Abstract

Understanding genetic architecture of plasma lipidome could provide better insights into lipid metabolism and its link to cardiovascular diseases (CVDs). Here, we perform genome-wide association analyses of 141 lipid species (n = 2,181 individuals), followed by phenome-wide scans with 25 CVD related phenotypes (n = 511,700 individuals). We identify 35 lipid-species-associated loci (P <5 ×10−8), 10 of which associate with CVD risk including five new loci-COL5A1, GLTPD2, SPTLC3, MBOAT7 and GALNT16 (false discovery rate<0.05). We identify loci for lipid species that are shown to predict CVD e.g., SPTLC3 for CER(d18:1/24:1). We show that lipoprotein lipase (LPL) may more efficiently hydrolyze medium length triacylglycerides (TAGs) than others. Polyunsaturated lipids have highest heritability and genetic correlations, suggesting considerable genetic regulation at fatty acids levels. We find low genetic correlations between traditional lipids and lipid species. Our results show that lipidomic profiles capture information beyond traditional lipids and identify genetic variants modifying lipid levels and risk of CVD.

Cardiovascular diseases (CVD) are associated with plasma lipid levels. Here, Tabassum et al. perform genome-wide association studies for lipidomic profiles with 141 (non-standard) lipid species which highlights shared genetic loci with CVD and that traditional lipids have low genetic correlation with other lipids.

Details

Title
Genetic architecture of human plasma lipidome and its link to cardiovascular disease
Author
Tabassum Rubina 1 ; Rämö, Joel T 1 ; Ripatti Pietari 1   VIAFID ORCID Logo  ; Koskela, Jukka T 1   VIAFID ORCID Logo  ; Kurki Mitja 2 ; Karjalainen Juha 3 ; Palta Priit 4   VIAFID ORCID Logo  ; Shabbeer, Hassan 1 ; Nunez-Fontarnau, Javier 1 ; Kiiskinen Tuomo T J 5 ; Söderlund Sanni 6 ; Matikainen Niina 7   VIAFID ORCID Logo  ; Gerl, Mathias J 8   VIAFID ORCID Logo  ; Surma, Michal A 9   VIAFID ORCID Logo  ; Klose, Christian 8 ; Stitziel, Nathan O 10 ; Laivuori Hannele 11   VIAFID ORCID Logo  ; Havulinna, Aki S 5 ; Service, Susan K 12 ; Salomaa Veikko 13   VIAFID ORCID Logo  ; Pirinen Matti 14   VIAFID ORCID Logo  ; Jalanko Anu 1 ; Kaprio Jaakko 1 ; Donner Kati 1 ; Kaunisto Mari 1 ; Mars, Nina 1 ; Dada, Alexander 1 ; Shcherban Anastasia 1 ; Ganna, Andrea 1 ; Lehisto Arto 1 ; Kilpeläinen Elina 1 ; Brein Georg 1 ; Ghazal, Awaisa 1 ; Harju Jarmo 1 ; Pärn Kalle 1 ; Parolo Pietro Della Briotta 1 ; Kajanne Risto 1 ; Lemmelä Susanna 1 ; Sipilä, Timo P 1 ; Sipilä Tuomas 1 ; Lyhs Ulrike 1 ; Llorens, Vincent 1 ; Niiranen Teemu 13 ; Kristiansson Kati 13 ; Männikkö Lotta 13 ; Jiménez, Manuel González 13 ; Perola Markus 13 ; Wong, Regis 13 ; Kilpi Terhi 13 ; Hiekkalinna Tero 13 ; Järvensivu Elina 13 ; Kaiharju Essi 13 ; Mattsson Hannele 13 ; Laukkanen Markku 13 ; Laiho Päivi 13 ; Lähteenmäki Sini 13 ; Sistonen Tuuli 13 ; Soini Sirpa 13 ; Ziemann, Adam 15 ; Lehtonen, Anne 15 ; Lertratanakul Apinya 15 ; Georgantas Bob 15 ; Riley-Gillis, Bridget 15 ; Quarless Danjuma 15 ; Rahimov Fedik 15 ; Heap, Graham 15 ; Howard, Jacob 15 ; Waring, Jeffrey 15 ; Davis, Justin Wade 15 ; Smaoui Nizar 15 ; Popovic Relja 15 ; Esmaeeli Sahar 15 ; Waring, Jeff 15 ; Matakidou Athena 16 ; Challis, Ben 16 ; Close, David 16 ; Petrovski Slavé 16 ; Karlsson Antti 17 ; Schleutker Johanna 17 ; Pulkki Kari 17 ; Virolainen Petri 17 ; Kallio Lila 18 ; Mannermaa Arto 19 ; Heikkinen Sami 19 ; Kosma Veli-Matti 20 ; Chia-Yen, Chen 21 ; Runz Heiko 21 ; Liu, Jimmy 21 ; Bronson, Paola 21 ; John, Sally 21 ; Sanni, Lahdenperä 21 ; Eaton, Susan 21 ; Zhou, Wei 22 ; Hendolin Minna 23 ; Tuovila Outi 23 ; Pakkanen Raimo 23 ; Maranville, Joseph 24 ; Usiskin Keith 24 ; Hochfeld Marla 24 ; Plenge, Robert 24 ; Yang, Robert 24 ; Biswas Shameek 24 ; Greenberg, Steven 24 ; Laakkonen Eija 25 ; Kononen Juha 25 ; Paloneva Juha 25 ; Kujala Urho 25 ; Teijo, Kuopio 26 ; Laukkanen Jari 27 ; Kangasniemi Eeva 28 ; Savinainen Kimmo 28 ; Laaksonen Reijo 28 ; Arvas Mikko 29 ; Ritari Jarmo 29 ; Partanen Jukka 29 ; Hyvärinen Kati 29 ; Wahlfors Tiina 29 ; Peterson, Andrew 30 ; Oh, Danny 30 ; Chang, Diana 30 ; Teng Edmond 30 ; Strauss, Erich 30 ; Kerchner Geoff 30 ; Chen, Hao 30 ; Chen, Hubert 30 ; Schutzman, Jennifer 30 ; Michon, John 30 ; Hunkapiller, Julie 30 ; McCarthy, Mark 30 ; Bowers, Natalie 30 ; Lu, Tim 30 ; Bhangale Tushar 30 ; Pulford, David 31 ; Waterworth, Dawn 31 ; Kulkarni Diptee 31 ; Xu Fanli 31 ; Betts, Jo 31 ; Gordillo, Jorge Esparza 31 ; Hoffman, Joshua 31 ; Auro Kirsi 31 ; McCarthy, Linda 31 ; Ghosh Soumitra 31 ; Ehm Meg 31 ; Pitkänen Kimmo 32 ; Mäkelä Tomi 33 ; Loukola Anu 34 ; Joensuu Heikki 34 ; Sinisalo Juha 34 ; Eklund, Kari 34 ; Aaltonen Lauri 34 ; Färkkilä Martti 34 ; Carpen Olli 34 ; Kauppi, Paula 34 ; Tienari Pentti 34 ; Ollila Terhi 34 ; Tuomi Tiinamaija 34 ; Meretoja Tuomo 34 ; Pitkäranta, Anne 34 ; Turunen Joni 34 ; Hannula-Jouppi Katariina 34 ; Pikkarainen Sampsa 34 ; Seitsonen Sanna 34 ; Koskinen Miika 34 ; Palomäki Antti 35 ; Rinne Juha 35 ; Metsärinne Kaj 35 ; Elenius, Klaus 35 ; Pirilä, Laura 35 ; Koulu Leena 35 ; Voutilainen Markku 35 ; Juonala Markus 35 ; Peltonen Sirkku 35 ; Aaltonen Vesa 35 ; Loboda Andrey 36 ; Podgornaia Anna 36 ; Chhibber Aparna 36 ; Chu, Audrey 36 ; Fox, Caroline 36 ; Diogo Dorothee 36 ; Holzinger, Emily 36 ; Eicher, John 36 ; Gormley Padhraig 36 ; Mehta Vinay 36 ; Wang Xulong 36 ; Kettunen, Johannes 37 ; Pylkäs Katri 37 ; Kalaoja Marita 37 ; Karjalainen Minna 37 ; Hinttala Reetta 37 ; Kaarteenaho Riitta 37 ; Vainio Seppo 37 ; Mantere Tuomo 37 ; Remes, Anne 38 ; Huhtakangas Johanna 38 ; Junttila Juhani 38 ; Tasanen Kaisa 38 ; Huilaja Laura 38 ; Luodonpää Marja 38 ; Hautala, Nina 38 ; Karihtala Peeter 38 ; Kauppila Saila 38 ; Harju Terttu 38 ; Blomster Timo 38 ; Soininen Hilkka 39 ; Harvima Ilkka 39 ; Pihlajamäki Jussi 39 ; Kaarniranta Kai 39 ; Pelkonen Margit 39 ; Laakso Markku 39 ; Hiltunen Mikko 39 ; Kiviniemi Mikko 39 ; Kaipiainen-Seppänen Oili 39 ; Auvinen Päivi 39 ; Kälviäinen Reetta 39 ; Julkunen Valtteri 39 ; Malarstig Anders 40 ; Hedman Åsa 40 ; Marshall, Catherine 40 ; Whelan, Christopher 40 ; Lehtonen Heli 40 ; Parkkinen Jaakko 40 ; Linden, Kari 40 ; Kalpala Kirsi 40 ; Miller, Melissa 40 ; Bing, Nan 40 ; McDonough, Stefan 40 ; Chen, Xing 40 ; Hu, Xinli 40 ; Wu, Ying 40 ; Auranen Annika 41 ; Jussila Airi 41 ; Uusitalo-Järvinen Hannele 41 ; Kankaanranta Hannu 41 ; Uusitalo Hannu 41 ; Peltola Jukka 41 ; Kähönen Mika 41 ; Isomäki Pia 41 ; Laitinen Tarja 41 ; Salmi Teea 41 ; Muslin, Anthony 42 ; Wang, Clarence 42 ; Chatelain Clement 42 ; Xu, Ethan 42 ; Auge Franck 42 ; Call, Kathy 42 ; Klinger, Kathy 42 ; Crohns Marika 42 ; Gossel Matthias 42 ; Palin Kimmo 43 ; Rivas, Manuel 44 ; Siirtola Harri 45 ; Tabuenca Javier Gracia 45 ; Jauhiainen Matti 46 ; Daly, Mark J 47 ; Freimer, Nelson B 12   VIAFID ORCID Logo  ; Palotie Aarno 48 ; Taskinen Marja-Riitta 6 ; Simons, Kai 49 ; Ripatti Samuli 50 

1  HiLIFE, University of Helsinki, Institute for Molecular Medicine Finland, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071) 
2  HiLIFE, University of Helsinki, Institute for Molecular Medicine Finland, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071); Broad Institute of MIT and Harvard, Program in Medical and Population Genetics and Genetic Analysis Platform, Stanley Center for Psychiatric Research, Cambridge, USA (GRID:grid.66859.34); Massachusetts General Hospital, Psychiatric & Neurodevelopmental Genetics Unit, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924) 
3  HiLIFE, University of Helsinki, Institute for Molecular Medicine Finland, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071); Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, USA (GRID:grid.66859.34); Massachusetts General Hospital and Harvard Medical School, Analytic and Translational Genetics Unit, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924) 
4  HiLIFE, University of Helsinki, Institute for Molecular Medicine Finland, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071); University of Tartu, Estonian Genome Center, Institute of Genomics, Tartu, Estonia (GRID:grid.10939.32) (ISNI:0000 0001 0943 7661) 
5  HiLIFE, University of Helsinki, Institute for Molecular Medicine Finland, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071); National Institute for Health and Welfare, Helsinki, Finland (GRID:grid.14758.3f) (ISNI:0000 0001 1013 0499) 
6  Helsinki University Hospital, Research Programs Unit, Diabetes & Obesity, University of Helsinki and Department of Internal Medicine, Helsinki, Finland (GRID:grid.15485.3d) (ISNI:0000 0000 9950 5666) 
7  Helsinki University Hospital, Research Programs Unit, Diabetes & Obesity, University of Helsinki and Department of Internal Medicine, Helsinki, Finland (GRID:grid.15485.3d) (ISNI:0000 0000 9950 5666); Helsinki University Hospital, Endocrinology, Abdominal Center, Helsinki, Finland (GRID:grid.15485.3d) (ISNI:0000 0000 9950 5666) 
8  Lipotype GmbH, Dresden, Germany (GRID:grid.15485.3d) 
9  Lipotype GmbH, Dresden, Germany (GRID:grid.15485.3d); Łukasiewicz Research Network-PORT Polish Center for Technology Development, Wroclaw, Poland (GRID:grid.15485.3d) 
10  Washington University School of Medicine, Cardiovascular Division, Department of Medicine, Saint Louis, USA (GRID:grid.4367.6) (ISNI:0000 0001 2355 7002); Washington University School of Medicine, Department of Genetics, Saint Louis, USA (GRID:grid.4367.6) (ISNI:0000 0001 2355 7002); Washington University School of Medicine, McDonnell Genome Institute, Saint Louis, USA (GRID:grid.4367.6) (ISNI:0000 0001 2355 7002) 
11  HiLIFE, University of Helsinki, Institute for Molecular Medicine Finland, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071); Faculty of Medicine and Health Technology, Department of Obstetrics and Gynecology, Tampere University Hospital and Tampere University, Tampere, Finland (GRID:grid.7737.4); University of Helsinki and Helsinki University Hospital, Medical and Clinical Genetics, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071) 
12  University of California, Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718) 
13  National Institute for Health and Welfare, Helsinki, Finland (GRID:grid.14758.3f) (ISNI:0000 0001 1013 0499) 
14  HiLIFE, University of Helsinki, Institute for Molecular Medicine Finland, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071); University of Helsinki, Department of Public Health, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071); University of Helsinki, Helsinki Institute for Information Technology HIIT and Department of Mathematics and Statistics, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071) 
15  Abbvie, Chicago, USA (GRID:grid.431072.3) (ISNI:0000 0004 0572 4227) 
16  Astra Zeneca, Cambridge, UK (GRID:grid.431072.3) 
17  Auria Biobank, University of Turku and Hospital District of Southwest Finland, Turku, Finland (GRID:grid.426612.5) (ISNI:0000 0004 0366 9623) 
18  Auria Biobank, Turku, Finland (GRID:grid.426612.5) 
19  University of Eastern Finland and Northern Savo Hospital District, Biobank of Eastern Finland, Kuopio, Finland (GRID:grid.9668.1) (ISNI:0000 0001 0726 2490) 
20  Biobank of Eastern Finland, Kuopio, Finland (GRID:grid.9668.1) 
21  Biogen, Cambridge, USA (GRID:grid.417832.b) (ISNI:0000 0004 0384 8146) 
22  Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, USA (GRID:grid.66859.34) 
23  Business Finland, Helsinki, Finland (GRID:grid.66859.34) 
24  Celgene, Summit, USA (GRID:grid.418722.a) (ISNI:0000 0004 0461 1802) 
25  University of Jyväskylä and Central Finland Health Care District, Central Finland Biobank, Jyväskylä, Finland (GRID:grid.460356.2) (ISNI:0000 0004 0449 0385) 
26  Central Finland Biobank, Jyväskylä, Finland (GRID:grid.460356.2) 
27  Central Finland Health Care District, Jyväskylä, Finland (GRID:grid.460356.2) (ISNI:0000 0004 0449 0385) 
28  University of Tampere and Pirkanmaa Hospital District, Finnish Clinical Biobank Tampere, Tampere, Finland (GRID:grid.502801.e) (ISNI:0000 0001 2314 6254) 
29  Finnish Red Cross Blood Service and Finnish Hematology Registry and Clinical Biobank, Helsinki, Finland (GRID:grid.452433.7) (ISNI:0000 0000 9387 9501) 
30  Genentech, San Francisco, USA (GRID:grid.418158.1) (ISNI:0000 0004 0534 4718) 
31  GlaxoSmithKline, Brentford, UK (GRID:grid.418236.a) (ISNI:0000 0001 2162 0389) 
32  Helsinki Biobank, Helsinki, Finland (GRID:grid.418236.a) 
33  HiLIFE, University of Helsinki, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071) 
34  Hospital District of Helsinki and Uusimaa, Helsinki, Finland (GRID:grid.424664.6) (ISNI:0000 0004 0410 2290) 
35  Hospital District of Southwest Finland, Turku, Finland (GRID:grid.426612.5) (ISNI:0000 0004 0366 9623) 
36  Merck, Kenilworth, USA (GRID:grid.417993.1) (ISNI:0000 0001 2260 0793) 
37  University of Oulu and Northern Ostrobothnia Hospital District, Northern Finland Biobank Borealis, Oulu, Finland (GRID:grid.437577.5) 
38  Northern Ostrobothnia Hospital District, Oulu, Finland (GRID:grid.437577.5) 
39  Northern Savo Hospital District, Kuopio, Finland (GRID:grid.437577.5) 
40  Pfizer, New York, USA (GRID:grid.410513.2) (ISNI:0000 0000 8800 7493) 
41  Pirkanmaa Hospital District, Tampere, Finland (GRID:grid.415018.9) (ISNI:0000 0004 0472 1956) 
42  Sanofi, Paris, France (GRID:grid.417924.d) 
43  University of Helsinki, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071) 
44  University of Stanford, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956) 
45  University of Tampere, Tampere, Finland (GRID:grid.502801.e) (ISNI:0000 0001 2314 6254) 
46  National Institute for Health and Welfare, Helsinki, Finland (GRID:grid.14758.3f) (ISNI:0000 0001 1013 0499); Minerva Foundation Institute for Medical Research, Biomedicum, Helsinki, Finland (GRID:grid.452540.2) 
47  HiLIFE, University of Helsinki, Institute for Molecular Medicine Finland, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071); Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, USA (GRID:grid.66859.34) 
48  HiLIFE, University of Helsinki, Institute for Molecular Medicine Finland, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071); Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, USA (GRID:grid.66859.34); Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry, Analytic and Translational Genetics Unit, Department of Medicine, and the Department of Neurology, Massachusetts General Hospital, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924) 
49  Lipotype GmbH, Dresden, Germany (GRID:grid.15485.3d); Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany (GRID:grid.419537.d) (ISNI:0000 0001 2113 4567) 
50  HiLIFE, University of Helsinki, Institute for Molecular Medicine Finland, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071); Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, USA (GRID:grid.66859.34); University of Helsinki, Department of Public Health, Clinicum, Faculty of Medicine, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071) 
Publication year
2019
Publication date
2019
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-019-11954-8
ProQuest document ID
2296636752
Copyright
© The Author(s) 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.