Abstract

Cardiovascular diseases are the leading cause of premature death and disability worldwide, with both genetic and environmental determinants. While genome-wide association studies have identified multiple genetic loci associated with cardiovascular diseases, exact genes driving these associations remain mostly uncovered. Due to Finland’s population history, many deleterious and high-impact variants are enriched in the Finnish population giving a possibility to find genetic associations for protein-truncating variants that likely tie the association to a gene and that would not be detected elsewhere. In a large Finnish biobank study FinnGen, we identified an association between an inframe insertion rs534125149 in MFGE8 (encoding lactadherin) and protection against coronary atherosclerosis. This variant is highly enriched in Finland, and the protective association was replicated in meta-analysis of BioBank Japan and Estonian biobank. Additionally, we identified a protective association between splice acceptor variant rs201988637 in MFGE8 and coronary atherosclerosis, independent of the rs534125149, with no significant risk-increasing associations. This variant was also associated with lower pulse pressure, pointing towards a function of MFGE8 in arterial aging also in humans in addition to previous evidence in mice. In conclusion, our results suggest that inhibiting the production of lactadherin could lower the risk for coronary heart disease substantially.

A genome-wide association study identifies MFGE8 as protective against coronary atherosclerosis in European and East Asian populations.

Details

Title
Inframe insertion and splice site variants in MFGE8 associate with protection against coronary atherosclerosis
Author
Ruotsalainen, Sanni E. 1   VIAFID ORCID Logo  ; Surakka, Ida 2 ; Mars, Nina 1 ; Karjalainen, Juha 3 ; Kurki, Mitja 3 ; Kanai, Masahiro 4   VIAFID ORCID Logo  ; Krebs, Kristi 5   VIAFID ORCID Logo  ; Graham, Sarah 2 ; Mishra, Pashupati P. 6 ; Mishra, Binisha H. 6 ; Sinisalo, Juha 7 ; Palta, Priit 8   VIAFID ORCID Logo  ; Lehtimäki, Terho 6 ; Raitakari, Olli 9 ; Esko, Tõnu 5 ; Metspalu, Andres 5 ; Mägi, Reedik 5 ; Nelis, Mari 5 ; Milani, Lili 5 ; Matsuda, Koichi 10 ; Yamanashi, Yuji 11 ; Furukawa, Yoichi 12 ; Morisaki, Takayuki 12 ; Murakami, Yoshinori 13 ; Kamatani, Yoichiro 14 ; Muto, Kaori 15 ; Nagai, Akiko 15 ; Obara, Wataru 16 ; Yamaji, Ken 17 ; Takahashi, Kazuhisa 18 ; Asai, Satoshi 19 ; Takahashi, Yasuo 20 ; Suzuki, Takao 21 ; Sinozaki, Nobuaki 21 ; Yamaguchi, Hiroki 22 ; Minami, Shiro 23 ; Murayama, Shigeo 24 ; Yoshimori, Kozo 25 ; Nagayama, Satoshi 26 ; Obata, Daisuke 27 ; Higashiyama, Masahiko 28 ; Masumoto, Akihide 29 ; Koretsune, Yukihiro 30 ; Okada, Yukinori 31   VIAFID ORCID Logo  ; Palotie, Aarno 1 ; Daly, Mark 1 ; Riley-Gills, Bridget 32 ; Jacob, Howard 32 ; Paul, Dirk 33 ; Runz, Heiko 34 ; John, Sally 34 ; Plenge, Robert 35 ; McCarthy, Mark 36 ; Hunkapiller, Julie 36 ; Ehm, Meg 37 ; Auro, Kirsi 37 ; Fox, Caroline 38 ; Mälarstig, Anders 39 ; Klinger, Katherine 40 ; Raipal, Deepak 40 ; Behrens, Tim 41 ; Yang, Robert 42 ; Siegel, Richard 43 ; Mäkelä, Tomi 44 ; Kaprio, Jaakko 1 ; Virolainen, Petri 45 ; Hakanen, Antti 45 ; Kilpi, Terhi 46 ; Perola, Markus 46 ; Partanen, Jukka 47 ; Pitkäranta, Anne 48 ; Junttila, Juhani 49 ; Serpi, Raisa 49 ; Laitinen, Tarja 50 ; Mäkelä, Johanna 50 ; Kosma, Veli-Matti 51 ; Kujala, Urho 52 ; Tuovila, Outi 53 ; Pakkanen, Raimo 53 ; Waring, Jeffrey 32 ; Abbasi, Ali 32 ; Liu, Mengzhen 32 ; Tachmazidou, Ioanna 33 ; Chen, Chia-Yen 34 ; Biswas, Shameek 35 ; Raghavan, Neha 38 ; Huertas-Vazquez, Adriana 38 ; Hu, Xinli 39 ; Gossel, Matthias 40 ; Graham, Robert 41 ; Cummings, Beryl 41 ; Fleuren, Wilco 42 ; Waterworth, Dawn 42 ; Renaud, Nicole 43 ; Obeidat, Ma´en 43 ; Ripatti, Samuli 1 ; Schleutker, Johanna 45 ; Arvas, Mikko 47 ; Carpén, Olli 48 ; Hinttala, Reetta 49 ; Kettunen, Johannes 49 ; Mannermaa, Arto 51 ; Laukkanen, Jari 52 ; Kälviäinen, Reetta 54 ; Julkunen, Valtteri 54 ; Soininen, Hilkka 54 ; Remes, Anne 55 ; Hiltunen, Mikko 56 ; Peltola, Jukka 57 ; Tienari, Pentti 58 ; Rinne, Juha 59 ; Kallionpää, Roosa 59 ; Ziemann, Adam 32 ; Esmaeeli, Sahar 32 ; Smaoui, Nizar 32 ; Lehtonen, Anne 32 ; Eaton, Susan 34 ; Lahdenperä, Sanni 34 ; van Adelsberg, Janet 35 ; Bowers, Natalie 36 ; Teng, Edmond 36 ; Pendergrass, Sarah 36 ; Soylemez, Onuralp 38 ; Linden, Kari 39 ; Xu, Fanli 37 ; Pulford, David 37 ; Addis, Laura 37 ; Eicher, John 37 ; Raivio, Minna 58 ; Partanen, Juulia 1 ; Färkkilä, Martti 58 ; Koskela, Jukka 58 ; Pikkarainen, Sampsa 58 ; Jussila, Airi 57 ; Kaukinen, Katri 57 ; Blomster, Timo 55 ; Kiviniemi, Mikko 56 ; Voutilainen, Markku 59 ; Heap, Graham 32 ; Rahimov, Fedik 32 ; Usiskin, Keith 35 ; Lu, Tim 36 ; Oh, Danny 36 ; Kalpala, Kirsi 39 ; Miller, Melissa 39 ; McCarthy, Linda 37 ; Eklund, Kari 58 ; Palomäki, Antti 59 ; Isomäki, Pia 57 ; Pirilä, Laura 59 ; Kaipiainen-Seppänen, Oili 60 ; Huhtakangas, Johanna 55 ; Lertratanakul, Apinya 32 ; Close, David 33 ; Hochfeld, Marla 35 ; Bing, Nan 39 ; Gordillo, Jorge Esparza 37 ; Pelkonen, Margit 61 ; Kauppi, Paula 58 ; Kankaanranta, Hannu 57 ; Harju, Terttu 55 ; Lahesmaa, Riitta 59 ; Mackay, Alex 33 ; Lassi, Glenda 33 ; Greenberg, Steven 35 ; Chen, Hubert 36 ; Betts, Joanna 37 ; Ghosh, Soumitra 37 ; Mishra, Rajashree 37 ; Rüeger, Sina 1 ; Niiranen, Teemu 62 ; Vaura, Felix 62 ; Salomaa, Veikko 62 ; Juonala, Markus 59 ; Metsärinne, Kaj 59 ; Kähönen, Mika 57 ; Laakso, Markku 56 ; Pihlajamäki, Jussi 56 ; Gordin, Daniel 58 ; Taskinen, Marja-Riitta 58 ; Tuomi, Tiinamaija 58 ; Challis, Benjamin 33 ; Parkkinen, Jaakko 39 ; Miller, Russell 39 ; Chu, Audrey 37 ; Elliott, Amanda 63 ; Rämö, Joel 1 ; Reeve, Mary Pat 1 ; Ruotsalainen, Sanni 1 ; Meretoja, Tuomo 58 ; Joensuu, Heikki 58 ; Aaltonen, Lauri 58 ; Mattson, Johanna 58 ; Auranen, Annika 57 ; Karihtala, Peeter 55 ; Kauppila, Saila 55 ; Auvinen, Päivi 56 ; Elenius, Klaus 59 ; Popovic, Relja 32 ; Riley-Gillis, Bridget 32 ; Schutzman, Jennifer 36 ; Loboda, Andrey 38 ; Chhibber, Aparna 38 ; Lehtonen, Heli 39 ; McDonough, Stefan 39 ; Crohns, Marika 40 ; Vuoti, Sauli 40 ; Kulkarni, Diptee 37 ; Pitkänen, Esa 1 ; Kaarniranta, Kai 64 ; Turunen, Joni A. 58 ; Ollila, Terhi 58 ; Seitsonen, Sanna 58 ; Uusitalo, Hannu 57 ; Aaltonen, Vesa 59 ; Uusitalo-Järvinen, Hannele 57 ; Luodonpää, Marja 55 ; Hautala, Nina 55 ; Loomis, Stephanie 34 ; Strauss, Erich 36 ; Chen, Hao 36 ; Podgornaia, Anna 38 ; Tasanen, Kaisa 55 ; Huilaja, Laura 55 ; Hannula-Jouppi, Katariina 58 ; Salmi, Teea 57 ; Peltonen, Sirkku 59 ; Koulu, Leena 59 ; Wu, Ying 39 ; Choy, David 36 ; Pussinen, Pirkko 58 ; Salminen, Aino 58 ; Salo, Tuula 58 ; Rice, David 58 ; Nieminen, Pekka 58 ; Palotie, Ulla 58 ; Siponen, Maria 65 ; Suominen, Liisa 65 ; Mäntylä, Päivi 65 ; Gursoy, Ulvi 59 ; Anttonen, Vuokko 55 ; Sipilä, Kirsi 55 ; Laivuori, Hannele 1 ; Kurra, Venla 57 ; Heikinheimo, Oskari 58 ; Kalliala, Ilkka 58 ; Kotaniemi-Talonen, Laura 57 ; Nieminen, Kari 57 ; Polo, Päivi 59 ; Mäkikallio, Kaarin 59 ; Ekholm, Eeva 59 ; Vääräsmäki, Marja 55 ; Uimari, Outi 55 ; Morin-Papunen, Laure 55 ; Tuppurainen, Marjo 56 ; Kivinen, Katja 1 ; Tukiainen, Taru 1 ; Aoxing, Liu 1 ; Laakkonen, Eija 66 ; Välimäki, Niko 67 ; Kumar, Janet 37 ; Ganna, Andrea 1 ; Davis, Justin Wade 32 ; Quarless, Danjuma 32 ; Petrovski, Slavé 33 ; Wigmore, Eleonor 33 ; Mitchell, Adele 34 ; Sun, Benjamin 34 ; Tsai, Ellen 34 ; Baird, Denis 34 ; Bronson, Paola 34 ; Tian, Ruoyu 34 ; Huang, Yunfeng 34 ; Maranville, Joseph 35 ; Mohammed, Elmutaz 35 ; Wadhawan, Samir 35 ; Kvikstad, Erika 35 ; Caliskan, Minal 35 ; Chang, Diana 36 ; Bhangale, Tushar 36 ; Shkura, Kirill 38 ; Neduva, Victor 38 ; Chen, Xing 39 ; Hedman, Åsa 39 ; King, Karen S. 37 ; Gormley, Padhraig 37 ; Liu, Jimmy 37 ; Wang, Clarence 40 ; Xu, Ethan 40 ; Auge, Franck 40 ; Chatelain, Clement 40 ; Rajpal, Deepak 40 ; Liu, Dongyu 40 ; Call, Katherine 40 ; Xia, Tai-He 40 ; Brauer, Matt 41 ; Xu, Huilei 43 ; Cole, Amy 43 ; Chung, Jonathan 43 ; Jacob, Jaison 43 ; de Lange, Katrina 43 ; Zierer, Jonas 43 ; Havulinna, Aki 1 ; Mehtonen, Juha 1 ; Hassan, Shabbeer 1 ; Della Briotta Parolo, Pietro 1 ; Zhou, Wei 3 ; Maasha, Mutaamba 3 ; Lemmelä, Susanna 1 ; Rivas, Manuel 68 ; Lehisto, Arto 1 ; Llorens, Vincent 1 ; Niemi, Mari E. 1 ; Heyne, Henrike 1 ; Palin, Kimmo 67 ; Garcia-Tabuenca, Javier 69 ; Siirtola, Harri 69 ; Kiiskinen, Tuomo 1 ; Lee, Jiwoo 63 ; Tsuo, Kristin 63 ; Kristiansson, Kati 46 ; Hyvärinen, Kati 70 ; Ritari, Jarmo 70 ; Koskinen, Miika 48 ; Pylkäs, Katri 71 ; Kalaoja, Marita 71 ; Karjalainen, Minna 71 ; Mantere, Tuomo 49 ; Kangasniemi, Eeva 50 ; Heikkinen, Sami 72 ; Heron, Samuel 73 ; Jambulingam, Dhanaprakash 73 ; Rathinakannan, Venkat Subramaniam 73 ; Pitkänen, Nina 45 ; Kallio, Lila 45 ; Soini, Sirpa 46 ; Punkka, Eero 48 ; Kuopio, Teijo 52 ; Jalanko, Anu 1 ; Shen, Huei-Yi 1 ; Kajanne, Risto 1 ; Aavikko, Mervi 1 ; Lahtela, L. Elisa 1 ; Kaunisto, Mari 1 ; Kilpeläinen, Elina 1 ; Sipilä, Timo P. 1 ; Brein, Georg 1 ; Dada, Oluwaseun Alexander 1 ; Ghazal, Awaisa 1 ; Shcherban, Anastasia 1 ; Donner, Kati 1 ; Loukola, Anu 48 ; Laiho, Päivi 46 ; Sistonen, Tuuli 46 ; Kaiharju, Essi 46 ; Laukkanen, Markku 46 ; Järvensivu, Elina 46 ; Lähteenmäki, Sini 46 ; Männikkö, Lotta 46 ; Wong, Regis 46 ; Mattsson, Hannele 46 ; Koskelainen, Sami 46 ; Hiekkalinna, Tero 46 ; Paajanen, Teemu 46 ; Pärn, Kalle 1 ; Luo, Shuang 1 ; Sinha, Vishal 1 ; Gracia-Tabuenca, Javier 69 ; Helminen, Mika 69 ; Luukkaala, Tiina 69 ; Vähätalo, Iida 69 ; Jyrhämä, Tero 1 ; Hautalahti, Marco 74 ; Mustaniemi, Laura 74 ; Koivusalo, Mirkka 74 ; Smith, Sarah 74 ; Southerington, Tom 74 ; Widen, Elisabeth 1 ; Daly, Mark J. 75 

1  University of Helsinki, Institute for Molecular Medicine Finland (FIMM), HiLIFE, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071) 
2  University of Michigan, Department of Internal Medicine, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370) 
3  The Broad Institute of MIT and Harvard, Cambridge, USA (GRID:grid.66859.34) (ISNI:0000 0004 0546 1623) 
4  The Broad Institute of MIT and Harvard, Cambridge, USA (GRID:grid.66859.34) (ISNI:0000 0004 0546 1623); Harvard Medical School, Analytic and Translational Genetics Unit, Masfsachusetts General Hospital, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Osaka University Graduate School of Medicine, Department of Statistical Genetics, Suita, Japan (GRID:grid.136593.b) (ISNI:0000 0004 0373 3971) 
5  University of Tartu, Estonian Genome Centre, Institute of Genomics, Tartu, Estonia (GRID:grid.10939.32) (ISNI:0000 0001 0943 7661) 
6  Tampere University, Department of Clinical Chemistry, Faculty of Medicine and Health Technology, Tampere, Finland (GRID:grid.502801.e) (ISNI:0000 0001 2314 6254); Tampere University, Finnish Cardiovascular Research Centre, Faculty of Medicine and Health Technology, Tampere, Finland (GRID:grid.502801.e) (ISNI:0000 0001 2314 6254); Fimlab Laboratories, Department of Clinical Chemistry, Tampere, Finland (GRID:grid.511163.1) (ISNI:0000 0004 0518 4910) 
7  Helsinki University Hospital and Helsinki University, Heart and Lung Center, Helsinki, Finland (GRID:grid.15485.3d) (ISNI:0000 0000 9950 5666) 
8  University of Helsinki, Institute for Molecular Medicine Finland (FIMM), HiLIFE, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071); University of Tartu, Estonian Genome Centre, Institute of Genomics, Tartu, Estonia (GRID:grid.10939.32) (ISNI:0000 0001 0943 7661) 
9  University of Turku, Research Centre of Applied and Preventive Cardiovascular Medicine, Turku, Finland (GRID:grid.1374.1) (ISNI:0000 0001 2097 1371); University of Turku, Turku University Hospital, Centre for Population Health Research, Turku, Finland (GRID:grid.1374.1) (ISNI:0000 0001 2097 1371); University of Turku, Department of Clinical Physiology and Nuclear Medicine, Turku, Finland (GRID:grid.1374.1) (ISNI:0000 0001 2097 1371) 
10  The University of Tokyo, Laboratory of Genome Technology, Human Genome Center, Institute of Medical Science, Tokyo, Japan (GRID:grid.26999.3d) (ISNI:0000 0001 2151 536X); The University of Tokyo, Laboratory of Clinical Genome Sequencing, Graduate School of Frontier Sciences, Tokyo, Japan (GRID:grid.26999.3d) (ISNI:0000 0001 2151 536X) 
11  The University of Tokyo, Division of Genetics, The Institute of Medical Science, Tokyo, Japan (GRID:grid.26999.3d) (ISNI:0000 0001 2151 536X) 
12  The University of Tokyo, Division of Molecular Pathology, IMSUT Hospital Department of Internal Medicine, Institute of Medical Science, Tokyo, Japan (GRID:grid.26999.3d) (ISNI:0000 0001 2151 536X) 
13  The University of Tokyo, Department of Cancer Biology, Institute of Medical Science, Tokyo, Japan (GRID:grid.26999.3d) (ISNI:0000 0001 2151 536X) 
14  The University of Tokyo, Laboratory of Clinical Genome Sequencing, Graduate School of Frontier Sciences, Tokyo, Japan (GRID:grid.26999.3d) (ISNI:0000 0001 2151 536X); The University of Tokyo, Laboratory of Complex Trait Genomics, Graduate School of Frontier Sciences, Tokyo, Japan (GRID:grid.26999.3d) (ISNI:0000 0001 2151 536X) 
15  The University of Tokyo, Department of Public Policy, Institute of Medical Science, Tokyo, Japan (GRID:grid.26999.3d) (ISNI:0000 0001 2151 536X) 
16  Iwate Medical University, Department of Urology, Iwate, Japan (GRID:grid.411790.a) (ISNI:0000 0000 9613 6383) 
17  Juntendo University Graduate School of Medicine, Department of Internal Medicine and Rheumatology, Tokyo, Japan (GRID:grid.258269.2) (ISNI:0000 0004 1762 2738) 
18  Juntendo University Graduate School of Medicine, Department of Respiratory Medicine, Tokyo, Japan (GRID:grid.258269.2) (ISNI:0000 0004 1762 2738) 
19  Nihon University School of Medicine, Division of Pharmacology, Department of Biomedical Science, Tokyo, Japan (GRID:grid.260969.2) (ISNI:0000 0001 2149 8846); Clinical Trials Research Center, Nihon University. School of Medicine, Division of Genomic Epidemiology and Clinical Trials, Tokyo, Japan (GRID:grid.260969.2) (ISNI:0000 0001 2149 8846) 
20  Clinical Trials Research Center, Nihon University. School of Medicine, Division of Genomic Epidemiology and Clinical Trials, Tokyo, Japan (GRID:grid.260969.2) (ISNI:0000 0001 2149 8846) 
21  Tokushukai Group, Tokyo, Japan (GRID:grid.260969.2) 
22  Nippon Medical School, Departmentof Hematology, Tokyo, Japan (GRID:grid.410821.e) (ISNI:0000 0001 2173 8328) 
23  Nippon Medical School, Department of Bioregulation, Kawasaki, Japan (GRID:grid.410821.e) (ISNI:0000 0001 2173 8328) 
24  Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan (GRID:grid.417092.9) 
25  Japan Anti-Tuberculosis Association, Fukujuji Hospital, Tokyo, Japan (GRID:grid.419151.9) (ISNI:0000 0001 1545 6914) 
26  The Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan (GRID:grid.410807.a) (ISNI:0000 0001 0037 4131) 
27  Shiga University of Medical Science, Center for Clinical Research and Advanced Medicine, Shiga, Japan (GRID:grid.410827.8) (ISNI:0000 0000 9747 6806) 
28  Osaka International Cancer Institute, Department of General Thoracic Surgery, Osaka, Japan (GRID:grid.489169.b) (ISNI:0000 0004 8511 4444) 
29  IIZUKA HOSPITAL, Fukuoka, Japan (GRID:grid.413984.3) 
30  National Hospital Organization Osaka National Hospital, Osaka, Japan (GRID:grid.416803.8) (ISNI:0000 0004 0377 7966) 
31  Osaka University Graduate School of Medicine, Department of Statistical Genetics, Suita, Japan (GRID:grid.136593.b) (ISNI:0000 0004 0373 3971); RIKEN Center for Integrative Medical Sciences, Laboratory for Statistical Analysis, Yokohama, Japan (GRID:grid.509459.4) (ISNI:0000 0004 0472 0267) 
32  Abbvie, Chicago, USA (GRID:grid.431072.3) (ISNI:0000 0004 0572 4227) 
33  Astra Zeneca, Cambridge, UK (GRID:grid.417815.e) (ISNI:0000 0004 5929 4381) 
34  Biogen, Cambridge, USA (GRID:grid.417832.b) (ISNI:0000 0004 0384 8146) 
35  Celgene, Summit, NJ, United States/Bristol Myers Squibb, New York, USA (GRID:grid.419971.3) (ISNI:0000 0004 0374 8313) 
36  Genentech, San Francisco, USA (GRID:grid.418158.1) (ISNI:0000 0004 0534 4718) 
37  GlaxoSmithKline, Brentford, UK (GRID:grid.418236.a) (ISNI:0000 0001 2162 0389) 
38  Merck, Kenilworth, USA (GRID:grid.417993.1) (ISNI:0000 0001 2260 0793) 
39  Pfizer, New York, USA (GRID:grid.410513.2) (ISNI:0000 0000 8800 7493) 
40  Sanofi, Paris, France (GRID:grid.417924.d) 
41  Maze Therapeutics, San Francisco, USA (GRID:grid.511646.1) (ISNI:0000 0004 7480 276X) 
42  Janssen Biotech, Beerse, Belgium (GRID:grid.511646.1) 
43  Novartis, Basel, Switzerland (GRID:grid.419481.1) (ISNI:0000 0001 1515 9979) 
44  HiLIFE, University of Helsinki, Finland, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071) 
45  Auria Biobank/University of Turku/Hospital District of Southwest Finland, Turku, Finland (GRID:grid.1374.1) (ISNI:0000 0001 2097 1371) 
46  THL Biobank/The National Institute of Health and Welfare Helsinki, Helsinki, Finland (GRID:grid.14758.3f) (ISNI:0000 0001 1013 0499) 
47  Finnish Red Cross Blood Service/Finnish Hematology Registry and Clinical Biobank, Helsinki, Finland (GRID:grid.452433.7) (ISNI:0000 0000 9387 9501) 
48  Helsinki Biobank/Helsinki University and Hospital District of Helsinki and Uusimaa, Helsinki, Finland (GRID:grid.424664.6) (ISNI:0000 0004 0410 2290) 
49  Northern Finland Biobank Borealis/University of Oulu/Northern Ostrobothnia Hospital District, Oulu, Finland (GRID:grid.10858.34) (ISNI:0000 0001 0941 4873) 
50  Finnish Clinical Biobank Tampere/University of Tampere/Pirkanmaa Hospital District, Tampere, Finland (GRID:grid.502801.e) (ISNI:0000 0001 2314 6254) 
51  Biobank of Eastern Finland/University of Eastern Finland/Northern Savo Hospital District, Kuopio, Finland (GRID:grid.9668.1) (ISNI:0000 0001 0726 2490) 
52  Central Finland Biobank/University of Jyväskylä/Central Finland Health Care District, Jyväskylä, Finland (GRID:grid.9681.6) (ISNI:0000 0001 1013 7965) 
53  Business Finland, Helsinki, Finland (GRID:grid.511030.6) 
54  Northern Savo Hospital District, Kuopio, Finland (GRID:grid.9681.6) 
55  Northern Ostrobothnia Hospital District, Oulu, Finland (GRID:grid.437577.5) (ISNI:0000 0004 0450 6025) 
56  Northern Savo Hospital District, Kuopio, Finland (GRID:grid.437577.5) 
57  Pirkanmaa Hospital District, Tampere, Finland (GRID:grid.415018.9) (ISNI:0000 0004 0472 1956) 
58  Hospital District of Helsinki and Uusimaa, Helsinki, Finland (GRID:grid.424664.6) (ISNI:0000 0004 0410 2290) 
59  Hospital District of Southwest Finland, Turku, Finland (GRID:grid.426612.5) (ISNI:0000 0004 0366 9623) 
60  Northern Savo Hospital District, Kuopio, Finland (GRID:grid.426612.5) 
61  Northern Savo Hospital District, Kuopio, Finland (GRID:grid.415018.9) 
62  The National Institute of Health and Welfare Helsinki, Helsinki, Finland (GRID:grid.14758.3f) (ISNI:0000 0001 1013 0499) 
63  University of Helsinki, Institute for Molecular Medicine Finland (FIMM), HiLIFE, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071); The Broad Institute of MIT and Harvard, Cambridge, USA (GRID:grid.66859.34) (ISNI:0000 0004 0546 1623) 
64  Northern Savo Hospital District, Kuopio, Finland (GRID:grid.7737.4) 
65  Northern Savo Hospital District, Kuopio, Finland (GRID:grid.424664.6) 
66  University of Jyväskylä, Jyväskylä, Finland (GRID:grid.9681.6) (ISNI:0000 0001 1013 7965) 
67  University of Helsinki, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071) 
68  University of Stanford, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956) 
69  University of Tampere, Tampere, Finland (GRID:grid.502801.e) (ISNI:0000 0001 2314 6254) 
70  Finnish Red Cross Blood Service, Helsinki, Finland (GRID:grid.452433.7) (ISNI:0000 0000 9387 9501) 
71  University of Oulu, Oulu, Finland (GRID:grid.10858.34) (ISNI:0000 0001 0941 4873) 
72  University of Eastern Finland, Kuopio, Finland (GRID:grid.9668.1) (ISNI:0000 0001 0726 2490) 
73  University of Turku, Turku, Finland (GRID:grid.1374.1) (ISNI:0000 0001 2097 1371) 
74  Finnish Biobank Cooperative—FINBB, Helsinki, Finland (GRID:grid.7737.4) 
75  University of Helsinki, Institute for Molecular Medicine Finland (FIMM), HiLIFE, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071); The Broad Institute of MIT and Harvard, Cambridge, USA (GRID:grid.66859.34) (ISNI:0000 0004 0546 1623); Harvard Medical School, Analytic and Translational Genetics Unit, Masfsachusetts General Hospital, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
Publication year
2022
Publication date
2022
Publisher
Nature Publishing Group
e-ISSN
23993642
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s42003-022-03552-0
ProQuest document ID
2703236663
Copyright
© The Author(s) 2022. 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.