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Geographic variation and bias in polygenic scores of complex diseases and traits in Finland

View ORCID ProfileSini Kerminen, Alicia R. Martin, Jukka Koskela, Sanni E. Ruotsalainen, Aki S. Havulinna, Ida Surakka, Aarno Palotie, Markus Perola, Veikko Salomaa, Mark J. Daly, Samuli Ripatti, View ORCID ProfileMatti Pirinen
doi: https://doi.org/10.1101/485441
Sini Kerminen
Institute for Molecular Medicine Finland, Helsinki Institute of Life Sciences, University of Helsinki, Finland
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Alicia R. Martin
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, USAStanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, USAProgram in Medical and Population Genetics, Broad Institute, Cambridge, USA
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Jukka Koskela
Institute for Molecular Medicine Finland, Helsinki Institute of Life Sciences, University of Helsinki, Finland
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Sanni E. Ruotsalainen
Institute for Molecular Medicine Finland, Helsinki Institute of Life Sciences, University of Helsinki, Finland
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Aki S. Havulinna
Institute for Molecular Medicine Finland, Helsinki Institute of Life Sciences, University of Helsinki, FinlandNational Institute of Health and Welfare, Helsinki, Finland
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Ida Surakka
Institute for Molecular Medicine Finland, Helsinki Institute of Life Sciences, University of Helsinki, FinlandDepartment of Internal Medicine, University of Michigan, Ann Arbor, MI, US
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Aarno Palotie
Institute for Molecular Medicine Finland, Helsinki Institute of Life Sciences, University of Helsinki, FinlandAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, USAStanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, USAPsychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, USADepartment of Neurology, Massachusetts General Hospital, Boston, USA
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Markus Perola
Institute for Molecular Medicine Finland, Helsinki Institute of Life Sciences, University of Helsinki, FinlandNational Institute of Health and Welfare, Helsinki, Finland
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Veikko Salomaa
National Institute of Health and Welfare, Helsinki, Finland
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Mark J. Daly
Institute for Molecular Medicine Finland, Helsinki Institute of Life Sciences, University of Helsinki, FinlandAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, USAStanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, USAProgram in Medical and Population Genetics, Broad Institute, Cambridge, USA
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Samuli Ripatti
Institute for Molecular Medicine Finland, Helsinki Institute of Life Sciences, University of Helsinki, FinlandDepartment of Public Health, University of Helsinki, Helsinki, Finland
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Matti Pirinen
Institute for Molecular Medicine Finland, Helsinki Institute of Life Sciences, University of Helsinki, FinlandDepartment of Public Health, University of Helsinki, Helsinki, FinlandHelsinki Institute for Information Technology HIIT and Department of Mathematics and Statistics, University of Helsinki, Helsinki, Finland
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Abstract

Polygenic scores (PS) are becoming a useful tool to identify individuals with high genetic risk for complex diseases and several projects are currently testing their utility for translational applications. It is also tempting to use PS to assess whether genetic variation can explain a part of the geographic distribution of a phenotype. However, it is not well known how population genetic properties of the training and target samples affect the geographic distribution of PS. Here, we evaluate geographic differences, and related biases, of PS in Finland with geographically well-defined sample of 2,376 individuals from the National FINRISK study. First, we detect geographic differences in PS for coronary artery disease (CAD), rheumatoid arthritis, schizophrenia, waits-hip ratio (WHR), body-mass index (BMI) and height, but not for Crohn’s disease or ulcerative colitis. Second, we use height as a model trait to thoroughly assess the possible population genetic biases in PS and apply similar approaches to the other phenotypes. Most importantly, we detect suspiciously large accumulation of geographic differences for CAD, WHR, BMI and height, suggesting bias arising from population genetic structure rather than from a direct genotype-phenotype association. This work demonstrates how sensitive the geographic patterns of current PS are for small biases even within relatively homogenous populations and provides simple tools to identify such biases. A thorough understanding of the effects of population genetic structure on PS is essential for translational applications of PS.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted December 04, 2018.
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Geographic variation and bias in polygenic scores of complex diseases and traits in Finland
Sini Kerminen, Alicia R. Martin, Jukka Koskela, Sanni E. Ruotsalainen, Aki S. Havulinna, Ida Surakka, Aarno Palotie, Markus Perola, Veikko Salomaa, Mark J. Daly, Samuli Ripatti, Matti Pirinen
bioRxiv 485441; doi: https://doi.org/10.1101/485441
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Geographic variation and bias in polygenic scores of complex diseases and traits in Finland
Sini Kerminen, Alicia R. Martin, Jukka Koskela, Sanni E. Ruotsalainen, Aki S. Havulinna, Ida Surakka, Aarno Palotie, Markus Perola, Veikko Salomaa, Mark J. Daly, Samuli Ripatti, Matti Pirinen
bioRxiv 485441; doi: https://doi.org/10.1101/485441

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