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PreprintCited by 115Genetic Associations and EpidemiologyGenetic and phenotypic traits in livestockForensic and Genetic Research

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

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Kerminen, Sini, Martin, Alicia R., Koskela, Jukka, Ruotsalainen, Sanni E., Havulinna, Aki S., Surakka, Ida, Palotie, Aarno, Perola, Markus +4 more·2018·The American Journal of Human Genetics
DOI 10.1101/485441PMC PMC6562021

Preprint — published as 10.1016/j.ajhg.2019.05.001

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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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Cited by

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Authors
Kerminen, S., Martin, A. R., Koskela, J., Ruotsalainen, S. E., Havulinna, A. S., Surakka, I., Palotie, A., Perola, M., Salomaa, V., Daly, M. J., Ripatti, S., & Pirinen, M.
Affiliations
  • University of Helsinki (FI)
  • Broad Institute (US)
  • Finnish Institute for Health and Welfare (FI)
Corresponding author
Pirinen, Matti
ORCID
Venue
The American Journal of Human Genetics
Publisher
openRxiv
Published
2018-12-04
Volume
104
Issue
6
Pages
1169-1181
ISSN
0002-9297 (ISSN-L)
DOI
10.1101/485441
PMC
PMC6562021
OpenAlex
W2950577582
Cited by
115
References
1
Citations by year
2026: 5 · 2025: 8 · 2024: 16 · 2023: 10 · 2022: 18 · 2021: 25 · 2020: 21 · 2019: 11 · 2017: 1
FWCI
11.30
Type
journal article
Language
en
Open access
Locations
  • The American Journal of Human Genetics (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Työväentutkimus Vuosikirja (submittedVersion, other-oa)
Funders
  • Foundation for Cardiovascular Research
  • Helsingin Yliopisto
  • Academy of Finland (129680, 288509, 294050, 213506 and 129680, #213506, 139635, 285380, 251217)
  • Novo Nordisk
  • Sydäntutkimussäätiö
  • Sigrid Juséliuksen Säätiö
  • Terveyden ja hyvinvoinnin laitos
  • National Institutes of Health
  • National Institute of Mental Health (K99MH117229)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and phenotypic traits in livestock
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Forensic and Genetic Research
Keywords
polygenic risk score, regional variation, population structure, complex diseases, coronary artery disease, rheumatoid arthritis, schizophrenia, Crohn's disease, ulcerative colitis, waist-to-hip ratio, body mass index, height, FINRISK Study, Finnish population
MeSH terms
Adult, Aged, Arthritis, Rheumatoid, Colitis, Ulcerative, Coronary Artery Disease, Crohn Disease, Female, Finland, Genetic Markers, Genetics, Population, Geography, Humans, Male, Middle Aged, Risk Factors, Schizophrenia, Body Mass Index, Quantitative Trait, Heritable, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Waist-Hip Ratio, Genetic Association Studies

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