학술논문
Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis
Document Type
Academic Journal
Author
Kanoni, Stavroula; Graham, Sarah E.; Wang, Yuxuan; Surakka, Ida; Ramdas, Shweta; Zhu, Xiang; Clarke, Shoa L.; Bhatti, Konain Fatima; Vedantam, Sailaja; Winkler, Thomas W.; Locke, Adam E.; Marouli, Eirini; Zajac, Greg J. M.; Wu, Kuan-Han H.; Ntalla, Ioanna; Hui, Qin; Klarin, Derek; Hilliard, Austin T.; Wang, Zeyuan; Xue, Chao; Thorleifsson, Gudmar; Helgadottir, Anna; Gudbjartsson, Daniel F.; Holm, Hilma; Olafsson, Isleifur; Hwang, Mi Yeong; Han, Sohee; Akiyama, Masato; Sakaue, Saori; Terao, Chikashi; Kanai, Masahiro; Zhou, Wei; Brumpton, Ben M.; Rasheed, Humaira; Havulinna, Aki S.; Veturi, Yogasudha; Pacheco, Jennifer Allen; Rosenthal, Elisabeth A.; Lingren, Todd; Feng, QiPing; Kullo, Iftikhar J.; Narita, Akira; Takayama, Jun; Martin, Hilary C.; Hunt, Karen A.; Trivedi, Bhavi; Haessler, Jeffrey; Giulianini, Franco; Bradford, Yuki; Miller, Jason E.; Campbell, Archie; Lin, Kuang; Millwood, Iona Y.; Rasheed, Asif; Hindy, George; Faul, Jessica D.; Zhao, Wei; Weir, David R.; Turman, Constance; Huang, Hongyan; Graff, Mariaelisa; Choudhury, Ananyo; Sengupta, Dhriti; Mahajan, Anubha; Brown, Michael R.; Zhang, Weihua; Yu, Ketian; Schmidt, Ellen M.; Pandit, Anita; Gustafsson, Stefan; Yin, Xianyong; Luan, Jian'an; Zhao, Jing-Hua; Matsuda, Fumihiko; Jang, Hye-Mi; Yoon, Kyungheon; Medina-Gomez, Carolina; Pitsillides, Achilleas; Hottenga, Jouke Jan; Wood, Andrew R.; Ji, Yingji; Gao, Zishan; Haworth, Simon; Yousri, Noha A.; Mitchell, Ruth E.; Chai, Jin Fang; Aadahl, Mette; Bjerregaard, Anne A.; Yao, Jie; Manichaikul, Ani; Hwu, Chii-Min; Hung, Yi-Jen; Warren, Helen R.; Ramirez, Julia; Bork-Jensen, Jette; Kårhus, Line L.; Goel, Anuj; Sabater-Lleal, Maria; Noordam, Raymond; Mauro, Pala; Matteo, Floris; McDaid, Aaron F.; Marques-Vidal, Pedro; Wielscher, Matthias; Trompet, Stella; Sattar, Naveed; Mallehave, Line T.; Munz, Matthias; Zeng, Lingyao; Huang, Jianfeng; Yang, Bin; Poveda, Alaitz; Kurbasic, Azra; Lamina, Claudia; Forer, Lukas; Scholz, Markus; Galesloot, Tessel E.; Bradfield, Jonathan P.; Ruotsalainen, Sanni E.; Daw, EWarwick; Zmuda, Joseph M.; Mitchell, Jonathan S.; Fuchsberger, Christian; Christensen, Henry; Brody, Jennifer A.; Vazquez-Moreno, Miguel; Feitosa, Mary F.; Wojczynski, Mary K.; Wang, Zhe; Preuss, Michael H.; Mangino, Massimo; Christofidou, Paraskevi; Verweij, Niek; Benjamins, Jan W.; Engmann, Jorgen; Tsao, Noah L.; Verma, Anurag; Slieker, Roderick C.; Lo, Ken Sin; Zilhao, Nuno R.; Le, Phuong; Kleber, Marcus E.; Delgado, Graciela E.; Huo, Shaofeng; Ikeda, Daisuke D.; Iha, Hiroyuki; Yang, Jian; Liu, Jun; Demirkan, AyÅe; Leonard, Hampton L.; Marten, Jonathan; Frank, Mirjam; Schmidt, Börge; Smyth, Laura J.; Caéadas-Garre, Marisa; Wang, Chaolong; Nakatochi, Masahiro; Wong, Andrew; Hutri-Kähönen, Nina; Sim, Xueling; Xia, Rui; Huerta-Chagoya, Alicia; Fernandez-Lopez, Juan Carlos; Lyssenko, Valeriya; Nongmaithem, Suraj S.; Bayyana, Swati; Stringham, Heather M.; Irvin, Marguerite R.; Oldmeadow, Christopher; Kim, Han-Na; Ryu, Seungho; Timmers, Paul R. H. J.; Arbeeva, Liubov; Dorajoo, Rajkumar; Lange, Leslie A.; Prasad, Gauri; Lorés-Motta, Laura; Pauper, Marc; Long, Jirong; Li, Xiaohui; Theusch, Elizabeth; Takeuchi, Fumihiko; Spracklen, Cassandra N.; Loukola, Anu; Bollepalli, Sailalitha; Warner, Sophie C.; Wang, Ya Xing; Wei, Wen B.; Nutile, Teresa; Ruggiero, Daniela; Sung, Yun Ju; Chen, Shufeng; Liu, Fangchao; Yang, Jingyun; Kentistou, Katherine A.; Banas, Bernhard; Nardone, Giuseppe Giovanni; Meidtner, Karina; Bielak, Lawrence F.; Smith, Jennifer A.; Hebbar, Prashantha; Farmaki, Aliki-Eleni; Hofer, Edith; Lin, Maoxuan; Concas, Maria Pina; Vaccargiu, Simona; van der Most, Peter J.; Pitkänen, Niina; Cade, Brian E.; van der Laan, Sander W.; Chitrala, Kumaraswamy Naidu; Weiss, Stefan; Bentley, Amy R.; Doumatey, Ayo P.; Adeyemo, Adebowale A.; Lee, Jong Young; Petersen, Eva R. B.; Nielsen, Aneta A.; Choi, Hyeok Sun; Nethander, Maria; Freitag-Wolf, Sandra; Southam, Lorraine; Rayner, Nigel W.; Wang, Carol A.; Lin, Shih-Yi; Wang, Jun-Sing; Couture, Christian; Lyytikäinen, Leo-Pekka; Nikus, Kjell; Cuellar-Partida, Gabriel; Vestergaard, Henrik; Hidalgo, Bertha; Giannakopoulou, Olga; Cai, Qiuyin; Obura, Morgan O.; van Setten, Jessica; Li, Xiaoyin; Liang, Jingjing; Tang, Hua; Terzikhan, Natalie; Shin, Jae Hun; Jackson, Rebecca D.; Reiner, Alexander P.; Martin, Lisa Warsinger; Chen, Zhengming; Li, Liming; Kawaguchi, Takahisa; Thiery, Joachim; Bis, Joshua C.; Launer, Lenore J.; Li, Huaixing; Nalls, Mike A.; Raitakari, Olli T.; Ichihara, Sahoko; Wild, Sarah H.; Nelson, Christopher P.; Campbell, Harry; Jäger, Susanne; Nabika, Toru; Al-Mulla, Fahd; Niinikoski, Harri; Braund, Peter S.; Kolcic, Ivana; Kovacs, Peter; Giardoglou, Tota; Katsuya, Tomohiro; de Kleijn, Dominique; de Borst, Gert J.; Kim, Eung Kweon; Adams, Hieab H. H.; Ikram, M. Arfan; Zhu, Xiaofeng; Asselbergs, Folkert W.; Kraaijeveld, Adriaan O.; Beulens, Joline W. J.; Shu, Xiao-Ou; Rallidis, Loukianos S.; Pedersen, Oluf; Hansen, Torben; Mitchell, Paul; Hewitt, Alex W.; Kähönen, Mika; Pérusse, Louis; Bouchard, Claude; Tönjes, Anke; Chen, Yii-Der Ida; Pennell, Craig E.; Mori, Trevor A.; Lieb, Wolfgang; Franke, Andre; Ohlsson, Claes; Mellström, Dan; Cho, Yoon Shin; Lee, Hyejin; Yuan, Jian-Min; Koh, Woon-Puay; Rhee, Sang Youl; Woo, Jeong-Taek; Heid, Iris M.; Stark, Klaus J.; Zimmermann, Martina E.; Völzke, Henry; Homuth, Georg; Evans, Michele K.; Zonderman, Alan B.; Polasek, Ozren; Pasterkamp, Gerard; Hoefer, Imo E.; Redline, Susan; Pahkala, Katja; Oldehinkel, Albertine J.; Snieder, Harold; Biino, Ginevra; Schmidt, Reinhold; Schmidt, Helena; Bandinelli, Stefania; Dedoussis, George; Thanaraj, Thangavel Alphonse; Kardia, Sharon L. R.; Peyser, Patricia A.; Kato, Norihiro; Schulze, Matthias B.; Girotto, Giorgia; Böger, Carsten A.; Jung, Bettina; Joshi, Peter K.; Bennett, David A.; De Jager, Philip L.; Lu, Xiangfeng; Mamakou, Vasiliki; Brown, Morris; Caulfield, Mark J.; Munroe, Patricia B.; Guo, Xiuqing; Ciullo, Marina; Jonas, Jost B.; Samani, Nilesh J.; Kaprio, Jaakko; Pajukanta, Päivi; Tusié-Luna, Teresa; Aguilar-Salinas, Carlos A.; Adair, Linda S.; Bechayda, Sonny Augustin; de Silva, H. Janaka; Wickremasinghe, Ananda R.; Krauss, Ronald M.; Wu, Jer-Yuarn; Zheng, Wei; Hollander, Anneke Iden; Bharadwaj, Dwaipayan; Correa, Adolfo; Wilson, James G.; Lind, Lars; Heng, Chew-Kiat; Nelson, Amanda E.; Golightly, Yvonne M.; Wilson, James F.; Penninx, Brenda; Kim, Hyung-Lae; Attia, John; Scott, Rodney J.; Rao, D. C.; Arnett, Donna K.; Hunt, Steven C.; Walker, Mark; Koistinen, Heikki A.; Chandak, Giriraj R.; Mercader, Josep M.; Costanzo, Maria C.; Jang, Dongkeun; Burtt, Noël P.; Villalpando, Clicerio Gonzalez; Orozco, Lorena; Fornage, Myriam; Tai, EShyong; van Dam, Rob M.; Lehtimäki, Terho; Chaturvedi, Nish; Yokota, Mitsuhiro; Liu, Jianjun; Reilly, Dermot F.; McKnight, Amy Jayne; Kee, Frank; Jöckel, Karl-Heinz; McCarthy, Mark I.; Palmer, Colin N. A.; Vitart, Veronique; Hayward, Caroline; Simonsick, Eleanor; van Duijn, Cornelia M.; Jin, Zi-Bing; Qu, Jia; Hishigaki, Haretsugu; Lin, Xu; März, Winfried; Gudnason, Vilmundur; Tardif, Jean-Claude; Lettre, Guillaume; Hart, Leen M.'t; Elders, Petra J. M.; Damrauer, Scott M.; Kumari, Meena; Kivimaki, Mika; van der Harst, Pim; Spector, Tim D.; Loos, Ruth J. F.; Province, Michael A.; Parra, Esteban J.; Cruz, Miguel; Psaty, Bruce M.; Brandslund, Ivan; Pramstaller, Peter P.; Rotimi, Charles N.; Christensen, Kaare; Ripatti, Samuli; Widén, Elisabeth; Hakonarson, Hakon; Grant, Struan F. A.; Kiemeney, Lambertus A. L. M.; de Graaf, Jacqueline; Loeffler, Markus; Kronenberg, Florian; Gu, Dongfeng; Erdmann, Jeanette; Schunkert, Heribert; Franks, Paul W.; Linneberg, Allan; Jukema, J. Wouter; Khera, Amit V.; Männikkö, Minna; Jarvelin, Marjo-Riitta; Kutalik, Zoltan; Francesco, Cucca; Mook-Kanamori, Dennis O.; van Dijk, Ko Willems; Watkins, Hugh; Strachan, David P.; Grarup, Niels; Sever, Peter; Poulter, Neil; Chuang, Lee-Ming; Rotter, Jerome I.; Dantoft, Thomas M.; Karpe, Fredrik; Neville, Matt J.; Timpson, Nicholas J.; Cheng, Ching-Yu; Wong, Tien-Yin; Khor, Chiea Chuen; Li, Hengtong; Sabanayagam, Charumathi; Peters, Annette; Gieger, Christian; Hattersley, Andrew T.; Pedersen, Nancy L.; Magnusson, Patrik K. E.; Boomsma, Dorret I.; Willemsen, Allegonda H. M.; Cupples, LAdrienne; van Meurs, Joyce B. J.; Ghanbari, Mohsen; Gordon-Larsen, Penny; Huang, Wei; Kim, Young Jin; Tabara, Yasuharu; Wareham, Nicholas J.; Langenberg, Claudia; Zeggini, Eleftheria; Kuusisto, Johanna; Laakso, Markku; Ingelsson, Erik; Abecasis, Goncalo; Chambers, John C.; Kooner, Jaspal S.; de Vries, Paul S.; Morrison, Alanna C.; Hazelhurst, Scott; Ramsay, Michèle; North, Kari E.; Daviglus, Martha; Kraft, Peter; Martin, Nicholas G.; Whitfield, John B.; Abbas, Shahid; Saleheen, Danish; Walters, Robin G.; Holmes, Michael V.; Black, Corri; Smith, Blair H.; Baras, Aris; Justice, Anne E.; Buring, Julie E.; Ridker, Paul M.; Chasman, Daniel I.; Kooperberg, Charles; Tamiya, Gen; Yamamoto, Masayuki; van Heel, David A.; Trembath, Richard C.; Wei, Wei-Qi; Jarvik, Gail P.; Namjou, Bahram; Hayes, M. Geoffrey; Ritchie, Marylyn D.; Jousilahti, Pekka; Salomaa, Veikko; Hveem, Kristian; Ãsvold, Bjarn Olav; Kubo, Michiaki; Kamatani, Yoichiro; Okada, Yukinori; Murakami, Yoshinori; Kim, Bong-Jo; Thorsteinsdottir, Unnur; Stefansson, Kari; Zhang, Jifeng; Chen, YEugene; Ho, Yuk-Lam; Lynch, Julie A.; Rader, Daniel J.; Tsao, Philip S.; Chang, Kyong-Mi; Cho, Kelly; O'Donnell, Christopher J.; Gaziano, John M.; Wilson, Peter W. F.; Frayling, Timothy M.; Hirschhorn, Joel N.; Kathiresan, Sekar; Mohlke, Karen L.; Sun, Yan V.; Morris, Andrew P.; Boehnke, Michael; Brown, Christopher D.; Natarajan, Pradeep; Deloukas, Panos; Willer, Cristen J.; Assimes, Themistocles L.; Peloso, Gina M.
Source
Genome Biology (Online Edition). December 27, 2022, Vol. 23 Issue 1
Subject
Language
English
Abstract
Author(s): Stavroula Kanoni[sup.1], Sarah E. Graham[sup.2], Yuxuan Wang[sup.3], Ida Surakka[sup.2], Shweta Ramdas[sup.4], Xiang Zhu[sup.5,6,7,8], Shoa L. Clarke[sup.7,9], Konain Fatima Bhatti[sup.1], Sailaja Vedantam[sup.10,11], Thomas W. Winkler[sup.12], Adam E. Locke[sup.13], Eirini Marouli[sup.1], [...]
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. Keywords: Cholesterol, Lipids, Genetics, Genome-wide association study, GWAS
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. Keywords: Cholesterol, Lipids, Genetics, Genome-wide association study, GWAS