Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis
Authors: 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 , Møllehave 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 Ayşe , Leonard Hampton L. , Marten Jonathan , Frank Mirjam , Schmidt Börge , Smyth Laura J. , Cañadas-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 , Åsvold Bjørn 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. 
Published: December 2022

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.