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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis
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 Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.pdf | Published version | 2.18 MB | Adobe PDF | View/Open |
| Title: | Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis |
| Authors: | Kanoni, S Graham, SE Wang, Y Surakka, I Ramdas, S Zhu, X Clarke, SL Bhatti, KF Vedantam, S Winkler, TW Locke, AE Marouli, E Zajac, GJM Wu, K-HH Ntalla, I Hui, Q Klarin, D Hilliard, AT Wang, Z Xue, C Thorleifsson, G Helgadottir, A Gudbjartsson, DF Holm, H Olafsson, I Hwang, MY Han, S Akiyama, M Sakaue, S Terao, C Kanai, M Zhou, W Brumpton, BM Rasheed, H Havulinna, AS Veturi, Y Pacheco, JA Rosenthal, EA Lingren, T Feng, Q Kullo, IJ Narita, A Takayama, J Martin, HC Hunt, KA Trivedi, B Haessler, J Giulianini, F Bradford, Y Miller, JE Campbell, A Lin, K Millwood, IY Rasheed, A Hindy, G Faul, JD Zhao, W Weir, DR Turman, C Huang, H Graf, M Choudhury, A Sengupta, D Mahajan, A Brown, MR Zhang, W Yu, K Schmidt, EM Pandit, A Gustafsson, S Yin, X Luan, J Zhao, J-H Matsuda, F Jang, H-M Yoon, K Medina-Gomez, C Pitsillides, A Hottenga, JJ Wood, AR Ji, Y Gao, Z Haworth, S Yousri, NA Mitchell, RE Chai, JF Aadahl, M Bjerregaard, AA Yao, J Manichaikul, A Hwu, C-M Hung, Y-J Warren, HR Ramirez, J Bork-Jensen, J Karhus, LL Goel, A Sabater-Lleal, M Noordam, R Mauro, P Matteo, F McDaid, AF Marques-Vidal, P Wielscher, M Trompet, S Sattar, N Mollehave, LT Munz, M Zeng, L Huang, J Yang, B Poveda, A Kurbasic, A Lamina, C Forer, L Scholz, M Galesloot, TE Bradfeld, JP Ruotsalainen, SE Daw, E Zmuda, JM Mitchell, JS Fuchsberger, C Christensen, H Brody, JA Vazquez-Moreno, M Feitosa, MF Wojczynski, MK Wang, Z Preuss, MH Mangino, M Christofdou, P Verweij, N Benjamins, JW Engmann, J Tsao, NL Verma, A Slieker, RC Lo, KS Zilhao, NR Le, P Kleber, ME Delgado, GE Huo, S Ikeda, DD Iha, H Yang, J Liu, J Leonard, HL Marten, J Frank, M Schmidt, B Smyth, LJ Canadas-Garre, M Wang, C Nakatochi, M Wong, A Hutri-Kahonen, N Sim, X Xia, R Huerta-Chagoya, A Fernandez-Lopez, JC Lyssenko, V Nongmaithem, SS Bayyana, S Stringham, HM Irvin, MR Oldmeadow, C Kim, H-N Ryu, S Timmers, PRHJ Arbeeva, L Dorajoo, R Lange, LA Prasad, G Lores-Motta, L Pauper, M Long, J Li, X Theusch, E Takeuchi, F Spracklen, CN Loukola, A Bollepalli, S Warner, SC Wang, YX Wei, WB Nutile, T Ruggiero, D Sung, YJ Chen, S Liu, F Yang, J Kentistou, KA Banas, B Nardone, GG Meidtner, K Bielak, LF Smith, JA Hebbar, P Farmaki, A-E Hofer, E Lin, M Concas, MP Vaccargiu, S Van der Most, PJ Pitkanen, N Cade, BE Van der Laan, SW Chitrala, KN Weiss, S Bentley, AR Doumatey, AP Adeyemo, AA Lee, JY Petersen, ERB Nielsen, AA Choi, HS Nethander, M Freitag-Wolf, S Southam, L Rayner, NW Wang, CA Lin, S-Y Wang, J-S Couture, C Lyytikainen, L-P Nikus, K Cuellar-Partida, G Vestergaard, H Hidalgo, B Giannakopoulou, O Cai, Q Obura, MO Van Setten, J Li, X Liang, J Tang, H Terzikhan, N Shin, JH Jackson, RD Reiner, AP Martin, LW Chen, Z Li, L Kawaguchi, T Thiery, J Bis, JC Launer, LJ Li, H Nalls, MA Raitakari, OT Ichihara, S Wild, SH Nelson, CP Campbell, H Jager, S Nabika, T Al-Mulla, F Niinikoski, H Braund, PS Kolcic, I Kovacs, P Giardoglou, T Katsuya, T De Kleijn, D De Borst, GJ Kim, EK Adams, HHH Ikram, MA Zhu, X Asselbergs, FW Kraaijeveld, AO Beulens, JWJ Shu, X-O Rallidis, LS Pedersen, O Hansen, T Mitchell, P Hewitt, AW Kahonen, M Perusse, L Bouchard, C Tonjes, A Chen, Y-DI Pennell, CE Mori, TA Lieb, W Franke, A Ohlsson, C Mellstrom, D Cho, YS Lee, H Yuan, J-M Koh, W-P Rhee, SY Woo, J-T Heid, IM Stark, KJ Zimmermann, ME Volzke, H Homuth, G Evans, MK Zonderman, AB Polasek, O Pasterkamp, G Hoefer, IE Redline, S Pahkala, K Oldehinkel, AJ Snieder, H Biino, G Schmidt, R Schmidt, H Bandinelli, S Dedoussis, G Thanaraj, TA Kardia, SLR Peyser, PA Kato, N Schulze, MB Girotto, G Boger, CA Jung, B Joshi, PK Bennett, DA De Jager, PL Lu, X Mamakou, V Brown, M Caulfeld, MJ Munroe, PB Guo, X Ciullo, M Jonas, JB Samani, NJ Kaprio, J Pajukanta, P Tusie-Luna, T Aguilar-Salinas, CA Adair, LS Bechayda, SA De Silva, HJ Wickremasinghe, AR Krauss, RM Wu, J-Y Zheng, W Hollander, AI Bharadwaj, D Correa, A Wilson, JG Lind, L Heng, C-K Nelson, AE Golightly, YM Wilson, JF Penninx, B Kim, H-L Attia, J Scott, RJ Rao, DC Arnett, DK Hunt, SC Walker, M Koistinen, HA Chandak, GR Mercader, JM Costanzo, MC Jang, D Burtt, NP Villalpando, CG Orozco, L Fornage, M Tai, E Van Dam, RM Lehtimaki, T Chaturvedi, N Yokota, M Liu, J Reilly, DF McKnight, AJ Kee, F Jockel, K-H McCarthy, M Palmer, CNA Vitart, V Hayward, C Simonsick, E Van Duijn, CM Jin, Z-B Qu, J Hishigaki, H Lin, X Marz, W Gudnason, V Tardif, J-C Lettre, G T Hart, LM Elders, PJM Damrauer, SM Kumari, M Kivimaki, M Van der Harst, P Spector, TD Loos, RJF Province, MA Parra, EJ Cruz, M Psaty, BM Brandslund, I Pramstaller, PP Rotimi, CN Christensen, K Ripatti, S Widen, E Hakonarson, H Grant, SFA Kiemeney, LALM De Graaf, J Loefer, M Kronenberg, F Gu, D Erdmann, J Schunkert, H Franks, PW Linneberg, A Jukema, JW Khera, A Mannikko, M Jarvelin, M-R Kutalik, Z Francesco, C Mook-Kanamori, DO Van Dijk, KW Watkins, H Strachan, DP Grarup, N Sever, P Poulter, N Chuang, L-M Rotter, J Dantoft, TM Karpe, F Neville, MJ Timpson, NJ Cheng, C-Y Wong, T-Y Khor, CC Li, H Sabanayagam, C Peters, A Gieger, C Hattersley, AT Pedersen, NL Magnusson, PKE Boomsma, D Willemsen, AHM Cupples, L Van Meurs, JBJ Ghanbari, M Gordon-Larsen, P Huang, W Kim, YJ Tabara, Y Wareham, NJ Langenberg, C Zeggini, E Kuusisto, J Laakso, M Ingelsson, E Abecasis, G Chambers, JC Kooner, JS De Vries, PS Morrison, AC Hazelhurst, S Ramsay, M North, KE Daviglus, M Kraft, P Martin, NG Whitfeld, JB Abbas, S Saleheen, D Walters, RG Holmes, M Black, C Smith, BH Baras, A Justice, AE Buring, JE Ridker, PM Chasman, D Kooperberg, C Tamiya, G Yamamoto, M Van Heel, DA Trembath, RC Wei, W-Q Jarvik, GP Namjou, B Hayes, MG Ritchie, MD Jousilahti, P Salomaa, V Hveem, K Asvold, BO Kubo, M Kamatani, Y Okada, Y Murakami, Y Kim, B-J Thorsteinsdottir, U Stefansson, K Zhang, J Chen, YE Ho, Y-L Lynch, JA Rader, DJ Tsao, PS Chang, K-M Cho, K O'Donnell, CJ Gaziano, JM Wilson, PWF Frayling, TM Hirschhorn, JN Kathiresan, S Mohlke, KL Sun, Y Morris, AP Boehnke, M Brown, CD Natarajan, P Deloukas, P Willer, CJ Assimes, TL Peloso, GM Demirkan, A |
| Item Type: | Journal Article |
| 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. |
| Issue Date: | 27-Dec-2022 |
| Date of Acceptance: | 6-Dec-2022 |
| URI: | http://hdl.handle.net/10044/1/108049 |
| DOI: | 10.1186/s13059-022-02837-1 |
| ISSN: | 1474-7596 |
| Publisher: | BMC |
| Journal / Book Title: | Genome Biology |
| Volume: | 23 |
| Copyright Statement: | © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the mate‑ rial. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publi cdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
| Publication Status: | Published |
| Article Number: | 268 |
| Online Publication Date: | 2022-12-27 |
| Appears in Collections: | National Heart and Lung Institute School of Public Health |
This item is licensed under a Creative Commons License
