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Polygenic and clinical risk scores and their impact on age at onset and prediction of cardiometabolic diseases and common cancers

Nature Medicine volume 26, pages 549–557 (2020)Cite this article

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Abstract

Polygenic risk scores (PRSs) have shown promise in predicting susceptibility to common diseases1,2,3. We estimated their added value in clinical risk prediction of five common diseases, using large-scale biobank data (FinnGen; n = 135,300) and the FINRISK study with clinical risk factors to test genome-wide PRSs for coronary heart disease, type 2 diabetes, atrial fibrillation, breast cancer and prostate cancer. We evaluated the lifetime risk at different PRS levels, and the impact on disease onset and on prediction together with clinical risk scores. Compared to having an average PRS, having a high PRS contributed 21% to 38% higher lifetime risk, and 4 to 9 years earlier disease onset. PRSs improved model discrimination over age and sex in type 2 diabetes, atrial fibrillation, breast cancer and prostate cancer, and over clinical risk in type 2 diabetes, breast cancer and prostate cancer. In all diseases, PRSs improved reclassification over clinical thresholds, with the largest net reclassification improvements for early-onset coronary heart disease, atrial fibrillation and prostate cancer. This study provides evidence for the additional value of PRSs in clinical disease prediction. The practical applications of polygenic risk information for stratified screening or for guiding lifestyle and medical interventions in the clinical setting remain to be defined in further studies.

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Fig. 1: Adjusted survival curves from Cox proportional hazards models showing the cumulative risk of disease by PRS category in FinnGen (n = 135,300 individuals).
Fig. 2: The proportions of early- and late-onset cases with high clinical risk, high polygenic risk or neither.

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Data availability

The FinnGen data may be accessed through Finnish Biobanks’ FinnBB portal (www.finbb.fi) and THL Biobank data may be accessed through THL Biobank (https://thl.fi/en/web/thl-biobank).

Code availability

The full genotyping and imputation protocol for FinnGen is described at https://doi.org/10.17504/protocols.io.nmndc5e.

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Acknowledgements

We thank S. Kivikko, H.-Y. Shen and U. Tuomainen for management assistance. The FINRISK analyses were conducted using the THL biobank permission for project BB2015_55.1. The FINRISK data used for the research were obtained from THL Biobank. For the Finnish Institute of Health and Welfare (THL)-driven FinnGen preparatory project (here called FinnGen), all patients and control subjects had provided informed consent for biobank research, based on the Finnish Biobank Act. Alternatively, older cohorts were based on study-specific consents and later transferred to the THL Biobank after approval by Valvira, the National Supervisory Authority for Welfare and Health. Recruitment protocols followed the biobank protocols approved by Valvira. The Ethics Review Board of the Hospital District of Helsinki and Uusimaa approved the FinnGen study protocol no. HUS/990/2017. The FinnGen preparatory project is approved by THL, approval number THL/2031/6.02.00/2017, amendments THL/341/6.02.00/2018, THL/2222/6.02.00/2018 and THL/283/6.02.00/2019. The following biobanks are acknowledged for collecting the FinnGen project samples: Auria Biobank (https://www.auria.fi/biopankki/en), THL Biobank (https://thl.fi/fi/web/thl-biopankki), Helsinki Biobank (https://www.terveyskyla.fi/helsinginbiopankki/en), Northern Finland Biobank Borealis (https://www.ppshp.fi/Tutkimus-ja-opetus/Biopankki), Finnish Clinical Biobank Tampere (https://www.tays.fi/en-US/Research_and_development/Finnish_Clinical_Biobank_Tampere), Biobank of Eastern Finland (https://ita-suomenbiopankki.fi/), Central Finland Biobank (https://www.ksshp.fi/fi-FI/Potilaalle/Biopankki), Finnish Red Cross Blood Service Biobank (https://www.bloodservice.fi/Research%20Projects/biobanking). We thank all study participants for their generous participation in FINRISK and FinnGen. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was supported by the Finnish Foundation for Cardiovascular Research (to S.R., V.S. and A.P.); Sigrid Jusélius Foundation (to S.R. and A.P.); University of Helsinki HiLIFE Fellow grants 2017–2020 (to S.R.); Academy of Finland Center of Excellence in Complex Disease Genetics (grant number 312062 to S.R., 312074 to A.P., 312075 to M.D.); Academy of Finland (grant number 285380 to S.R., 128650 to A.P.); The Finnish Innovation Fund Tekes (grant number 2273/31/2017 to E.W.); Horizon 2020 Research and Innovation Programme (grant number 667301 (COSYN) to A.P.); Ida Montin Foundation (to P.R.); Doctoral Programme in Population Health, University of Helsinki (to P.R.); and Emil Aaltonen Foundation (to P.R.). The FinnGen project is funded by two grants from Business Finland (HUS 4685/31/2016 and UH 4386/31/2016) and nine industry partners (AbbVie, AstraZeneca, Biogen, Celgene, Genentech, GSK, MSD, Pfizer and Sanofi). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Author information

Authors and Affiliations

  1. Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, Helsinki, Finland

    Nina Mars, Jukka T. Koskela, Pietari Ripatti, Tuomo T. J. Kiiskinen, Aki S. Havulinna, Ari Ahola-Olli, Mitja Kurki, Juha Karjalainen, Priit Palta, Mark Daly, Aarno Palotie, Elisabeth Widén & Samuli Ripatti

  2. Finnish Institute for Health and Welfare, Helsinki, Finland

    Aki S. Havulinna, Veikko Salomaa, Teemu Niiranen & Veikko Salomaa

  3. Department of Public Health, Clinicum, University of Helsinki, Helsinki, Finland

    Joni V. Lindbohm & Samuli Ripatti

  4. Program in Medical and Population Genetics and Genetic Analysis Platform, Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Mitja Kurki & Benjamin M. Neale

  5. Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry, Analytic and Translational Genetics Unit, Department of Medicine, and the Department of Neurology, Massachusetts General Hospital, Boston, MA, USA

    Mitja Kurki & Aarno Palotie

  6. Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA

    Juha Karjalainen, Mark Daly, Aarno Palotie & Samuli Ripatti

  7. Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Juha Karjalainen & Benjamin M. Neale

  8. Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia

    Priit Palta

  9. Institute for Molecular Medicine Finland, HiLIFE, University of Helsinki, Helsinki, Finland

    Aarno Palotie, Mark Daly, Jaakko Kaprio, Samuli Ripatti, Nina Mars, Anu Jalanko, Risto Kajanne, Ulrike Lyhs, Mari Kaunisto, Mitja Kurki, Samuli Ripatti, Mark Daly, Juha Karjalainen, Aki Havulinna, Anu Jalanko, Priit Palta, Pietro Della Briotta Parolo, Susanna Lemmelä, Jarmo Harju, Aarno Palotie, Arto Lehisto, Andrea Ganna, Vincent Llorens, Susanna Lemmelä, Kati Donner, Priit Palta, Kalle Pärn, Javier Nunez-Fontarnau, Jarmo Harju, Elina Kilpeläinen, Timo P. Sipilä, Georg Brein, Alexander Dada, Ghazal Awaisa, Anastasia Shcherban, Tuomas Sipilä, Hannele Laivuori, Aki Havulinna, Susanna Lemmelä & Tuomo Kiiskinen

  10. Abbvie, Chicago, IL, USA

    Howard Jacob, Jeff Waring, Bridget Riley-Gillis, Adam Ziemann, Jeffrey Waring, Sahar Esmaeeli, Nizar Smaoui, Anne Lehtonen, Bob Georgantas, Graham Heap, Jeffrey Waring, Nizar Smaoui, Fedik Rahimov, Anne Lehtonen, Bob Georgantas, Jeffrey Waring, Fedik Rahimov, Apinya Lertratanakul, Nizar Smaoui, Anne Lehtonen, Nizar Smaoui, Relja Popovic, Jeffrey Waring, Bridget Riley-Gillis, Anne Lehtonen, Nizar Smaoui, Fedik Rahimov, Anne Lehtonen, Justin Wade Davis, Bridget Riley-Gillis & Danjuma Quarless

  11. Astra Zeneca, Cambridge, UK

    Athena Matakidou, Athena Matakidou, David Close, David Close, Ben Challis, Athena Matakidou & Slavé Petrovski

  12. Biogen, Cambridge, MA, USA

    Heiko Runz, Sally John, Heiko Runz, Jimmy Liu, Susan Eaton, Heiko Runz, Sanni Lahdenperä, Heiko Runz, Jimmy Liu, Chia-Yen Chen & Paola Bronson

  13. Celgene, Summit, NJ, USA

    Robert Plenge, Shameek Biswas, Shameek Biswas, Keith Usiskin, Joseph Maranville, Marla Hochfeld, Steven Greenberg, Robert Yang, Joseph Maranville & Shameek Biswas

  14. Genentech, San Francisco, CA, USA

    Mark McCarthy, Julie Hunkapiller, Julie Hunkapiller, John Michon, Geoff Kerchner, Julie Hunkapiller, Natalie Bowers, Edmond Teng, Tim Lu, Natalie Bowers, Danny Oh, John Michon, Natalie Bowers, John Michon, Hubert Chen, Natalie Bowers, John Michon, Andrew Peterson, Julie Hunkapiller, Natalie Bowers, John Michon, Jennifer Schutzman, Julie Hunkapiller, Natalie Bowers, John Michon, Erich Strauss, Natalie Bowers, Hao Chen, John Michon, David Choy, John Michon, Diana Chang, Julie Hunkapiller, Tushar Bhangale & Natalie Bowers

  15. GlaxoSmithKline, Brentford, UK

    Meg Ehm, Dawn Waterworth, Dawn Waterworth, Meg Ehm, Fanli Xu, David Pulford, Linda McCarthy, Jorge Esparza Gordillo, Jo Betts, Soumitra Ghosh, Dawn Waterworth, Diptee Kulkarni, Joshua Hoffman, Dawn Waterworth & Kirsi Auro

  16. Merck, Kenilworth, NJ, USA

    Caroline Fox, Dorothee Diogo, Caroline Fox, John Eicher, Vinay Mehta, Padhraig Gormley, Vinay Mehta, Dorothee Diogo, Vinay Mehta, Vinay Mehta, Dorothee Diogo, Audrey Chu, Vinay Mehta, Vinay Mehta, Andrey Loboda, Aparna Chhibber, Anna Podgornaia, Vinay Mehta, Dorothee Diogo, Dorothee Diogo, Emily Holzinger, Padhraig Gormley & Xulong Wang

  17. Pfizer, New York, NY, USA

    Anders Malarstig, Anders Malarstig, Catherine Marshall, Xinli Hu, Kari Linden, Christopher Whelan, Kirsi Kalpala, Melissa Miller, Xinli Hu, Kirsi Kalpala, Nan Bing, Xinli Hu, Jaakko Parkkinen, Melissa Miller, Heli Lehtonen, Stefan McDonough, Kirsi Kalpala, Ying Wu, Xing Chen & Åsa Hedman

  18. Sanofi, Paris, France

    Kathy Klinger, Kathy Call, Kathy Call, Kathy Klinger, Matthias Gossel, Anthony Muslin, Marika Crohns, Clarence Wang, Ethan Xu, Franck Auge & Clement Chatelain

  19. HiLIFE, University of Helsinki, Helsinki, Finland

    Tomi Mäkelä

  20. Auria Biobank, Univ. of Turku, Hospital District of Southwest Finland, Turku, Finland

    Petri Virolainen, Kari Pulkki, Johanna Schleutker & Antti Karlsson

  21. THL Biobank, Finnish Institute for Health and Welfare, Helsinki, Finland

    Terhi Kilpi, Markus Perola, Markus Perola, Kati Kristiansson, Päivi Laiho, Tuuli Sistonen, Essi Kaiharju, Markku Laukkanen, Elina Järvensivu, Sini Lähteenmäki, Lotta Männikkö, Regis Wong, Kati Kristiansson, Hannele Mattsson, Tero Hiekkalinna & Manuel González Jiménez

  22. Finnish Red Cross Blood Service, Finnish Hematology Registry and Clinical Biobank, Helsinki, Finland

    Jukka Partanen, Mikko Arvas, Mikko Arvas, Kati Hyvärinen, Jarmo Ritari & Tiina Wahlfors

  23. Hospital District of Helsinki and Uusimaa, Helsinki, Finland

    Anne Pitkäranta, Olli Carpen, Pentti Tienari, Martti Färkkilä, Sampsa Pikkarainen, Kari Eklund, Paula Kauppi, Juha Sinisalo, Marja-Riitta Taskinen, Tiinamaija Tuomi, Heikki Joensuu, Tuomo Meretoja, Olli Carpen, Lauri Aaltonen, Joni Turunen, Terhi Ollila, Sanna Seitsonen, Katariina Hannula-Jouppi, Miika Koskinen, Olli Carpen & Anu Loukola

  24. Northern Finland Biobank Borealis, University of Oulu, Northern Ostrobothnia Hospital District, Oulu, Finland

    Riitta Kaarteenaho, Seppo Vainio, Reetta Hinttala, Johannes Kettunen, Johannes Kettunen, Katri Pylkäs, Marita Kalaoja, Minna Karjalainen & Tuomo Mantere

  25. Finnish Clinical Biobank Tampere, University of Tampere, Pirkanmaa Hospital District, Tampere, Finland

    Kimmo Savinainen, Reijo Laaksonen & Eeva Kangasniemi

  26. Biobank of Eastern Finland, University of Eastern Finland, Northern Savo Hospital District, Kuopio, Finland

    Veli-Matti Kosma, Arto Mannermaa, Sami Heikkinen & Arto Mannermaa

  27. Central Finland Biobank, University of Jyväskylä, Central Finland Health Care District, Jyväskylä, Finland

    Urho Kujala, Juha Paloneva, Urho Kujala, Eija Laakkonen & Juha Kononen

  28. Business Finland, Helsinki, Finland

    Outi Tuovila, Minna Hendolin, Raimo Pakkanen, Outi Tuovila, Minna Hendolin & Raimo Pakkanen

  29. Northern Savo Hospital District, Kuopio, Finland

    Hilkka Soininen, Valtteri Julkunen, Reetta Kälviäinen, Mikko Hiltunen, Mikko Kiviniemi, Oili Kaipiainen-Seppänen, Margit Pelkonen, Markku Laakso, Jussi Pihlajamäki, Päivi Auvinen, Kai Kaarniranta & Ilkka Harvima

  30. Northern Ostrobothnia Hospital District, Oulu, Finland

    Anne Remes, Timo Blomster, Johanna Huhtakangas, Terttu Harju, Juhani Junttila, Peeter Karihtala, Saila Kauppila, Marja Luodonpää, Nina Hautala, Kaisa Tasanen & Laura Huilaja

  31. Pirkanmaa Hospital District, Tampere, Finland

    Jukka Peltola, Airi Jussila, Pia Isomäki, Tarja Laitinen, Hannu Kankaanranta, Mika Kähönen, Hannu Uusitalo, Hannele Uusitalo-Järvinen, Teea Salmi & Tarja Laitinen

  32. Hospital District of Southwest Finland, Turku, Finland

    Juha Rinne, Markku Voutilainen, Antti Palomäki, Laura Pirilä, Markus Juonala, Kaj Metsärinne, Klaus Elenius, Vesa Aaltonen, Sirkku Peltonen & Leena Koulu

  33. Central Finland Health Care District, Jyväskylä, Finland

    Jari Laukkanen

  34. Pirkanmaa Hospital District, Tampere, Finland

    Annika Auranen

  35. Broad Institute, Cambridge, MA, USA

    Mitja Kurki, Juha Karjalainen & Wei Zhou

  36. University of Helsinki, Helsinki, Finland

    Kimmo Palin

  37. University of Stanford, Stanford, CA, USA

    Manuel Rivas

  38. University of Tampere, Tampere, Finland

    Harri Siirtola & Javier Gracia Tabuenca

  39. Auria Biobank, Turku, Finland

    Lila Kallio

  40. THL Biobank, Helsinki, Finland

    Sirpa Soini

  41. Blood Service Biobank, Helsinki, Finland

    Jukka Partanen

  42. Helsinki Biobank, Helsinki, Finland

    Miika Koskinen, Olli Carpen & Kimmo Pitkänen

  43. Northern Finland Biobank Borealis, Oulu, Finland

    Seppo Vainio

  44. Tampere Biobank, Tampere, Finland

    Kimmo Savinainen

  45. Biobank of Eastern Finland, Kuopio, Finland

    Veli-Matti Kosma

  46. Central Finland Biobank, Jyväskylä, Finland

    Teijo Kuopio

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  1. Nina Mars
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Consortia

FinnGen

  • Steering Committee

    • Aarno Palotie
    •  & Mark Daly

  • Pharmaceutical companies

    • Howard Jacob
    • , Athena Matakidou
    • , Heiko Runz
    • , Sally John
    • , Robert Plenge
    • , Mark McCarthy
    • , Julie Hunkapiller
    • , Meg Ehm
    • , Dawn Waterworth
    • , Caroline Fox
    • , Anders Malarstig
    • , Kathy Klinger
    •  & Kathy Call

  • University of Helsinki and biobanks

    • Tomi Mäkelä
    • , Jaakko Kaprio
    • , Petri Virolainen
    • , Kari Pulkki
    • , Terhi Kilpi
    • , Markus Perola
    • , Jukka Partanen
    • , Anne Pitkäranta
    • , Riitta Kaarteenaho
    • , Seppo Vainio
    • , Kimmo Savinainen
    • , Veli-Matti Kosma
    •  & Urho Kujala

  • Other experts/non-voting members

    • Outi Tuovila
    • , Minna Hendolin
    •  & Raimo Pakkanen
  • , Scientific Committee

  • Pharmaceutical companies

    • Jeff Waring
    • , Bridget Riley-Gillis
    • , Athena Matakidou
    • , Heiko Runz
    • , Jimmy Liu
    • , Shameek Biswas
    • , Julie Hunkapiller
    • , Dawn Waterworth
    • , Meg Ehm
    • , Dorothee Diogo
    • , Caroline Fox
    • , Anders Malarstig
    • , Catherine Marshall
    • , Xinli Hu
    • , Kathy Call
    • , Kathy Klinger
    •  & Matthias Gossel

  • University of Helsinki and biobanks

    • Samuli Ripatti
    • , Johanna Schleutker
    • , Markus Perola
    • , Mikko Arvas
    • , Olli Carpen
    • , Reetta Hinttala
    • , Johannes Kettunen
    • , Reijo Laaksonen
    • , Arto Mannermaa
    • , Juha Paloneva
    •  & Urho Kujala

  • Other experts/non-voting members

    • Outi Tuovila
    • , Minna Hendolin
    •  & Raimo Pakkanen

  • Clinical Groups

    • Neurology Group

      • Hilkka Soininen
      • , Valtteri Julkunen
      • , Anne Remes
      • , Reetta Kälviäinen
      • , Mikko Hiltunen
      • , Jukka Peltola
      • , Pentti Tienari
      • , Juha Rinne
      • , Adam Ziemann
      • , Jeffrey Waring
      • , Sahar Esmaeeli
      • , Nizar Smaoui
      • , Anne Lehtonen
      • , Susan Eaton
      • , Heiko Runz
      • , Sanni Lahdenperä
      • , Shameek Biswas
      • , John Michon
      • , Geoff Kerchner
      • , Julie Hunkapiller
      • , Natalie Bowers
      • , Edmond Teng
      • , John Eicher
      • , Vinay Mehta
      • , Padhraig Gormley
      • , Kari Linden
      • , Christopher Whelan
      • , Fanli Xu
      •  & David Pulford

    • Gastroenterology Group

      • Martti Färkkilä
      • , Sampsa Pikkarainen
      • , Airi Jussila
      • , Timo Blomster
      • , Mikko Kiviniemi
      • , Markku Voutilainen
      • , Bob Georgantas
      • , Graham Heap
      • , Jeffrey Waring
      • , Nizar Smaoui
      • , Fedik Rahimov
      • , Anne Lehtonen
      • , Keith Usiskin
      • , Joseph Maranville
      • , Tim Lu
      • , Natalie Bowers
      • , Danny Oh
      • , John Michon
      • , Vinay Mehta
      • , Kirsi Kalpala
      • , Melissa Miller
      • , Xinli Hu
      •  & Linda McCarthy

    • Rheumatology Group

      • Kari Eklund
      • , Antti Palomäki
      • , Pia Isomäki
      • , Laura Pirilä
      • , Oili Kaipiainen-Seppänen
      • , Johanna Huhtakangas
      • , Bob Georgantas
      • , Jeffrey Waring
      • , Fedik Rahimov
      • , Apinya Lertratanakul
      • , Nizar Smaoui
      • , Anne Lehtonen
      • , David Close
      • , Marla Hochfeld
      • , Natalie Bowers
      • , John Michon
      • , Dorothee Diogo
      • , Vinay Mehta
      • , Kirsi Kalpala
      • , Nan Bing
      • , Xinli Hu
      • , Jorge Esparza Gordillo
      •  & Nina Mars

    • Pulmonology Group

      • Tarja Laitinen
      • , Margit Pelkonen
      • , Paula Kauppi
      • , Hannu Kankaanranta
      • , Terttu Harju
      • , Nizar Smaoui
      • , David Close
      • , Steven Greenberg
      • , Hubert Chen
      • , Natalie Bowers
      • , John Michon
      • , Vinay Mehta
      • , Jo Betts
      •  & Soumitra Ghosh

    • Cardiometabolic Diseases Group

      • Veikko Salomaa
      • , Teemu Niiranen
      • , Markus Juonala
      • , Kaj Metsärinne
      • , Mika Kähönen
      • , Juhani Junttila
      • , Markku Laakso
      • , Jussi Pihlajamäki
      • , Juha Sinisalo
      • , Marja-Riitta Taskinen
      • , Tiinamaija Tuomi
      • , Jari Laukkanen
      • , Ben Challis
      • , Andrew Peterson
      • , Julie Hunkapiller
      • , Natalie Bowers
      • , John Michon
      • , Dorothee Diogo
      • , Audrey Chu
      • , Vinay Mehta
      • , Jaakko Parkkinen
      • , Melissa Miller
      • , Anthony Muslin
      •  & Dawn Waterworth

    • Oncology Group

      • Heikki Joensuu
      • , Tuomo Meretoja
      • , Olli Carpen
      • , Lauri Aaltonen
      • , Annika Auranen
      • , Peeter Karihtala
      • , Saila Kauppila
      • , Päivi Auvinen
      • , Klaus Elenius
      • , Relja Popovic
      • , Jeffrey Waring
      • , Bridget Riley-Gillis
      • , Anne Lehtonen
      • , Athena Matakidou
      • , Jennifer Schutzman
      • , Julie Hunkapiller
      • , Natalie Bowers
      • , John Michon
      • , Vinay Mehta
      • , Andrey Loboda
      • , Aparna Chhibber
      • , Heli Lehtonen
      • , Stefan McDonough
      • , Marika Crohns
      •  & Diptee Kulkarni

    • Ophthalmology Group

      • Kai Kaarniranta
      • , Joni Turunen
      • , Terhi Ollila
      • , Sanna Seitsonen
      • , Hannu Uusitalo
      • , Vesa Aaltonen
      • , Hannele Uusitalo-Järvinen
      • , Marja Luodonpää
      • , Nina Hautala
      • , Heiko Runz
      • , Erich Strauss
      • , Natalie Bowers
      • , Hao Chen
      • , John Michon
      • , Anna Podgornaia
      • , Vinay Mehta
      • , Dorothee Diogo
      •  & Joshua Hoffman

    • Dermatology Group

      • Kaisa Tasanen
      • , Laura Huilaja
      • , Katariina Hannula-Jouppi
      • , Teea Salmi
      • , Sirkku Peltonen
      • , Leena Koulu
      • , Ilkka Harvima
      • , Kirsi Kalpala
      • , Ying Wu
      • , David Choy
      • , John Michon
      • , Nizar Smaoui
      • , Fedik Rahimov
      • , Anne Lehtonen
      •  & Dawn Waterworth

  • FinnGen Teams

    • Administration Team

      • Anu Jalanko
      • , Risto Kajanne
      •  & Ulrike Lyhs

    • Communication

      • Mari Kaunisto

    • Analysis Team

      • Justin Wade Davis
      • , Bridget Riley-Gillis
      • , Danjuma Quarless
      • , Slavé Petrovski
      • , Jimmy Liu
      • , Chia-Yen Chen
      • , Paola Bronson
      • , Robert Yang
      • , Joseph Maranville
      • , Shameek Biswas
      • , Diana Chang
      • , Julie Hunkapiller
      • , Tushar Bhangale
      • , Natalie Bowers
      • , Dorothee Diogo
      • , Emily Holzinger
      • , Padhraig Gormley
      • , Xulong Wang
      • , Xing Chen
      • , Åsa Hedman
      • , Kirsi Auro
      • , Clarence Wang
      • , Ethan Xu
      • , Franck Auge
      • , Clement Chatelain
      • , Mitja Kurki
      • , Samuli Ripatti
      • , Mark Daly
      • , Juha Karjalainen
      • , Aki Havulinna
      • , Anu Jalanko
      • , Kimmo Palin
      • , Priit Palta
      • , Pietro Della Briotta Parolo
      • , Wei Zhou
      • , Susanna Lemmelä
      • , Manuel Rivas
      • , Jarmo Harju
      • , Aarno Palotie
      • , Arto Lehisto
      • , Andrea Ganna
      • , Vincent Llorens
      • , Antti Karlsson
      • , Kati Kristiansson
      • , Mikko Arvas
      • , Kati Hyvärinen
      • , Jarmo Ritari
      • , Tiina Wahlfors
      • , Miika Koskinen
      • , Olli Carpen
      • , Johannes Kettunen
      • , Katri Pylkäs
      • , Marita Kalaoja
      • , Minna Karjalainen
      • , Tuomo Mantere
      • , Eeva Kangasniemi
      • , Sami Heikkinen
      • , Arto Mannermaa
      • , Eija Laakkonen
      •  & Juha Kononen

    • Sample Collection Coordination

      • Anu Loukola

    • Sample Logistics

      • Päivi Laiho
      • , Tuuli Sistonen
      • , Essi Kaiharju
      • , Markku Laukkanen
      • , Elina Järvensivu
      • , Sini Lähteenmäki
      • , Lotta Männikkö
      •  & Regis Wong

    • Registry Data Operations

      • Kati Kristiansson
      • , Hannele Mattsson
      • , Susanna Lemmelä
      • , Tero Hiekkalinna
      •  & Manuel González Jiménez

    • Genotyping

      • Kati Donner

    • Sequencing Informatics

      • Priit Palta
      • , Kalle Pärn
      •  & Javier Nunez-Fontarnau

    • Data Management and IT Infrastructure

      • Jarmo Harju
      • , Elina Kilpeläinen
      • , Timo P. Sipilä
      • , Georg Brein
      • , Alexander Dada
      • , Ghazal Awaisa
      • , Anastasia Shcherban
      •  & Tuomas Sipilä

    • Clinical Endpoint Development

      • Hannele Laivuori
      • , Aki Havulinna
      • , Susanna Lemmelä
      •  & Tuomo Kiiskinen

    • Trajectory Team

      • Tarja Laitinen
      • , Harri Siirtola
      •  & Javier Gracia Tabuenca

    • Biobank Directors

      • Lila Kallio
      • , Sirpa Soini
      • , Jukka Partanen
      • , Kimmo Pitkänen
      • , Seppo Vainio
      • , Kimmo Savinainen
      • , Veli-Matti Kosma
      •  & Teijo Kuopio

Contributions

S.R. and N.M. conceived and designed the study. N.M. and P.R. carried out the statistical and computational analyses with advice from S.R., J.T.K., E.W., J.V.L., A.A.-O., M.D., V.S., B.M.N. and A.P. Quality control of the data was carried out by N.M., A.S.H., T.T.J.K., M.K., J.K. and P.P. The manuscript was written and revised by all of the co-authors. All co-authors have approved the final version of the manuscript.

Corresponding author

Correspondence to Samuli Ripatti.

Ethics declarations

Competing interests

A.P. is a member of the Pfizer Genetics Scientific Advisory Panel. V.S. has participated in a conference trip sponsored by Novo Nordisk and received an honorarium for participating in an advisory board meeting (unrelated to the present study). V.S. also has research collaboration with Bayer Ltd (unrelated to the present study). B.M.N. is a member of the scientific advisory board at Deep Genomics and a consultant for Camp4 Therapeutics, Takeda Pharmaceutical and Biogen.

Additional information

Peer review information Kate Gao was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Investigating goodness-of-fit by polygenic risk score deciles in FinnGen (n = 135,300). Y-axis represents the expected and observed risks in each decile.

Goodness-of-fit test for the Cox proportional hazards model with R package survMisc, following the methodology in May & Hosmer (2004).41 Error bars for the expected counts represent the 95% confidence intervals.

Extended Data Fig. 2 With any breast cancer as the outcome in FinnGen (n = 135,300), adjusted survival curves for estrogen receptor-specific polygenic risk scores (PRS).

The PRS for any breast cancer showed high correlation with the estrogen receptor-positive PRS (Pearson correlation r = 0.93) and moderate correlation with estrogen receptor-negative PRS (r = 0.54).

Extended Data Fig. 3 Difference in age at disease onset estimates across polygenic risk score categories in FinnGen (n = 135,300).

CHD = coronary heart disease, AF = atrial fibrillation or flutter, T2D = type 2 diabetes. The estimands are restricted mean survival times (RMST) for age at onset, and the error bars represent their 95% confidence intervals. Incident and prevalent cases included. All tests were two-tailed.

Extended Data Fig. 4 Difference in age at disease onset estimates by sex, across polygenic risk score categories (FinnGen, n = 135,300).

CHD = coronary heart disease, AF = atrial fibrillation or flutter, T2D = type 2 diabetes. The estimands are restricted mean survival times (RMST) for age at onset, and the error bars represent their 95% confidence intervals. Incident and prevalent cases included. All tests were two-tailed.

Extended Data Fig. 5 Correlation between polygenic and clinical risk.

PRS = polygenic risk score, CHD = coronary heart disease, AF = atrial fibrillation or flutter, T2D = type 2 diabetes. Sample size in FINRISK (CHD, n = 20,165; AF, n = 21,030; T2D n = 10,561) and in FinnGen (breast cancer, n = 37,841; prostate cancer n = 48,851), using respective incident disease cases and controls. Correlation was assessed with Pearson correlation.

Extended Data Fig. 6 Adjusted survival curves in FINRISK, showing cumulative risk of incident disease in by polygenic risk score (PRS) categories.

The FINRISK cohorts (total n = 21,813) comprised of 2,197 incident cases of CHD, 1,431 cases of AF, 2,516 cases of T2D, 404 cases of breast cancer, and 444 cases of prostate cancer. Only incident cases included.

Extended Data Fig. 7 Manhattan plot (A) and quantile-quantile plot (B) for the genome-wide association study (n = 408,961 from UK Biobank) for PheCode 411 (Ischemic heart disease) by Zhou et al.

For the GWAS, they used a generalized mixed model implemented in SAIGE.36 These summary statistics were used for constructing our polygenic risk score for coronary heart disease36.

Supplementary information

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Supplementary Tables 1–11.

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Mars, N., Koskela, J.T., Ripatti, P. et al. Polygenic and clinical risk scores and their impact on age at onset and prediction of cardiometabolic diseases and common cancers. Nat Med 26, 549–557 (2020). https://doi.org/10.1038/s41591-020-0800-0

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