A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids
Authors: Ramdas Shweta , Judd Jonathan , Graham Sarah E , Kanoni Stavroula , Wang Yuxuan , Surakka Ida , Wenz Brandon , Clarke Shoa L , Chesi Alessandra , Wells Andrew , Bhatti Konain Fatima , Vedantam Sailaja , Winkler Thomas W , Locke Adam E , Marouli Eirini , Zajac Greg JM , 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 , Mitchell Ruth E , Chai Jin Fang , Aadahl Mette , Bjerregaard Anne A , Yao Jie , Manichaikul Ani , Wen-Jane  , Chao A , 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 , Schönherr Sebastian , Forer Lukas , Scholz Markus , Galesloot Tessel E. , Bradfield Jonathan P. , Ruotsalainen Sanni E , Daw E Warwick , Zmuda Joseph M , Mitchell Jonathan S , Fuchsberger Christian , Christensen Henry , Brody Jennifer A , Le Phuong , Feitosa Mary F , Wojczynski Mary K , Hemerich Daiane , Preuss Michael , Mangino Massimo , Christofidou Paraskevi , Verweij Niek , Benjamins Jan W , Engmann Jorgen , Noah Tsao L. , Verma Anurag , Slieker Roderick C , Lo Ken Sin , Zilhao Nuno R , Kleber Marcus E , Delgado Graciela E , Huo Shaofeng , Ikeda Daisuke D , Iha Hiroyuki , Yang Jian , Liu Jun , Demirkan Ayşe , Leonard Hampton L , Marten Jonathan , Emmel Carina , 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 , Sankareswaran Alagu , Irvin Marguerite R , Oldmeadow Christopher , Kim Han-Na , Ryu Seungho , Timmers Paul RHJ , 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 , Morgan Anna , 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 RB , 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 , He Karen Y. , 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 WJ , 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 , 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 , den Hollander Anneke I , 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 , Walker Mark , Scott Laura J , Koistinen Heikki A , Chandak Giriraj R , Mercader Josep M , Tusie-Luna Teresa , Aguilar-Salinas Carlos , Villalpando Clicerio Gonzalez , Orozco Lorena , Fornage Myriam , Tai E Shyong , 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 NA , Vitart Veronique , Hayward Caroline , Simonsick Eleanor , van Duijn Cornelia M , Jin Zi-Bing , Lu Fan , Hishigaki Haretsugu , Lin Xu , März Winfried , Gudnason Vilmundur , Tardif Jean-Claude , Lettre Guillaume , t Hart Leen M , Elders Petra JM , Rader Daniel J , 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 ALM , 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 , Sheu Wayne Huey-Herng , 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 KE , Boomsma Dorret I , de Geus Eco JC , Cupples L Adrienne , van Meurs Joyce B.J. , Ikram Arfan , Ghanbari Mohsen , Gordon-Larsen Penny , Huang Wei , Kim Young Jin , Tabara Yasuharu , Wareham Nicholas J , Langenberg Claudia , Zeggini Eleftheria , Tuomilehto Jaakko , 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 Y Eugene , Ho Yuk-Lam , Lynch Julie A , Rader Daniel , Tsao Philip S , Chang Kyong-Mi , Cho Kelly , O’Donnell Christopher J , Gaziano John M , Wilson Peter , Mohlke Karen L , Frayling Timothy M , Hirschhorn Joel N , Kathiresan Sekar , Boehnke Michael ,   Million Veterans Program,   Global Lipids Genetics Consortium, Grant Struan , Natarajan Pradeep , Sun Yan V , Morris Andrew P , Deloukas Panos , Peloso Gina , Assimes Themistocles L , Willer Cristen J , Zhu Xiang , Brown Christopher D 
Published: December 2021

A major challenge of genome-wide association studies (GWAS) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations, and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels, and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. Two prioritized genes, CREBRF and RRBP1, show convergent evidence across functional datasets supporting their roles in lipid biology.