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Exome-wide association study of plasma lipids in >300,000 individuals.
| File | Description | Size | Format | ||
|---|---|---|---|---|---|
 GLGC_writeup_Nat_Genet_Revision2_091317_SK_clean.docx | Accepted version | 341.81 kB | Microsoft Word | View/Open | |
| GLGC_Supplementary_Notes_090117.docx | Supporting information | 161.91 kB | Microsoft Word | View/Open | |
| GLGC_SUPPLEMENT_TABLES_090117.xlsx | Supporting information | 367.1 kB | Microsoft Excel | View/Open | |
| Title: | Exome-wide association study of plasma lipids in >300,000 individuals. |
| Authors: | Liu, DJ Peloso, GM Yu, H Butterworth, AS Wang, X Mahajan, A Saleheen, D Emdin, C Alam, D Alves, AC Amouyel, P Stitziel, N Strauch, K Stringham, HM Surendran, P Tada, H Tall, AR Tang, H Tardif, J-C Taylor, KD Bis, JC Langenberg, C Trompet, S Tsao, PS Tuomilehto, J Tybjaerg-Hansen, A Van Zuydam, NR Varbo, A Varga, TV Virtamo, J Waldenberger, M Wang, N Langsted, A Boehnke, M Wareham, NJ Warren, HR Weeke, PE Weinstock, J Wessel, J Wilson, JG Wilson, PWF Xu, M Yaghootkar, H Launer, LJ Young, R Boerwinkle, E Zeggini, E Zhang, H Zheng, NS Zhang, W Zhang, Y Zhou, W Zhou, Y Zoledziewska, M Lauritzen, T Charge Diabetes Working Group EPIC-InterAct Consortium Bork-Jensen, J EPIC-CVD Consortium GOLD Consortium VA Million Veteran Program Howson, JMM Danesh, J McCarthy, MI Cowan, CA Liewald, DCM Abecasis, G Deloukas, P Musunuru, K Bottinger, EP Willer, CJ Kathiresan, S Brandslund, I Brown, M Busonero, F Caulfield, MJ Lin, LA Chambers, JC Chasman, DI Chen, YE Chen, Y-DI Chowdhury, R Christensen, C Chu, AY Connell, JM Cucca, F Cupples, LA Linneberg, A Damrauer, SM Davies, G Deary, IJ Dedoussis, G Denny, JC Dominiczak, A Dubé, M-P Ebeling, T Eiriksdottir, G Esko, T Loos, RJF Farmaki, A-E Feitosa, MF Ferrario, M Ferrieres, J Ford, I Fornage, M Franks, PW Frayling, TM Frikke-Schmidt, R Fritsche, LG Lu, Y Frossard, P Fuster, V Ganesh, SK Gao, W Garcia, ME Gieger, C Giulianini, F Goodarzi, MO Grallert, H Grarup, N Lu, X Groop, L Grove, ML Gudnason, V Hansen, T Harris, TB Hayward, C Hirschhorn, JN Holmen, OL Huffman, J Huo, Y Di Angelantonio, E Hveem, K Jabeen, S Jackson, AU Jakobsdottir, J Jarvelin, M-R Jensen, GB Jørgensen, ME Jukema, JW Justesen, JM Kamstrup, PR Mägi, R Kanoni, S Karpe, F Kee, F Khera, AV Klarin, D Koistinen, HA Kooner, JS Kooperberg, C Kuulasmaa, K Kuusisto, J Malarstig, A Laakso, M Lakka, T Manichaikul, A Manning, AK Mäntyselkä, P Marouli, E Masca, NGD Maschio, A Meigs, JB Melander, O Arveiler, D Metspalu, A Morris, AP Morrison, AC Mulas, A Müller-Nurasyid, M Munroe, PB Neville, MJ Nielsen, JB Nielsen, SF Nordestgaard, BG Assimes, TL Ordovas, JM Mehran, R O'Donnell, CJ Orho-Melander, M Molony, CM Muntendam, P Padmanabhan, S Palmer, CNA Pasko, D Patel, AP Auer, PL Pedersen, O Perola, M Peters, A Pisinger, C Pistis, G Polasek, O Poulter, N Psaty, BM Rader, DJ Rasheed, A Baber, U Rauramaa, R Reilly, DF Reiner, AP Renström, F Rich, SS Ridker, PM Rioux, JD Robertson, NR Roden, DM Rotter, JI Ballantyne, CM Rudan, I Salomaa, V Samani, NJ Sanna, S Sattar, N Schmidt, EM Scott, RA Sever, P Sevilla, RS Shaffer, CM Bang, LE Sim, X Sivapalaratnam, S Small, KS Smith, AV Smith, BH Somayajula, S Southam, L Spector, TD Speliotes, EK Starr, JM Benn, M Stirrups, KE |
| Item Type: | Journal Article |
| Abstract: | We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD. |
| Issue Date: | 30-Oct-2017 |
| Date of Acceptance: | 26-Sep-2017 |
| URI: | http://hdl.handle.net/10044/1/53907 |
| DOI: | https://dx.doi.org/10.1038/ng.3977 |
| ISSN: | 1061-4036 |
| Publisher: | Nature Publishing Group |
| Start Page: | 1758 |
| End Page: | 1766 |
| Journal / Book Title: | Nature Genetics |
| Volume: | 49 |
| Copyright Statement: | Copyright © 2017, Rights Managed by Nature Publishing Group |
| Keywords: | Science & Technology Life Sciences & Biomedicine Genetics & Heredity APOBEC-1 COMPLEMENTATION FACTOR CODING-SEQUENCE VARIANTS TYROSINE KINASE JAK2 B MESSENGER-RNA MACULAR DEGENERATION GENETIC ARCHITECTURE LOW-FREQUENCY MYELOPROLIFERATIVE DISORDERS CARDIOVASCULAR-DISEASE CLONAL HEMATOPOIESIS Coronary Artery Disease Diabetes Mellitus, Type 2 Exome Genetic Association Studies Genetic Predisposition to Disease Genetic Variation Genotype Humans Lipids Macular Degeneration Phenotype Risk Factors Charge Diabetes Working Group EPIC-InterAct Consortium EPIC-CVD Consortium GOLD Consortium VA Million Veteran Program 11 Medical And Health Sciences 06 Biological Sciences Developmental Biology |
| Publication Status: | Published online |
| Appears in Collections: | National Heart and Lung Institute |