenore J. Launer, Mark Lathrop, Sudha Seshadri, Christophe Tzourio, Hieab H. Adams, Paul M. Matthews, Myriam Fornage, and Stéphanie Debette

Subjects
Science
Abstract

White matter hyperintensities (WMH) are a common brain-imaging feature of cerebral small vessel disease. Here, the authors carry out a GWAS and followup analyses for WMH-volume, implicating several variants with potential for risk stratification and drug targeting.

Published
2020
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11. Decoding the diversity of killer immunoglobulin-like receptors by deep sequencing and a high-resolution imputation method

Author

Saori Sakaue, Kazuyoshi Hosomichi, Jun Hirata, Hirofumi Nakaoka, Keiko Yamazaki, Makoto Yawata, Nobuyo Yawata, Tatsuhiko Naito, Junji Umeno, Takaaki Kawaguchi, Toshiyuki Matsui, Satoshi Motoya, Yasuo Suzuki, Hidetoshi Inoko, Atsushi Tajima, Takayuki Morisaki, Koichi Matsuda, Yoichiro Kamatani, Kazuhiko Yamamoto, Ituro Inoue, and Yukinori Okada

Subjects
killer cell immunoglobulin-like receptor, KIR, target sequencing, next-generation sequencing, imputation, PheWAS, Genetics, QH426-470, Internal medicine, RC31-1245
Abstract

Summary: The killer cell immunoglobulin-like receptor (KIR) recognizes human leukocyte antigen (HLA) class I molecules and modulates the function of natural killer cells. Despite its role in immunity, the complex genomic structure has limited a deep understanding of the KIR genomic landscape. Here we conduct deep sequencing of 16 KIR genes in 1,173 individuals. We devise a bioinformatics pipeline incorporating copy number estimation and insertion or deletion (indel) calling for high-resolution KIR genotyping. We define 118 alleles in 13 genes and demonstrate a linkage disequilibrium structure within and across KIR centromeric and telomeric regions. We construct a KIR imputation reference panel (nreference = 689, imputation accuracy = 99.7%), apply it to biobank genotype (ntotal = 169,907), and perform phenome-wide association studies of 85 traits. We observe a dearth of genome-wide significant associations, even in immune traits implicated previously to be associated with KIR (the smallest p = 1.5 × 10−4). Our pipeline presents a broadly applicable framework to evaluate innate immunity in large-scale datasets.

Published
2022
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12. Dimensionality reduction reveals fine-scale structure in the Japanese population with consequences for polygenic risk prediction

Author

Saori Sakaue, Jun Hirata, Masahiro Kanai, Ken Suzuki, Masato Akiyama, Chun Lai Too, Thurayya Arayssi, Mohammed Hammoudeh, Samar Al Emadi, Basel K. Masri, Hussein Halabi, Humeira Badsha, Imad W. Uthman, Richa Saxena, Leonid Padyukov, Makoto Hirata, Koichi Matsuda, Yoshinori Murakami, Yoichiro Kamatani, and Yukinori Okada

Subjects
Science
Abstract

Population structure, even subtle differences within seemingly homogenous populations, can have an impact on the accuracy of polygenic prediction. Here, Sakaue et al. use dimensionality reduction methods to reveal fine-scale structure in the Biobank Japan cohort and explore the performance of polygenic risk scores.

Published
2020
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13. Safety of procuring research tissue during a clinically indicated kidney biopsy from patients with lupus: data from the Accelerating Medicines Partnership RA/SLE Network

Author

Andrew Filer, Michael H Weisman, Judith A James, Kenneth Kalunian, Michelle A Petri, Chaim Putterman, H Michael Belmont, Ilfita Sahbudin, Karim Raza, Maria Dall'Era, Jill P Buyon, Diane L Kamen, Karen Salomon-Escoto, Kazuyoshi Ishigaki, Patrick Dunn, David Wofsy, Michele Bombardieri, Vivian Bykerk, Myles Lewis, Ming Wu, Soumya Raychaudhuri, Hemant Suryawanshi, Thomas Tuschl, Christopher Ritchlin, Maureen McMahon, Jennifer Grossman, Philip M Carlucci, Alessandra Nerviani, Peter M Izmirly, Fan Zhang, Felice Rivellese, Joan Bathon, Zhu Zhu, Qian Xiao, Jessica Li, Holden Maecker, Nir Hacohen, Rong Mao, Jennifer Anolik, Javier Rangel-Moreno, Nida Meednu, Susan Goodman, Lindsy Forbess, Mariko Ishimori, Kevin Deane, David Hildeman, Yuhong Li, Laura Hughes, Robert Clancy, ANNE DAVIDSON, Matthias Kretzler, Larry Moreland, Harris Perlman, Peter Gregersen, Celine C Berthier, Andrea Fava, David Boyle, Derek M Fine, Ami Ben-Artzi, P J Utz, Melanie Smith, Beatrice Goilav, Carla Cuda, Andrew McDavid, Deepak A Rao, Joshua Keegan, Ilya Korsunsky, Joel Guthridge, Kevin Wei, Arnon Arazi, Thomas Eisenhaure, Michael Brenner, Susan Macwana, Pavel Morozov, Manjunath Kustagi, Gerald Watts, Kristina K Deonaraine, Jose Monroy-Trujillo, Mohamed G Atta, Kristin Haag, William Apruzzese, Sean Connery, Fernanda Payan-Schober, Kerry Cho, Jennifer Goff, Aparna Nathan, Joseph Mears, Nghia Millard, Kathryn Weinand, Saori Sakaue, Bill Robinson, Wade DeJager, Louis Bridges, Laura Donlin, Edward DiCarlo, Amit Lakhanpal, Heather Sherman, Anvita Singaraju, Lorien Shakib, Brendan Boyce, Darren Tabechian, Jen Albrecht, James Lederer, A Helena Jonsson, Daimon Simmons, Gregory Keras, Adam Chicoine, Zhihan Jian Li, Mandy McGeachy, Gary Firestein, Arnold Ceponis, Diane Horowitz, Salina Dominguez, Arthur Mandelin, Anjali Thakrar, Mike Holers, Jennifer Seifert, Constanino Pitzalis, Ellen Gravallese, Jennifer Barnas, Raymond Hsu, Steven Woodle, Paul Hoover, Michael Peters, Tony Jones, David Lieb, Jeffrey Hodgin, and Raji Menon

Subjects
Immunologic diseases. Allergy, RC581-607
Abstract

Objectives In lupus nephritis the pathological diagnosis from tissue retrieved during kidney biopsy drives treatment and management. Despite recent approval of new drugs, complete remission rates remain well under aspirational levels, necessitating identification of new therapeutic targets by greater dissection of the pathways to tissue inflammation and injury. This study assessed the safety of kidney biopsies in patients with SLE enrolled in the Accelerating Medicines Partnership, a consortium formed to molecularly deconstruct nephritis.Methods 475 patients with SLE across 15 clinical sites in the USA consented to obtain tissue for research purposes during a clinically indicated kidney biopsy. Adverse events (AEs) were documented for 30 days following the procedure and were determined to be related or unrelated by all site investigators. Serious AEs were defined according to the National Institutes of Health reporting guidelines.Results 34 patients (7.2%) experienced a procedure-related AE: 30 with haematoma, 2 with jets, 1 with pain and 1 with an arteriovenous fistula. Eighteen (3.8%) experienced a serious AE requiring hospitalisation; four patients (0.8%) required a blood transfusion related to the kidney biopsy. At one site where the number of cores retrieved during the biopsy was recorded, the mean was 3.4 for those who experienced a related AE (n=9) and 3.07 for those who did not experience any AE (n=140). All related AEs resolved.Conclusions Procurement of research tissue should be considered feasible, accompanied by a complication risk likely no greater than that incurred for standard clinical purposes. In the quest for targeted treatments personalised based on molecular findings, enhanced diagnostics beyond histology will likely be required.

Published
2021
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14. Characterizing rare and low-frequency height-associated variants in the Japanese population

Author

Masato Akiyama, Kazuyoshi Ishigaki, Saori Sakaue, Yukihide Momozawa, Momoko Horikoshi, Makoto Hirata, Koichi Matsuda, Shiro Ikegawa, Atsushi Takahashi, Masahiro Kanai, Sadao Suzuki, Daisuke Matsui, Mariko Naito, Taiki Yamaji, Motoki Iwasaki, Norie Sawada, Kozo Tanno, Makoto Sasaki, Atsushi Hozawa, Naoko Minegishi, Kenji Wakai, Shoichiro Tsugane, Atsushi Shimizu, Masayuki Yamamoto, Yukinori Okada, Yoshinori Murakami, Michiaki Kubo, and Yoichiro Kamatani

Subjects
Science
Abstract

Thousands of genetic loci are known to associate with human height, but these are mainly based on studies in European ancestry populations. Here, Akiyama et al. construct a genotype reference panel for the Japanese population followed by GWAS and report 573 height associated variants in 191,787 Japanese.

Published
2019
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15. Next-generation sequencing identifies contribution of both class I and II HLA genes on susceptibility of multiple sclerosis in Japanese

Author

Kotaro Ogawa, Tatsusada Okuno, Kazuyoshi Hosomichi, Akiko Hosokawa, Jun Hirata, Ken Suzuki, Saori Sakaue, Makoto Kinoshita, Yoshihiro Asano, Katsuichi Miyamoto, Ituro Inoue, Susumu Kusunoki, Yukinori Okada, and Hideki Mochizuki

Subjects
Multiple sclerosis, Neuromyelitis optica spectrum disorder, HLA, Next-generation sequencing, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background The spectrum of classical and non-classical HLA genes related to the risk of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) in the Japanese population has not been studied in detail. We conducted a case-control analysis of classical and non-classical HLA genes. Methods We used next-generation sequencing (NGS)-based HLA genotyping methods for mapping risk for 45 MS patients, 31 NMOSD patients, and 429 healthy controls. We evaluated the association of the HLA variants with the risk of MS and NMOSD using logistic regression analysis and Fisher’s exact test. Results We confirmed that HLA-DRB1*15:01 showed the strongest association with MS (P = 2.1 × 10−5; odds ratio [OR] = 3.44, 95% confidence interval [95% CI] = 1.95–6.07). Stepwise conditional analysis identified HLA-DRB1*04:05, HLA-B*39:01, and HLA-B*15:01 as being associated with independent MS susceptibility (P Conditional

Published
2019
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16. Genome-wide analysis of dental caries and periodontitis combining clinical and self-reported data

Author

Dmitry Shungin, Simon Haworth, Kimon Divaris, Cary S. Agler, Yoichiro Kamatani, Myoung Keun Lee, Kelsey Grinde, George Hindy, Viivi Alaraudanjoki, Paula Pesonen, Alexander Teumer, Birte Holtfreter, Saori Sakaue, Jun Hirata, Yau-Hua Yu, Paul M. Ridker, Franco Giulianini, Daniel I. Chasman, Patrik K. E. Magnusson, Takeaki Sudo, Yukinori Okada, Uwe Völker, Thomas Kocher, Vuokko Anttonen, Marja-Liisa Laitala, Marju Orho-Melander, Tamar Sofer, John R. Shaffer, Alexandre Vieira, Mary L. Marazita, Michiaki Kubo, Yasushi Furuichi, Kari E. North, Steve Offenbacher, Erik Ingelsson, Paul W. Franks, Nicholas J. Timpson, and Ingegerd Johansson

Subjects
Science
Abstract

Dental caries and periodontitis are among the most common medical conditions. Here, the authors report a GWAS for measures of oral health that reveals 47 risk loci for caries, find genetic correlation with 31 other complex traits and use Mendelian randomization analyses to explore potential causal relationships.

Published
2019
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17. Whole genome sequence analyses of eGFR in 23,732 people representing multiple ancestries in the NHLBI trans-omics for precision medicine (TOPMed) consortium

Author

Bridget M Lin, Kelsey E Grinde, Jennifer A Brody, Charles E Breeze, Laura M Raffield, Josyf C Mychaleckyj, Timothy A Thornton, James A Perry, Leslie J Baier, Lisa de las Fuentes, Xiuqing Guo, Benjamin D Heavner, Robert L Hanson, Yi-Jen Hung, Huijun Qian, Chao A Hsiung, Shih-Jen Hwang, Margaret R Irvin, Deepti Jain, Tanika N Kelly, Sayuko Kobes, Leslie Lange, James P Lash, Yun Li, Xiaoming Liu, Xuenan Mi, Solomon K Musani, George J Papanicolaou, Afshin Parsa, Alex P Reiner, Shabnam Salimi, Wayne H-H Sheu, Alan R Shuldiner, Kent D Taylor, Albert V Smith, Jennifer A Smith, Adrienne Tin, Dhananjay Vaidya, Robert B Wallace, Kenichi Yamamoto, Saori Sakaue, Koichi Matsuda, Yoichiro Kamatani, Yukihide Momozawa, Lisa R Yanek, Betsi A Young, Wei Zhao, Yukinori Okada, Gonzalo Abecasis, Bruce M Psaty, Donna K Arnett, Eric Boerwinkle, Jianwen Cai, Ida Yii-Der Chen, Adolfo Correa, L Adrienne Cupples, Jiang He, Sharon LR Kardia, Charles Kooperberg, Rasika A Mathias, Braxton D Mitchell, Deborah A Nickerson, Steve T Turner, Vasan S Ramachandran, Jerome I Rotter, Daniel Levy, Holly J Kramer, Anna Köttgen, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Kidney Working Group, Stephen S Rich, Dan-Yu Lin, Sharon R Browning, and Nora Franceschini

Subjects
Whole genome sequencing, Kidney traits, Rare variants, Ancestry-specific variants, Medicine, Medicine (General), R5-920
Abstract

Background: Genetic factors that influence kidney traits have been understudied for low frequency and ancestry-specific variants. Methods: We combined whole genome sequencing (WGS) data from 23,732 participants from 10 NHLBI Trans-Omics for Precision Medicine (TOPMed) Program multi-ethnic studies to identify novel loci for estimated glomerular filtration rate (eGFR). Participants included European, African, East Asian, and Hispanic ancestries. We applied linear mixed models using a genetic relationship matrix estimated from the WGS data and adjusted for age, sex, study, and ethnicity. Findings: When testing single variants, we identified three novel loci driven by low frequency variants more commonly observed in non-European ancestry (PRKAA2, rs180996919, minor allele frequency [MAF] 0.04%, P = 6.1 × 10−11; METTL8, rs116951054, MAF 0.09%, P = 4.5 × 10−9; and MATK, rs539182790, MAF 0.05%, P = 3.4 × 10−9). We also replicated two known loci for common variants (rs2461702, MAF=0.49, P = 1.2 × 10−9, nearest gene GATM, and rs71147340, MAF=0.34, P = 3.3 × 10−9, CDK12). Testing aggregated variants within a gene identified the MAF gene. A statistical approach based on local ancestry helped to identify replication samples for ancestry-specific variants. Interpretation: This study highlights challenges in studying variants influencing kidney traits that are low frequency in populations and more common in non-European ancestry.

Published
2021
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18. Deep whole-genome sequencing reveals recent selection signatures linked to evolution and disease risk of Japanese

Author

Yukinori Okada, Yukihide Momozawa, Saori Sakaue, Masahiro Kanai, Kazuyoshi Ishigaki, Masato Akiyama, Toshihiro Kishikawa, Yasumichi Arai, Takashi Sasaki, Kenjiro Kosaki, Makoto Suematsu, Koichi Matsuda, Kazuhiko Yamamoto, Michiaki Kubo, Nobuyoshi Hirose, and Yoichiro Kamatani

Subjects
Science
Abstract

Recent natural selection left signals in human genomes. Here, Okada et al. generate high-depth whole-genome sequence (WGS) data (25.9×) from 2,234 Japanese people of the BioBank Japan Project (BBJ), and identify signals of recent natural selection which overlap variants associated with human traits.

Published
2018
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19. Author Correction: Characterizing rare and low-frequency height-associated variants in the Japanese population

Author

Masato Akiyama, Kazuyoshi Ishigaki, Saori Sakaue, Yukihide Momozawa, Momoko Horikoshi, Makoto Hirata, Koichi Matsuda, Shiro Ikegawa, Atsushi Takahashi, Masahiro Kanai, Sadao Suzuki, Daisuke Matsui, Mariko Naito, Taiki Yamaji, Motoki Iwasaki, Norie Sawada, Kozo Tanno, Makoto Sasaki, Atsushi Hozawa, Naoko Minegishi, Kenji Wakai, Shoichiro Tsugane, Atsushi Shimizu, Masayuki Yamamoto, Yukinori Okada, Yoshinori Murakami, Michiaki Kubo, and Yoichiro Kamatani

Subjects
Science
Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2020
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20. Multi-phenotype analyses of hemostatic traits with cardiovascular events reveal novel genetic associations

Author

Gerard Temprano‐Sagrera, Colleen M. Sitlani, William P. Bone, Miguel Martin‐Bornez, Benjamin F. Voight, Alanna C. Morrison, Scott M. Damrauer, Paul S. de Vries, Nicholas L. Smith, Maria Sabater‐Lleal, Abbas Dehghan, Adam S Heath, Alanna C Morrison, Alex P Reiner, Andrew Johnson, Anne Richmond, Annette Peters, Astrid van Hylckama Vlieg, Barbara McKnight, Bruce M Psaty, Caroline Hayward, Cavin Ward‐Caviness, Christopher O’Donnell, Daniel Chasman, David P Strachan, David A Tregouet, Dennis Mook‐Kanamori, Dipender Gill, Florian Thibord, Folkert W Asselbergs, Frank W.G. Leebeek, Frits R Rosendaal, Gail Davies, Georg Homuth, Gerard Temprano, Harry Campbell, Herman A Taylor, Jan Bressler, Jennifer E Huffman, Jerome I Rotter, Jie Yao, James F Wilson, Joshua C Bis, Julie M Hahn, Karl C Desch, Kerri L Wiggins, Laura M Raffield, Lawrence F Bielak, Lisa R Yanek, Marcus E Kleber, Martina Mueller, Maryam Kavousi, Massimo Mangino, Melissa Liu, Michael R Brown, Matthew P Conomos, Min‐A Jhun, Ming‐Huei Chen, Moniek P.M. de Maat, Nathan Pankratz, Nicholas L Smith, Patricia A Peyser, Paul Elliot, Paul S de Vries, Peng Wei, Philipp S Wild, Pierre E Morange, Pim van der Harst, Qiong Yang, Ngoc‐Quynh Le, Riccardo Marioni, Ruifang Li, Scott M Damrauer, Simon R Cox, Stella Trompet, Stephan B Felix, Uwe Völker, Weihong Tang, Wolfgang Koenig, J. Wouter Jukema, Xiuqing Guo, Sara Lindstrom, Lu Wang, Erin N Smith, William Gordon, Mariza de Andrade, Jennifer A Brody, Jack W Pattee, Jeffrey Haessler, Ben M Brumpton, Daniel I Chasman, Pierre Suchon, Constance Turman, Marine Germain, James MacDonald, Sigrid K Braekkan, Sebastian M Armasu, Rabecca D Jackson, Jonas B Nielsen, Franco Giulianini, Marja K Puurunen, Manal Ibrahim, Susan R Heckbert, Theo K Bammler, Kelly A Frazer, Bryan M McCauley, Kent Taylor, James S Pankow, Alexander P Reiner, Maiken E Gabrielsen, Jean‐François Deleuze, Chris J O’Donnell, Jihye Kim, Peter Kraft, John‐Bjarne Hansen, John A Heit, Charles Kooperberg, Kristian Hveem, Paul M Ridker, Pierre‐Emmanuel Morange, Andrew D Johnson, Christopher Kabrhel, David‐Alexandre Trégouët, Rainer Malik, Ganesh Chauhan, Matthew Traylor, Muralidharan Sargurupremraj, Yukinori Okada, Aniket Mishra, Loes Rutten‐Jacobs, Anne‐Katrin Giese, Sander W van der Laan, Solveig Gretarsdottir, Christopher D Anderson, Michael Chong, Hieab HH Adams, Tetsuro Ago, Peter Almgren, Philippe Amouyel, Hakan Ay, Traci M Bartz, Oscar R Benavente, Steve Bevan, Giorgio B Boncoraglio, Robert D Brown, Adam S Butterworth, Caty Carrera, Cara L Carty, Wei‐Min Chen, John W Cole, Adolfo Correa, Ioana Cotlarciuc, Carlos Cruchaga, John Danesh, Paul IW de Bakker, Anita L DeStefano, Marcel den Hoed, Qing Duan, Stefan T Engelter, Guido J Falcone, Rebecca F Gottesman, Raji P Grewal, Vilmundur Gudnason, Stefan Gustafsson, Tamara B Harris, Ahamad Hassan, Aki S Havulinna, Elizabeth G Holliday, George Howard, Fang‐Chi Hsu, Hyacinth I Hyacinth, M Arfan Ikram, Erik Ingelsson, Marguerite R Irvin, Xueqiu Jian, Jordi Jiménez‐Conde, Julie A Johnson, J Wouter Jukema, Masahiro Kanai, Keith L Keene, Brett M Kissela, Dawn O Kleindorfer, Michiaki Kubo, Leslie A Lange, Carl D Langefeld, Claudia Langenberg, Lenore J Launer, Jin‐Moo Lee, Robin Lemmens, Didier Leys, Cathryn M Lewis, Wei‐Yu Lin, Arne G Lindgren, Erik Lorentzen, Patrik K Magnusson, Jane Maguire, Ani Manichaikul, Patrick F McArdle, James F Meschia, Braxton D Mitchell, Thomas H Mosley, Michael A Nalls, Toshiharu Ninomiya, Martin J O’Donnell, Sara L Pulit, Kristiina Rannikmäe, Kathryn M Rexrode, Kenneth Rice, Stephen S Rich, Natalia S Rost, Peter M Rothwell, Tatjana Rundek, Ralph L Sacco, Saori Sakaue, Michele M Sale, Veikko Salomaa, Bishwa R Sapkota, Reinhold Schmidt, Carsten O Schmidt, Ulf Schminke, Pankaj Sharma, Agnieszka Slowik, Cathie LM Sudlow, Christian Tanislav, Turgut Tatlisumak, Kent D Taylor, Vincent NS Thijs, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Steffen Tiedt, Christophe Tzourio, Cornelia M van Duijn, Matthew Walters, Nicholas J Wareham, Sylvia Wassertheil‐Smoller, James G Wilson, Salim Yusuf, Najaf Amin, Hugo S Aparicio, Donna K Arnett, John Attia, Alexa S Beiser, Claudine Berr, Julie E Buring, Mariana Bustamante, Valeria Caso, Yu‐Ching Cheng, Seung Hoan Choi, Ayesha Chowhan, Natalia Cullell, Jean‐François Dartigues, Hossein Delavaran, Pilar Delgado, Marcus Dörr, Gunnar Engström, Ian Ford, Wander S Gurpreet, Anders Hamsten, Laura Heitsch, Atsushi Hozawa, Laura Ibanez, Andreea Ilinca, Martin Ingelsson, Motoki Iwasaki, Rebecca D Jackson, Katarina Jood, Pekka Jousilahti, Sara Kaffashian, Lalit Kalra, Masahiro Kamouchi, Takanari Kitazono, Olafur Kjartansson, Manja Kloss, Peter J Koudstaal, Jerzy Krupinski, Daniel L Labovitz, Cathy C Laurie, Christopher R Levi, Linxin Li, Lars Lind, Cecilia M Lindgren, Vasileios Lioutas, Yong Mei Liu, Oscar L Lopez, Hirata Makoto, Nicolas Martinez‐Majander, Koichi Matsuda, Naoko Minegishi, Joan Montaner, Andrew P Morris, Elena Muiño, Martina Müller‐Nurasyid, Bo Norrving, Soichi Ogishima, Eugenio A Parati, Leema Reddy Peddareddygari, Nancy L Pedersen, Joanna Pera, Markus Perola, Alessandro Pezzini, Silvana Pileggi, Raquel Rabionet, Iolanda Riba‐Llena, Marta Ribasés, Jose R Romero, Jaume Roquer, Anthony G Rudd, Antti‐Pekka Sarin, Ralhan Sarju, Chloe Sarnowski, Makoto Sasaki, Claudia L Satizabal, Mamoru Satoh, Naveed Sattar, Norie Sawada, Gerli Sibolt, Ásgeir Sigurdsson, Albert Smith, Kenji Sobue, Carolina Soriano‐Tárraga, Tara Stanne, O Colin Stine, David J Stott, Konstantin Strauch, Takako Takai, Hideo Tanaka, Kozo Tanno, Alexander Teumer, Liisa Tomppo, Nuria P Torres‐Aguila, Emmanuel Touze, Shoichiro Tsugane, Andre G Uitterlinden, Einar M Valdimarsson, Sven J van der Lee, Henry Völzke, Kenji Wakai, David Weir, Stephen R Williams, Charles DA Wolfe, Quenna Wong, Huichun Xu, Taiki Yamaji, Dharambir K Sanghera, Olle Melander, Christina Jern, Daniel Strbian, Israel Fernandez‐Cadenas, W T Longstreth, Arndt Rolfs, Jun Hata, Daniel Woo, Jonathan Rosand, Guillaume Pare, Jemma C Hopewell, Danish Saleheen, Kari Stefansson, Bradford B Worrall, Steven J Kittner, Sudha Seshadri, Myriam Fornage, Hugh S Markus, Joanna MM Howson, Yoichiro Kamatani, Stephanie Debette, Martin Dichgans, and VU University medical center

Subjects
Hemostasis, genome-wide association study, genetic pleiotropy, Hematology, Polymorphism, Single Nucleotide, Hemostatics, blood coagulation, cardiovascular diseases, Phenotype, Cardiovascular Diseases, Tissue Plasminogen Activator, hemostasis, Humans, Genetic Predisposition to Disease, Factor XI, Genome-Wide Association Study
Abstract

Background: Multi-phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes. Objectives: To discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events. Methods: Summary statistics from genome wide-association studies (GWAS) from seven hemostatic traits (factor VII [FVII], factor VIII [FVIII], von Willebrand factor [VWF] factor XI [FXI], fibrinogen, tissue plasminogen activator [tPA], plasminogen activator inhibitor 1 [PAI-1]) and three major cardiovascular (CV) events (venous thromboembolism [VTE], coronary artery disease [CAD], ischemic stroke [IS]), were combined in 27 multi-trait combinations using metaUSAT. Genetic correlations between phenotypes were calculated using Linkage Disequilibrium Score Regression (LDSC). Newly associated loci were investigated for colocalization. We considered a significance threshold of 1.85 × 10−9 obtained after applying Bonferroni correction for the number of multi-trait combinations performed (n = 27). Results: Across the 27 multi-trait analyses, we found 4 novel pleiotropic loci (XXYLT1, KNG1, SUGP1/MAU2, TBL2/MLXIPL) that were not significant in the original individual datasets, were not described in previous GWAS for the individual traits, and that presented a common associated variant between the studied phenotypes. Conclusions: The discovery of four novel loci contributes to the understanding of the relationship between hemostasis and CV events and elucidate common genetic factors between these traits.

Published
2022
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21. Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations

Author

Andrew D Beswick, Tõnu Esko, Niki Dimou, Xue Zhong, Jette Bork-Jensen, Petra Schubert, Masato Akiyama, Girish N. Nadkarni, Ruth J. F. Loos, Huijun Qian, Michele K. Evans, Stephen S. Rich, Nicole Soranzo, Henry Völzke, Yongmei Liu, Nicholas A. Watkins, Markus M. Lerch, Richard C. Trembath, Adam S. Butterworth, Erwin P. Bottinger, Jennifer E. Huffman, Bruce M. Psaty, Jingzhong Ding, Michael Preuss, Yoav Ben-Shlomo, Bhavi Trivedi, Yoichiro Kamatani, David A. van Heel, Kjell Nikus, Torben Hansen, Adolfo Correa, Mohsen Ghanbari, Paul L. Auer, Véronique Laplante, Ken Sin Lo, Hua Tang, Peter W.F. Wilson, Paul Elliott, David J. Roberts, Hilary C. Martin, Jean-Claude Tardif, Praveen Surendran, Regina Manansala, Terho Lehtimäki, Emanuele Di Angelantonio, Fotis Koskeridis, Alexander P. Reiner, Mélissa Beaudoin, Vijay G. Sankaran, Benjamin Rodriguez, William J. Astle, Parsa Akbari, Frank J. A. van Rooij, Yun Li, Andreas Greinacher, Abdou Mousas, Andrew D. Johnson, Yukinori Okada, Michael H. Guo, Leo-Pekka Lyytikäinen, Traci M. Bartz, Minhui Chen, Alan B. Zonderman, Niels Grarup, Oluf Pedersen, Kumaraswamynaidu Chitrala, Jeffrey Haessler, Ming-Huei Chen, Cassandra N. Spracklen, Karen L. Mohlke, Guillaume Lettre, Erik L. Bao, Bingshan Li, James S. Floyd, Wei Huang, Ani Manichaikul, John Danesh, Uwe Völker, Allan Linneberg, Evangelos Evangelou, Joanna M. M. Howson, Olli T. Raitakari, Tim Kacprowski, Jean-François Gauchat, Hélène Choquet, Arden Moscati, Saori Sakaue, Mika Kähönen, Linda Broer, Caleb A. Lareau, Qin Qin Huang, Matthias Nauck, Yoshinori Murakami, Charleston W. K. Chiang, VA Million Veteran Program, Nina Mononen, Tao Jiang, Laura M. Raffield, Jerome I. Rotter, Leslie A. Lange, Jonathan D. Rosen, Eric Jorgenson, Savita Karthikeyan, Karen A. Hunt, Nathan Pankratz, Kelly Cho, Masahiro Kanai, Willem H. Ouwehand, Jennifer A. Brody, Koichi Matsuda, Dragana Vuckovic, Epidemiology, and Internal Medicine

Subjects
LOCI, Mutation, Missense, Ethnic group, POLYGENIC RISK SCORES, HUMAN HEMATOPOIESIS, Biology, BIOBANK, phenome-wide association study, Polymorphism, Single Nucleotide, DISEASE, White People, General Biochemistry, Genetics and Molecular Biology, Article, Blood cell, 03 medical and health sciences, SINGLE-CELL, selective sweeps, 0302 clinical medicine, Asian People, parasitic diseases, Genetics, medicine, Humans, GENOME-WIDE ASSOCIATION, 030304 developmental biology, AFRICAN-AMERICANS, 0303 health sciences, interleukin-7, Interleukin-7, genetic architecture, Genetic architecture, TRAIT, HEK293 Cells, Phenotype, medicine.anatomical_structure, fine-mapping, polygenic trait score, lipids (amino acids, peptides, and proteins), FREQUENCY CODING VARIANTS, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Most loci identified by GWASs have been found in populations of European ancestry (EUR). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EUR individuals, we identified 5,552 trait-variant associations at p < 5 × 10-9, including 71 novel associations not found in EUR populations. We also identified 28 additional novel variants in ancestry-specific, non-EUR meta-analyses, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL-7 secretion levels in vitro. Fine-mapping prioritized variants annotated as functional and generated 95% credible sets that were 30% smaller when using the trans-ethnic as opposed to the EUR-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations and compared genetic architecture and the effect of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies.

Published
2020
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22. Functional variants in ADH1B and ALDH2 are non-additively associated with all-cause mortality in Japanese population

Author

Masato Akiyama, Yoshinori Murakami, Makoto Hirata, Yukinori Okada, Saori Sakaue, Koichi Matsuda, Yoichiro Kamatani, and Michiaki Kubo

Subjects
Oncology, Male, medicine.medical_specialty, Alcohol Drinking, Population, Biology, Brief Communication, Polymorphism, Single Nucleotide, 03 medical and health sciences, Japan, Internal medicine, Genotype, Genetics research, Genetics, medicine, Humans, Genetic variation, Clinical genetics, Allele, Mortality, education, Genetics (clinical), Selection (genetic algorithm), 030304 developmental biology, ALDH2, 0303 health sciences, education.field_of_study, Aldehyde Dehydrogenase, Mitochondrial, 030305 genetics & heredity, Alcohol Dehydrogenase, ADH1B, Japanese population, Outcomes research, Cohort, Female
Abstract

The functional variants involved in alcohol metabolism, the A allele of rs1229984:A > G in ADH1B and the A allele of rs671:G > A in ALDH2, are specifically prevalent among East Asian population. They are shown to be under recent positive selection, but the reasons for the selection are unknown. To test whether these positively selected variants have beneficial effects on survival in modern population, we performed the survival analyses using the large-scale Japanese cohort (n = 135,974) with genotype and follow-up survival data. The rs671-A allele was significantly associated with the better survival in the additive model (HR for mortality = 0.960, P = 1.7 × 10−5), and the rs1229984-A had both additive and non-additive effects (HR = 0.962, P = 0.0016 and HR = 0.958, P = 0.0066, respectively), which was consistent with the positive selection. The favorable effects of these alleles on survival were independent of the habit of alcohol consumption itself. The heterogenous combinatory effect between rs1229984 and rs671 genotype was also observed (HRs for AA genotype at rs671 were 1.03, 0.80, and 0.90 for GG, GA, and AA genotype at rs1229984, respectively), supposedly reflecting the synergistic effects on survival.

Published
2019

23. Integration of genetics and miRNA-target gene network identified disease biology implicated in tissue specificity

Author

Chikashi Terao, Ken Suzuki, Kazuhiko Yamamoto, Timo Lassmann, Jun Hirata, Kenichi Yamamoto, Kazuyoshi Ishigaki, Yoshihide Hayashizaki, Tatsuo Masuda, Eiryo Kawakami, Koichiro Ohmura, Yoichiro Kamatani, Naomasa Suita, Atsuo Taniguchi, Alistair R. R. Forrest, Masato Akiyama, Masayoshi Itoh, Atsushi Kumanogoh, Kotaro Ogawa, Takuro Nii, Hiromu Ito, Saori Sakaue, Yuichi Maeda, Yukihiko Saeki, Piero Carninci, M. Yoshimura, Hideya Kawaji, Hisashi Yamanaka, Masato Matsushita, Hiroyuki Yoshitomi, Hidetoshi Matsuoka, Toshihiro Kishikawa, Katsunori Ikari, Michiel J. L. de Hoon, and Yukinori Okada

Subjects
0301 basic medicine, Multifactorial Inheritance, Gene regulatory network, Genome-wide association study, Biology, Arthritis, Rheumatoid, 03 medical and health sciences, 0302 clinical medicine, microRNA, Genetics, Humans, Gene Regulatory Networks, Gene, Regulation of gene expression, Genome, Human, Gene Expression Profiling, Computational Biology, Genomics, Asthma, Graves Disease, Gene expression profiling, MicroRNAs, 030104 developmental biology, Gene Expression Regulation, Genetic Loci, Organ Specificity, 030220 oncology & carcinogenesis, Case-Control Studies, Biomarker (medicine), Colitis, Ulcerative, Candidate Disease Gene, Algorithms, Biomarkers, Genome-Wide Association Study, Signal Transduction
Abstract

MicroRNAs (miRNAs) modulate the post-transcriptional regulation of target genes and are related to biology of complex human traits, but genetic landscape of miRNAs remains largely unknown. Given the strikingly tissue-specific miRNA expression profiles, we here expand a previous method to quantitatively evaluate enrichment of genome-wide association study (GWAS) signals on miRNA–target gene networks (MIGWAS) to further estimate tissue-specific enrichment. Our approach integrates tissue-specific expression profiles of miRNAs (∼1800 miRNAs in 179 cells) with GWAS to test whether polygenic signals enrich in miRNA–target gene networks and whether they fall within specific tissues. We applied MIGWAS to 49 GWASs (nTotal = 3 520 246), and successfully identified biologically relevant tissues. Further, MIGWAS could point miRNAs as candidate biomarkers of the trait. As an illustrative example, we performed differentially expressed miRNA analysis between rheumatoid arthritis (RA) patients and healthy controls (n = 63). We identified novel biomarker miRNAs (e.g. hsa-miR-762) by integrating differentially expressed miRNAs with MIGWAS results for RA, as well as novel associated loci with significant genetic risk (rs56656810 at MIR762 at 16q11; n = 91 482, P = 3.6 × 10−8). Our result highlighted that miRNA–target gene network contributes to human disease genetics in a cell type-specific manner, which could yield an efficient screening of miRNAs as promising biomarkers.

Published
2018

24. The Polygenic and Monogenic Basis of Blood Traits and Diseases

Author

Jean-Claude Tardif, Kelly Cho, Adolfo Correa, Na Cai, Koichi Matsuda, Paul L. Auer, Ken Sin Lo, Jennifer A. Brody, Dragana Vuckovic, Oluf Pedersen, Eric Jorgenson, Cassandra N. Spracklen, Jennifer E. Huffman, Stefan Weiss, Tim Kacprowski, Nicholas A. Watkins, Yoichiro Kamatani, Michele K. Evans, John Danesh, Masahiro Kanai, Karyn Megy, Kumaraswamy Naidu Chitrala, Michael H. Guo, James S. Floyd, Savita Karthikeyan, Ani Manichaikul, Petra Schubert, Vijay G. Sankaran, Torben Hansen, Traci M. Bartz, Laura M. Raffield, Regina Manansala, Parsa Akbari, Scott C. Ritchie, Ruth J. F. Loos, Manuel Tardaguila, Willem H. Ouwehand, Peter W.F. Wilson, Emanuele Di Angelantonio, Abdou Mousas, Jeffrey Haessler, Yoav Ben-Shlomo, Benjamin Rodriguez, Karen L. Mohlke, Girish N. Nadkarni, Oliver Stegle, Paul Elliott, Erwin P. Bottinger, Nathan Pankratz, Hélène Choquet, Julian C. Knight, Niels Grarup, Niki Dimou, Leslie A. Lange, Stephan B. Felix, William J. Astle, Jerome I. Rotter, Frank J. A. van Rooij, Andreas Greinacher, Yongmei Liu, Tao Jiang, Michael Inouye, Ming-Huei Chen, Jingzhong Ding, Uwe Völker, Huijun Qian, Henry Völzke, Alan B. Zonderman, Evangelos Evangelou, Wei Huang, Jonathan D. Rosen, Christopher J. Penkett, Michel Georges, Kousik Kundu, Mohsen Ghanbari, Hannes Ponstingl, Adam S. Butterworth, Joanna M. M. Howson, Praveen Surendran, Terho Lehtimäki, Allan Linneberg, Emilie M. Wigdor, Michael Preuss, Olli T. Raitakari, Arden Moscati, Yukinori Okada, Yoshinori Murakami, Guillaume Lettre, Leo-Pekka Lyytikäinen, Hua Tang, Caleb A. Lareau, David J. Roberts, Saori Sakaue, Mika Kähönen, Alexander P. Reiner, VA Million Veteran Program, Fotis Koskeridis, Nina Mononen, Linda Broer, Kjell Nikus, Andrew D. Johnson, Patrick K. Albers, Stephen B. Watt, Erik L. Bao, Yun Li, Klaudia Walter, Stephen S. Rich, Nicole Soranzo, Bruce M. Psaty, Andrew D Beswick, Tõnu Esko, Jette Bork-Jensen, and Masato Akiyama

Subjects
Genetics, Gene regulatory network, Oxygen transport, Genome-wide association study, Biology, Genetic architecture, Blood cell, symbols.namesake, medicine.anatomical_structure, medicine, Mendelian inheritance, symbols, Allele, Allele frequency
Abstract

SummaryBlood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including 563,946 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering the full allele frequency spectrum of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood cell traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell GWAS to interrogate clinically meaningful variants across the full allelic spectrum of human variation.

Published
2020
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25. The Polygenic and Monogenic Basis of Blood Traits and Diseases

Author

Nicholas A. Watkins, Julian C. Knight, William J. Astle, Stephan B. Felix, Petra Schubert, Andreas Greinacher, Laura M. Raffield, Guillaume Lettre, Leslie A. Lange, Erwin P. Bottinger, Jonathan D. Rosen, Frank J. A. van Rooij, Tim Kacprowski, Hua Tang, Regina Manansala, Manuel Tardaguila, Mohsen Ghanbari, Tao Jiang, Torben Hansen, Abdou Mousas, Adam S. Butterworth, Yoav Ben-Shlomo, Praveen Surendran, Terho Lehtimäki, Peter W.F. Wilson, Parsa Akbari, Hélène Choquet, Niels Grarup, Girish N. Nadkarni, Jean-Claude Tardif, Jennifer E. Huffman, Dragana Vuckovic, Ruth J. F. Loos, Karyn Megy, Emilie M. Wigdor, Michael Preuss, Alan B. Zonderman, Yukinori Okada, Oluf Pedersen, Arden Moscati, Leo-Pekka Lyytikäinen, Masahiro Kanai, Wei Huang, Andrew D Beswick, Stephen B. Watt, Erik L. Bao, Allan Linneberg, Paul Elliott, Eric Jorgenson, Tõnu Esko, Michael H. Guo, VA Million Veteran Program, Saori Sakaue, Mika Kähönen, Olli T. Raitakari, Stefan Weiss, Traci M. Bartz, Nina Mononen, Jette Bork-Jensen, Willem H. Ouwehand, Linda Broer, John Danesh, Masato Akiyama, James S. Floyd, Scott C. Ritchie, Kjell Nikus, Paul L. Auer, Emanuele Di Angelantonio, Ken Sin Lo, Kelly Cho, Uwe Völker, Ming-Huei Chen, Evangelos Evangelou, David J. Roberts, Na Cai, Benjamin Rodriguez, Savita Karthikeyan, Yoichiro Kamatani, Michael Inouye, Yoshinori Murakami, Yongmei Liu, Alexander P. Reiner, Koichi Matsuda, Jingzhong Ding, Kumaraswamy Naidu Chitrala, Niki Dimou, Andrew D. Johnson, Nathan Pankratz, Jeffrey Haessler, Vijay G. Sankaran, Oliver Stegle, Qi Guo, Karen L. Mohlke, Jennifer A. Brody, Michele K. Evans, Fotios Koskeridis, Cassandra N. Spracklen, Jerome I. Rotter, Ani Manichaikul, Patrick K. Albers, Caleb A. Lareau, Michel Georges, Hannes Ponstingl, Stephen S. Rich, Nicole Soranzo, Bruce M. Psaty, Yun Li, Klaudia Walter, Huijun Qian, Henry Völzke, Christopher J. Penkett, J. M. M. Howson, Kousik Kundu, Epidemiology, and Internal Medicine

Subjects
Gene regulatory network, LOCI, EFFICIENT, Genome-wide association study, VARIANTS, Blood cell, 0302 clinical medicine, RARE, genetics, 11 Medical and Health Sciences, 0303 health sciences, rare diseases, Biobank, ddc, medicine.anatomical_structure, fine-mapping, VA Million Veteran Program, symbols, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, UK Biobank, polygenic risk, rare disease, Computational biology, Biology, Article, General Biochemistry, Genetics and Molecular Biology, GENETIC ARCHITECTURE, 03 medical and health sciences, symbols.namesake, splicing, blood, medicine, CELL, Allele, GENOME-WIDE ASSOCIATION, COMMON, 030304 developmental biology, Science & Technology, COMPLEX, Oxygen transport, Cell Biology, 06 Biological Sciences, Genetic architecture, hematopoiesis, INTERROGATION, Mendelian inheritance, chromatin, omnigenic, 030217 neurology & neurosurgery, Developmental Biology
Abstract

Summary Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation., Graphical Abstract, Highlights • Largest genome-wide association study of blood cell traits to date • Empiric assessments of omnigenic and infinitesimal models of polygenic variation • Functional insights into how genetic variants impact human hematopoiesis • Assessment of the effect of polygenic trait scores upon blood diseases, Analysis of blood cell traits in the UK Biobank and other cohorts illuminates the full genetic architecture of hematopoietic phenotypes, with evidence supporting the omnigenic model for complex traits and linking polygenic burden with monogenic blood diseases.

Published
2020
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26. Transethnic meta-analysis of genome-wide association studies identifies three new loci and characterizes population-specific differences for coronary artery disease

Author

Makoto Sasaki, Atsushi Takahashi, Mamoru Satoh, Hirotaka Ieki, Naoyuki Takashima, Yasuhiko Sakata, Shinichiro Suna, Yoshinori Murakami, Mariko Naito, Soichi Ogishima, Hiroshi Matsunaga, Issei Komuro, Atsushi Hozawa, Hiroshi Akazawa, Kaoru Ito, Michiaki Kubo, Hideo Tanaka, Saori Sakaue, Shoichiro Tsugane, Hiroaki Ikezaki, Taiki Yamaji, Norie Sawada, Yoichiro Kamatani, Masato Akiyama, Satoshi Koyama, Yoshihiro Onouchi, Kouichi Ozaki, Keitaro Tanaka, Kenji Wakai, Kokichi Arisawa, Koichi Matsuda, Hiroyuki Morita, Motoki Iwasaki, Masayuki Yamamoto, Seitaro Nomura, and Yasushi Sakata

Subjects
0301 basic medicine, Male, Single-nucleotide polymorphism, Genome-wide association study, Coronary Artery Disease, 030204 cardiovascular system & hematology, Biology, Quantitative trait locus, White People, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Asian People, Japan, Meta-Analysis as Topic, Population specific, medicine, Chromosomes, Human, Humans, Myocardial infarction, 1000 Genomes Project, Genetic association, Genetics, Chromosome, General Medicine, medicine.disease, Biobank, United Kingdom, 030104 developmental biology, Evolutionary biology, Genetic Loci, Meta-analysis, Female, Genome-Wide Association Study
Abstract

Background: Genome-wide association studies provided many biological insights into coronary artery disease (CAD), but these studies were mainly performed in Europeans. Genome-wide association studies in diverse populations have the potential to advance our understanding of CAD. Methods: We conducted 2 genome-wide association studies for CAD in the Japanese population, which included 12 494 cases and 28 879 controls and 2808 cases and 7261 controls, respectively. Then, we performed transethnic meta-analysis using the results of the coronary artery disease genome-wide replication and meta-analysis plus the coronary artery disease 1000 Genomes meta-analysis with UK Biobank. We then explored the pathophysiological significance of these novel loci and examined the differences in CAD-susceptibility loci between Japanese and Europeans. Results: We identified 3 new loci on chromosome 1q21 ( CTSS ), 10q26 ( WDR11-FGFR2 ), and 11q22 ( RDX - FDX1 ). Quantitative trait locus analyses suggested the association of CTSS and RDX - FDX1 with atherosclerotic immune cells. Tissue/cell type enrichment analysis showed the involvement of arteries, adrenal glands, and fat tissues in the development of CAD. We next compared the odds ratios of lead variants for myocardial infarction at 76 genome-wide significant loci in the transethnic meta-analysis and a moderate correlation between Japanese and Europeans, where 8 loci showed a difference. Finally, we performed tissue/cell type enrichment analysis using East Asian-frequent and European-frequent variants according to the risk allele frequencies and identified significant enrichment of adrenal glands in the East Asian-frequent group while the enrichment of arteries and fat tissues was found in the European-frequent group. These findings indicate biological differences in CAD susceptibility between Japanese and Europeans. Conclusions: We identified 3 new loci for CAD and highlighted the genetic differences between the Japanese and European populations. Moreover, our transethnic analyses showed both shared and unique genetic architectures between the Japanese and Europeans. While most of the underlying genetic bases for CAD are shared, further analyses in diverse populations will be needed to elucidate variations fully.

Published
2019
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27. Next-generation sequencing identifies contribution of both class I and II HLA genes on susceptibility of multiple sclerosis in Japanese

Author

Ken Suzuki, Saori Sakaue, Kazuyoshi Hosomichi, Susumu Kusunoki, Yoshihiro Asano, Yukinori Okada, Akiko Hosokawa, Kotaro Ogawa, Jun Hirata, Tatsusada Okuno, Hideki Mochizuki, Makoto Kinoshita, Ituro Inoue, and Katsuichi Miyamoto

Subjects
0301 basic medicine, Oncology, Adult, Male, medicine.medical_specialty, Multiple Sclerosis, Adolescent, Immunology, Human leukocyte antigen, Logistic regression, Polymorphism, Single Nucleotide, lcsh:RC346-429, 03 medical and health sciences, Cellular and Molecular Neuroscience, Young Adult, 0302 clinical medicine, Japan, HLA Antigens, Internal medicine, medicine, Humans, Spectrum disorder, Genetic Predisposition to Disease, lcsh:Neurology. Diseases of the nervous system, Alleles, Genetic Association Studies, Aged, Aged, 80 and over, Neuromyelitis optica, business.industry, General Neuroscience, Multiple sclerosis, Research, High-Throughput Nucleotide Sequencing, Odds ratio, Middle Aged, medicine.disease, Confidence interval, 3. Good health, HLA, Exact test, 030104 developmental biology, Neuromyelitis optica spectrum disorder, Neurology, Case-Control Studies, Next-generation sequencing, Female, business, 030217 neurology & neurosurgery
Abstract

Background The spectrum of classical and non-classical HLA genes related to the risk of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) in the Japanese population has not been studied in detail. We conducted a case-control analysis of classical and non-classical HLA genes. Methods We used next-generation sequencing (NGS)-based HLA genotyping methods for mapping risk for 45 MS patients, 31 NMOSD patients, and 429 healthy controls. We evaluated the association of the HLA variants with the risk of MS and NMOSD using logistic regression analysis and Fisher’s exact test. Results We confirmed that HLA-DRB1*15:01 showed the strongest association with MS (P = 2.1 × 10−5; odds ratio [OR] = 3.44, 95% confidence interval [95% CI] = 1.95–6.07). Stepwise conditional analysis identified HLA-DRB1*04:05, HLA-B*39:01, and HLA-B*15:01 as being associated with independent MS susceptibility (PConditional

Published
2019

28. Serum magnesium and calcium levels in relation to ischemic stroke Mendelian randomization study

Author

Susanna C. Larsson, Matthew Traylor, Stephen Burgess, Giorgio B. Boncoraglio, Christina Jern, Karl Michaëlsson, Hugh S. Markus, Rainer Malik, Ganesh Chauhan, Muralidharan Sargurupremraj, Yukinori Okada, Aniket Mishra, Loes Rutten-Jacobs, Anne-Katrin Giese, Sander W van der Laan, Solveig Gretarsdottir, Christopher D Anderson, Michael Chong, Hieab HH Adams, Tetsuro Ago, Peter Almgren, Philippe Amouyel, Hakan Ay, raci M Bartz, Oscar R Benavente, Steve Bevan, Giorgio B Boncoraglio, Robert D Brown, Adam S Butterworth, Caty Carrera, Cara L Carty, Daniel I Chasman, Wei-Min Chen, John W Cole, Adolfo Correa, Ioana Cotlarciuc, Carlos Cruchaga, John Danesh, Paul IW de Bakker, Anita L DeStefano, Marcel den Hoed, Qing Duan, Stefan T Engelter, Guido J Falcone, Rebecca F Gottesman, Raji P Grewal, Vilmundur Gudnason, Stefan Gustafsson, Jeffrey Haessler, Tamara B Harris, Ahamad Hassan, Aki S Havulinna, Susan R Heckbert, Elizabeth G Holliday, George Howard, Fang-Chi Hsu, Hyacinth I Hyacinth, M Arfan Ikram, Erik Ingelsson, Marguerite R Irvin, Xueqiu Jian, Jordi Jiménez-Conde, Julie A Johnson, J Wouter Jukema, Masahiro Kanai, Keith L Keene, Brett M Kissela, Dawn O Kleindorfer, Charles Kooperberg, Michiaki Kubo, Leslie A Lange, Carl D Langefeld, Claudia Langenberg, Lenore J Launer, Jin-Moo Lee, Robin Lemmens, Didier Leys, Cathryn M Lewis, Wei-Yu Lin, Arne G Lindgren, Erik Lorentzen, Patrik K Magnusson, Jane Maguire, Ani Manichaikul, Patrick F McArdle, James F Meschia, Braxton D Mitchell, Thomas H Mosley, Michael A Nalls, Toshiharu Ninomiya, Martin J O'Donnell, Bruce M Psaty, Sara L Pulit, Kristiina Rannikmäe, Alexander P Reiner, Kathryn M Rexrode, Kenneth Rice, Stephen S Rich, Paul M Ridker, Natalia S Rost, Peter M Rothwell, Jerome I Rotter, Tatjana Rundek, Ralph L Sacco, Saori Sakaue, Michele M Sale, Veikko Salomaa, Bishwa R Sapkota, Reinhold Schmidt, Carsten O Schmidt, Ulf Schminke, Pankaj Sharma, Agnieszka Slowik, Cathie LM Sudlow, Christian Tanislav, Turgut Tatlisumak, Kent D Taylor, Vincent NS Thijs, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Steffen Tiedt, Stella Trompet, Christophe Tzourio, Cornelia M van Duijn, Matthew Walters, Nicholas J Wareham, Sylvia Wassertheil-Smoller, James G Wilson, Kerri L Wiggins, Qiong Yang, Salim Yusuf, Najaf Amin, Hugo S Aparicio, Donna K Arnett, John Attia, Alexa S Beiser, Claudine Berr, Julie E Buring, Mariana Bustamante, Valeria Caso, Yu-Ching Cheng, Seung Hoan Choi, Ayesha Chowhan, Natalia Cullell, Jean-François Dartigues, Hossein Delavaran, Pilar Delgado, Marcus Dörr, Gunnar Engström, Ian Ford, Wander S Gurpreet, Anders Hamsten, Laura Heitsch, Atsushi Hozawa, Laura Ibanez, Andreea Ilinca, Martin Ingelsson, Motoki Iwasaki, Rebecca D Jackson, Katarina Jood, Pekka Jousilahti, Sara Kaffashian, Lalit Kalra, Masahiro Kamouchi, Takanari Kitazono, Olafur Kjartansson, Manja Kloss, Peter J Koudstaal, Jerzy Krupinski, Daniel L Labovitz, Cathy C Laurie, Christopher R Levi, Linxin Li, Lars Lind, Cecilia M Lindgren, Vasileios Lioutas, Yong Mei Liu, Oscar L Lopez, Hirata Makoto, Nicolas Martinez-Majander, Koichi Matsuda, Naoko Minegishi, Joan Montaner, Andrew P Morris, Elena Muiño, Martina Müller-Nurasyid, Bo Norrving, Soichi Ogishima, Eugenio A Parati, Leema Reddy Peddareddygari, Nancy L Pedersen, Joanna Pera, Markus Perola, Alessandro Pezzini, Silvana Pileggi, Raquel Rabionet, Iolanda Riba-Llena, Marta Ribasés, Jose R Romero, Jaume Roquer, Anthony G Rudd, Antti-Pekka Sarin, Ralhan Sarju, Chloe Sarnowski, Makoto Sasaki, Claudia L Satizabal, Mamoru Satoh, Naveed Sattar, Norie Sawada, Gerli Sibolt, Ásgeir Sigurdsson, Albert Smith, Kenji Sobue, Carolina Soriano-Tárraga, Tara Stanne, O Colin Stine, David J Stott, Konstantin Strauch, Takako Takai, Hideo Tanaka, Kozo Tanno, Alexander Teumer, Liisa Tomppo, Nuria P Torres-Aguila, Emmanuel Touze, Shoichiro Tsugane, Andre G Uitterlinden, Einar M Valdimarsson, Sven J van der Lee, Henry Völzke, Kenji Wakai, David Weir, Stephen R Williams, Charles DA Wolfe, Quenna Wong, Huichun Xu, Taiki Yamaji, Dharambir K Sanghera, Olle Melander, Daniel Strbian, Israel Fernandez-Cadenas, W T Longstreth, Arndt Rolfs, Jun Hata, Daniel Woo, Jonathan Rosand, Guillaume Pare, Jemma C Hopewell, Danish Saleheen, Kari Stefansson, Bradford B Worrall, Steven J Kittner, Sudha Seshadri, Myriam Fornage, Hugh S Markus, Joanna MM Howson, Yoichiro Kamatani, Stephanie Debette, Martin Dichgans, Berr, Claudine, Unit of Cardiovascular and Nutritional Epidemiology [Stockholm, Sweden], Karolinska Institutet [Stockholm]-Institute of Environmental Medicine [Stockholm, Sweden], Stroke Research Group [London, UK] (Department of Brain Repair and Rehabilitation), University of London - UCL [London, UK], MRC Biostatistics Unit [Cambridge, UK], University of Cambridge [UK] (CAM), Department of Public Health and Primary Care [Cambridge, UK] (Institute of Public Health), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Section of Clinical Immunology [Uppsala, Sweden] (Department of Immunology, Genetics and Pathology), Uppsala University, Department of Surgical Sciences [Uppsala, Sweden], This work was supported by the Swedish Research Council for Health, Working Life and Welfare (Forte) and the Swedish Research Council. Hugh Markus is supported by an NIHR Senior Investigator award. His and Matthew Traylor’s work is supported by infrastructural support from the Cambridge University Hospitals Trust NIHR Biomedical Research Centre., MEGASTROKE project of the International Stroke Genetics Consortium : Malik R, Chauhan G, Traylor M, Sargurupremraj M, Okada Y, Mishra A, Rutten-Jacobs L, Giese AK, van der Laan SW, Gretarsdottir S, Anderson CD, Chong M, Adams HH, Ago T, Almgren P, Amouyel P, Ay H, Bartz RM, Benavente OR, Bevan S, Boncoraglio GB, Brown RD Jr, Butterworth AS, Carrera C, Carty CL, Chasman DI, Chen WM, Cole JW, Correa A, Cotlarciuc I, Cruchaga C, Danesh J, de Bakker PI, DeStefano AL, Hoed MD, Duan Q, Engelter ST, Falcone GJ, Gottesman RF, Grewal RP, Gudnason V, Gustafsson S, Haessler J, Harris TB, Hassan A, Havulinna AS, Heckbert SR, Holliday EG, Howard G, Hsu FC, Hyacinth HI, Ikram MA, Ingelsson E, Irvin MR, Jian X, Jiménez-Conde J, Johnson JA, Jukema JW, Kanai M, Keene KL, Kissela BM, Kleindorfer DO, Kooperberg C, Kubo M, Lange LA, Langefeld CD, Langenberg C, Launer LJ, Lee JM, Lemmens R, Leys D, Lewis CM, Lin WY, Lindgren AG, Lorentzen E, Magnusson PK, Maguire J, Manichaikul A, McArdle PF, Meschia JF, Mitchell BD, Mosley TH, Nalls MA, Ninomiya T, O'Donnell MJ, Psaty BM, Pulit SL, Rannikmäe K, Reiner AP, Rexrode KM, Rice K, Rich SS, Ridker PM, Rost NS, Rothwell PM, Rotter JI, Rundek T, Sacco RL, Sakaue S, Sale MM, Salomaa V, Sapkota BR, Schmidt R, Schmidt CO, Schminke U, Sharma P, Slowik A, Sudlow CL, Tanislav C, Tatlisumak T, Taylor KD, Thijs VN, Thorleifsson G, Thorsteinsdottir U, Tiedt S, Trompet S, Tzourio C, van Duijn CM, Walters M, Wareham NJ, Wassertheil-Smoller S, Wilson JG, Wiggins KL, Yang Q, Yusuf S, Amin N, Aparicio HS, Arnett DK, Attia J, Beiser AS, Berr C, Buring JE, Bustamante M, Caso V, Cheng YC, Choi SH, Chowhan A, Cullell N, Dartigues JF, Delavaran H, Delgado P, Dörr M, Engström G, Ford I, Gurpreet WS, Hamsten A, Heitsch L, Hozawa A, Ibanez L, Ilinca A, Ingelsson M, Iwasaki M, Jackson RD, Jood K, Jousilahti P, Kaffashian S, Kalra L, Kamouchi M, Kitazono T, Kjartansson O, Kloss M, Koudstaal PJ, Krupinski J, Labovitz DL, Laurie CC, Levi CR, Li L, Lind L, Lindgren CM, Lioutas V, Liu YM, Lopez OL, Makoto H, Martinez-Majander N, Matsuda K, Minegishi N, Montaner J, Morris AP, Muiño E, Müller-Nurasyid M, Norrving B, Ogishima S, Parati EA, Peddareddygari LR, Pedersen NL, Pera J, Perola M, Pezzini A, Pileggi S, Rabionet R, Riba-Llena I, Ribasés M, Romero JR, Roquer J, Rudd AG, Sarin AP, Sarju R, Sarnowski C, Sasaki M, Satizabal CL, Satoh M, Sattar N, Sawada N, Sibolt G, Sigurdsson Á, Smith A, Sobue K, Soriano-Tárraga C, Stanne T, Stine OC, Stott DJ, Strauch K, Takai T, Tanaka H, Tanno K, Teumer A, Tomppo L, Torres-Aguila NP, Touze E, Tsugane S, Uitterlinden AG, Valdimarsson EM, van der Lee SJ, Völzke H, Wakai K, Weir D, Williams SR, Wolfe CD, Wong Q, Xu H, Yamaji T, Sanghera DK, Melander O, Jern C, Strbian D, Fernandez-Cadenas I, Longstreth WT Jr, Rolfs A, Hata J, Woo D, Rosand J, Pare G, Hopewell JC, Saleheen D, Stefansson K, Worrall BB, Kittner SJ, Seshadri S, Fornage M, Markus HS, Howson JM, Kamatani Y, Debette S, Dichgans M., Larsson, Susanna C [0000-0003-0118-0341], Apollo - University of Cambridge Repository, and Neurology

Subjects
medicine.medical_specialty, Neurology, Heredity, Neurologi, [SDV]Life Sciences [q-bio], chemistry.chemical_element, Calcium, Polymorphism, Single Nucleotide, Gastroenterology, Article, Brain Ischemia, Brain ischemia, 03 medical and health sciences, 0302 clinical medicine, Human genetics, Internal medicine, Mendelian randomization, Medicine, Humans, Magnesium, 030212 general & internal medicine, Stroke, Herència (Biologia), Genètica humana, business.industry, Neurosciences, Mendelian Randomization Analysis, Odds ratio, medicine.disease, Confidence interval, 3. Good health, [SDV] Life Sciences [q-bio], Intracranial Embolism, chemistry, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), business, 030217 neurology & neurosurgery, Neurovetenskaper
Abstract

Comment inThe yin and yang of magnesium and calcium: New genetic insights for stroke? [Neurology. 2019]; International audience; Objective To determine whether serum magnesium and calcium concentrations are causally associated with ischemic stroke or any of its subtypes using the mendelian randomization approach. Methods Analyses were conducted using summary statistics data for 13 single-nucleotide polymorphisms robustly associated with serum magnesium (n = 6) or serum calcium (n = 7) concentrations. The corresponding data for ischemic stroke were obtained from the MEGASTROKE consortium (34,217 cases and 404,630 noncases). Results In standard mendelian randomization analysis, the odds ratios for each 0.1 mmol/L (about 1 SD) increase in genetically predicted serum magnesium concentrations were 0.78 (95% confidence interval [CI] 0.69-0.89; p = 1.3 × 10 −4) for all ischemic stroke, 0.63 (95% CI 0.50-0.80; p = 1.6 × 10 −4) for cardioembolic stroke, and 0.60 (95% CI 0.44-0.82; p = 0.001) for large artery stroke; there was no association with small vessel stroke (odds ratio 0.90, 95% CI 0.67-1.20; p = 0.46). Only the association with cardioembolic stroke was robust in sensitivity analyses. There was no association of genetically predicted serum calcium concentrations with all ischemic stroke (per 0.5 mg/dL [about 1 SD] increase in serum calcium: odds ratio 1.03, 95% CI 0.88-1.21) or with any subtype. Conclusions This study found that genetically higher serum magnesium concentrations are associated with a reduced risk of cardioembolic stroke but found no significant association of genetically higher serum calcium concentrations with any ischemic stroke subtype.

Published
2019
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29. Genetic determinants of risk in autoimmune pulmonary alveolar proteinosis

Author

Tatsuo Masuda, Jun Hirata, Tomohiro Handa, Kyuto Sonehara, Kenichi Yamamoto, Yoshinori Tanino, Saori Sakaue, Meiko Takahashi, Takashi Yamada, Masaru Suzuki, Hiromasa Inoue, Konosuke Morimoto, Takafumi Suda, Toru Arai, Keisuke Tomii, Atsushi Kumanogoh, Hidenori Ibata, Fumihiko Matsuda, Yoshikazu Inoue, Koh Nakata, Nobuyuki Hizawa, Toshiyuki Kato, Yuichi Maeda, Hideki Mochizuki, Kiminobu Tanizawa, Kazuyoshi Imaizumi, Ken Suzuki, Masaki Watanabe, Naoya Takeda, Ryushi Tazawa, Hiroshi Kida, Satoshi Konno, Yasuhiro Goto, Toshihiro Kishikawa, Haruyuki Ishii, Masahiro Takaki, Koshi Yokomura, Manabu Ishida, Atsushi Nakagawa, Masaki Hirose, Takashi Matsui, Tomomitsu Hirota, Takefumi Nikaido, Satoru Miyawaki, Satoru Ito, Etsuro Yamaguchi, Taizou Hirano, Toshinori Takada, Shogo Dofuku, Yasuomi Satake, Shinya Ohkouchi, Kotaro Ogawa, Takuro Nii, Tomoyuki Fujisawa, Toshio Ichiwata, Mayumi Tamari, and Yukinori Okada

Subjects
0301 basic medicine, Male, General Physics and Astronomy, Gene Expression, Genome-wide association study, Genome-wide association studies, 0302 clinical medicine, Gene Frequency, Japan, Odds Ratio, Protein Isoforms, Surfactant homeostasis, education.field_of_study, Multidisciplinary, digestive, oral, and skin physiology, respiratory system, Middle Aged, 030220 oncology & carcinogenesis, Chromosomes, Human, Pair 6, Female, Pulmonary alveolar proteinosis, Adult, Risk, Science, Population, Human leukocyte antigen, Pulmonary Alveolar Proteinosis, General Biochemistry, Genetics and Molecular Biology, Article, Autoimmune Diseases, 03 medical and health sciences, Asian People, Genetic predisposition, medicine, Humans, Genetic Predisposition to Disease, education, Allele frequency, Alleles, Aged, Autoantibodies, Respiratory tract diseases, business.industry, Case-control study, Granulocyte-Macrophage Colony-Stimulating Factor, Pulmonary Surfactants, General Chemistry, medicine.disease, 030104 developmental biology, Case-Control Studies, Immunology, business, Genome-Wide Association Study, HLA-DRB1 Chains
Abstract

Pulmonary alveolar proteinosis (PAP) is a devastating lung disease caused by abnormal surfactant homeostasis, with a prevalence of 6–7 cases per million population worldwide. While mutations causing hereditary PAP have been reported, the genetic basis contributing to autoimmune PAP (aPAP) has not been thoroughly investigated. Here, we conducted a genome-wide association study of aPAP in 198 patients and 395 control participants of Japanese ancestry. The common genetic variant, rs138024423 at 6p21, in the major-histocompatibility-complex (MHC) region was significantly associated with disease risk (Odds ratio [OR] = 5.2; P = 2.4 × 10−12). HLA fine-mapping revealed that the common HLA class II allele, HLA-DRB1*08:03, strongly drove this signal (OR = 4.8; P = 4.8 × 10−12), followed by an additional independent risk allele at HLA-DPβ1 amino acid position 8 (OR = 0.28; P = 3.4 × 10−7). HLA-DRB1*08:03 was also associated with an increased level of anti-GM-CSF antibody, a key driver of the disease (β = 0.32; P = 0.035). Our study demonstrated a heritable component of aPAP, suggesting an underlying genetic predisposition toward an abnormal antibody production., Autoimmune pulmonary alveolar proteinosis (aPAP) is a complex lung disease caused by abnormal surfactant homeostasis. Here, the authors carry out a genome-wide association study of aPAP in a Japanese cohort, finding variants in the MHC and suggesting predisposition to abnormal antibody production.

Published
2021

30. Author Correction: Characterizing rare and low-frequency height-associated variants in the Japanese population

Author

Masahiro Kanai, Naoko Minegishi, Kazuyoshi Ishigaki, Masayuki Yamamoto, Masato Akiyama, Kozo Tanno, Mariko Naito, Atsushi Hozawa, Kenji Wakai, Yukinori Okada, Yukihide Momozawa, Atsushi Shimizu, Shiro Ikegawa, Yoichiro Kamatani, Sadao Suzuki, Momoko Horikoshi, Saori Sakaue, Michiaki Kubo, Yoshinori Murakami, Koichi Matsuda, Makoto Hirata, Taiki Yamaji, Daisuke Matsui, Atsushi Takahashi, Norie Sawada, Shoichiro Tsugane, Makoto Sasaki, and Motoki Iwasaki

Subjects
Adult, Male, Genotype, Science, Quantitative Trait Loci, MEDLINE, General Physics and Astronomy, Biology, Quantitative trait, Genome-wide association studies, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Asian People, Gene Frequency, Japan, Humans, Author Correction, lcsh:Science, Multidisciplinary, Published Erratum, Genetic Variation, Rare variants, General Chemistry, Retinoic Acid 4-Hydroxylase, Japanese population, Fatty Acid Transport Proteins, Body Height, Phenotype, Heritable quantitative trait, Female, lcsh:Q, Genome-Wide Association Study, Demography
Abstract

Human height is a representative phenotype to elucidate genetic architecture. However, the majority of large studies have been performed in European population. To investigate the rare and low-frequency variants associated with height, we construct a reference panel (N = 3,541) for genotype imputation by integrating the whole-genome sequence data from 1,037 Japanese with that of the 1000 Genomes Project, and perform a genome-wide association study in 191,787 Japanese. We report 573 height-associated variants, including 22 rare and 42 low-frequency variants. These 64 variants explain 1.7% of the phenotypic variance. Furthermore, a gene-based analysis identifies two genes with multiple height-increasing rare and low-frequency nonsynonymous variants (SLC27A3 and CYP26B1; P

Published
2020
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