A Multi-Layer Functional Genomic Analysis to Understand Noncoding Genetic Variation in Lipids

Citation

Ramdas, Shweta; Luan, Jian'an; Zhao, Jing-Hua; Matsuda, Fumihiko; Jang, Hye-Mi; Yoon, Kyungheon; Medina-Gomez, Carolina; Pitsillides, Achilleas; Hottenga, Jouke J.; & Wood, Andrew R., et al. (2022). A Multi-Layer Functional Genomic Analysis to Understand Noncoding Genetic Variation in Lipids. American Journal of Human Genetics, 109(8), 1366-1387. PMCID: PMC9388392

Abstract

A major challenge of genome-wide association studies (GWASs) 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. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.

URL

http://dx.doi.org/10.1016/j.ajhg.2022.06.012

Reference Type

Journal Article

Year Published

2022

Journal Title

American Journal of Human Genetics

Author(s)

Ramdas, Shweta
Luan, Jian'an
Zhao, Jing-Hua
Matsuda, Fumihiko
Jang, Hye-Mi
Yoon, Kyungheon
Medina-Gomez, Carolina
Pitsillides, Achilleas
Hottenga, Jouke J.
Wood, Andrew R.
Ji, Yingji
Gao, Zishan
Haworth, Simon
Mitchell, Ruth E.
Chai, Jin Fang
Aadahl, Mette
Bjerregaard, Anne A.
Yao, Jie
Manichaikul, Ani
Lee, Wen-Jane
Hsiung, 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, Ay
şe
Leonard, Hampton L.
Marten, Jonathan
Emmel, Carina
Schmidt, B
örge
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 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
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 N.
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
He, Karen Y.
Tang, Hua
Terzikhan, Natalie
Shin, Jae H.
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 K.
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
Ida Chen, Yii-Der
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 S.
Pahkala, Katja
Oldehinkel, Albertine J.
Snieder, Harold
Biino, Ginevra
Schmidt, Reinhold
Schmidt, Helena
Bandinelli, Stefania
Dedoussis, George
Thanaraj, Thangavel A.
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 J.
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 A.
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 W. J. H. W.
Kim, Hyung-Lae
Attia, John R.
Scott, Rodney J.
Rao, D. C.
Arnett, Donna K.
Walker, Mark
Scott, Laura J.
Koistinen, Heikki A.
Chandak, Giriraj R.
Mercader, Josep M.
Villalpando, Clicerio G.
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 N. A.
Vitart, Veronique
Hayward, Caroline
Simonsick, Eleanor
van Duijn, Cornelia M.
Jin, Zi-Bing
Lu, Fan
Hishigaki, Haretsugu
Lin, Xu
März, Winfried
Gudnason, Vilmundur G.
Tardif, Jean-Claude
Lettre, Guillaume
T. Hart, Leen M.
Elders, Petra J. M.
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 A.
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.
Willems van Dijk, Ko
Watkins, Hugh
Strachan, David P.
Grarup, Niels
Sever, Peter
Poulter, Neil
Huey-Herng Sheu, Wayne
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.
de Geus, Eco J. C.
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 R.
Chambers, John C.
Kooner, Jaspal S.
de Vries, Paul S.
Morrison, Alanna C.
Hazelhurst, Scott
Ramsay, Michèle
North, Kari E.
Daviglus, Martha L.
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.
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
Struan, Grant
Natarajan, Pradeep
Sun, Yan V.
Morris, Andrew P.
Deloukas, Panos
Peloso, Gina M.
Assimes, Themistocles L.
Willer, Cristen J.
Zhu, Xiang
Brown, Christopher D.

Article Type

Regular

PMCID

PMC9388392

Data Set/Study

Global Lipids Genetics Consortium (GLGC)

Race/Ethnicity

East Asian Ancestry
European Ancestry
Hispanic Ancestry
South Asian Ancestry
African Ancestry

ORCiD

Adair - 0000-0002-3670-8073
Gordon-Larsen - 0000-0001-5322-4188