Distribution and Medical Impact of Loss-of-Function Variants in the Finnish Founder Population
Open accessAbstract
Exome sequencing studies in complex diseases are challenged by the allelic heterogeneity, large number and modest effect sizes of associated variants on disease risk and the presence of large numbers of neutral variants, even in phenotypically relevant genes. Isolated populations with recent bottlenecks offer advantages for studying rare variants in complex diseases as they have deleterious variants that are present at higher frequencies as well as a substantial reduction in rare neutral variation. To explore the potential of the Finnish founder population for studying low-frequency (0.5-5%) variants in complex diseases, we compared exome sequence data on 3,000 Finns to the same number of non-Finnish Europeans and discovered that, despite having fewer variable sites overall, the average Finn has more low-frequency loss-of-function variants and complete gene knockouts. We then used several well-characterized Finnish population cohorts to study the phenotypic effects of 83 enriched loss-of-function variants across 60 phenotypes in 36,262 Finns. Using a deep set of quantitative traits collected on these cohorts, we show 5 associations (p<5×10⁻⁸) including splice variants in LPA that lowered plasma lipoprotein(a) levels (P = 1.5×10⁻¹¹⁷). Through accessing the national medical records of these participants, we evaluate the LPA finding via Mendelian randomization and confirm that these splice variants confer protection from cardiovascular disease (OR = 0.84, P = 3×10⁻⁴), demonstrating for the first time the correlation between very low levels of LPA in humans with potential therapeutic implications for cardiovascular diseases. More generally, this study articulates substantial advantages for studying the role of rare variation in complex phenotypes in founder populations like the Finns and by combining a unique population genetic history with data from large population cohorts and centralized research access to National Health Registers.
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Modest enrichment for homozygous predicted loss-of-function genotypes was shown in Finnish individuals.
“and modest enrichment for homozygous predicted LOF genotypes shown in Finnish individuals(4).”
From Health and population effects of rare gene knockouts in adult humans with related parents (2016) · cites this paper as [4]
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- Authors
- Lim, E. T., Würtz, P., Havulinna, A. S., Palta, P., Tukiainen, T., Rehnström, K., Esko, T., Mägi, R., Inouye, M., Lappalainen, T., Chan, Y., Salem, R. M., Lek, M., Flannick, J., Sim, X., Manning, A., Ladenvall, C., Bumpstead, S., Hämäläinen, E., Aalto, K., Maksimow, M., Salmi, M., Blankenberg, S., Ardissino, D., Shah, S., Horne, B., McPherson, R., Hovingh, G. K., Reilly, M. P., Watkins, H., Goel, A., Farrall, M., Girelli, D., Reiner, A. P., Stitziel, N. O., Kathiresan, S., Gabriel, S., Barrett, J. C., Lehtimäki, T., Laakso, M., Groop, L., Kaprio, J., Perola, M., McCarthy, M. I., Boehnke, M., Altshuler, D. M., Lindgren, C. M., Hirschhorn, J. N., Metspalu, A., Freimer, N. B., Zeller, T., Jalkanen, S., Koskinen, S., Raitakari, O., Durbin, R., MacArthur, D. G., Salomaa, V., Ripatti, S., Daly, M. J., Palotie, A., & for the Sequencing Initiative Suomi (SISu) Project
- Affiliations
- Broad Institute (US)
- University of Helsinki (FI)
- Finnish Institute for Health and Welfare (FI)
- Wellcome Sanger Institute (GB)
- University of Tartu (EE)
- The University of Melbourne (AU)
- Stanford University (US)
- University of Michigan (US)
- University of Turku (FI)
- Universität Hamburg (DE)
- Ospedale di Parma (IT)
- Duke Medical Center (US)
- Intermountain Healthcare (US)
- Ottawa Heart Institute (CA)
- Amsterdam UMC Location University of Amsterdam (NL)
- University of Pennsylvania (US)
- Centre for Human Genetics (GB)
- University of Verona (IT)
- University of Washington (US)
- Washington University in St. Louis (US)
- Massachusetts General Hospital (US)
- Tampere University (FI)
- University of Eastern Finland (FI)
- University of California, Los Angeles (US)
- Corresponding author
- Daly, Mark J.
- Palotie, Aarno
- ORCID
- Lim, Elaine T.
- Würtz, Peter
- Havulinna, Aki S.
- Palta, Priit
- Tukiainen, Taru
- Esko, Tõnu
- Mägi, Reedik
- Inouye, Michael
- Lappalainen, Tuuli
- Chan, Yingleong
- Salem, Rany M.
- Lek, Monkol
- Flannick, Jason
- Sim, Xueling
- Manning, Alisa
- Ladenvall, Claes
- Maksimow, Mikael
- Salmi, Marko
- Blankenberg, Stefan
- Ardissino, Diego
- Shah, Svati
- Horne, Benjamin
- McPherson, Ruth
- Reilly, Muredach P.
- Watkins, Hugh
- Goel, Anuj
- Farrall, Martin
- Girelli, Domenico
- Reiner, Alex P.
- Stitziel, Nathan O.
- Kathiresan, Sekar
- Gabriel, Stacey
- Barrett, Jeffrey C.
- Lehtimäki, Terho
- Laakso, Markku
- Groop, Leif
- Kaprio, Jaakko
- Perola, Markus
- McCarthy, Mark I.
- Boehnke, Michael
- Altshuler, David M.
- Lindgren, Cecilia M.
- Hirschhorn, Joel N.
- Metspalu, Andres
- Freimer, Nelson B.
- Zeller, Tanja
- Jalkanen, Sirpa
- Koskinen, Seppo
- Raitakari, Olli
- Durbin, Richard
- MacArthur, Daniel G.
- Salomaa, Veikko
- Ripatti, Samuli
- Daly, Mark J.
- Palotie, Aarno
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-07-31
- Volume
- 10
- Issue
- 7
- Pages
- e1004494
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC4117444
- OpenAlex
- W1584484141
- Cited by
- 49
- References
- 33
- Citations by year
- 2025: 3 · 2024: 4 · 2023: 6 · 2022: 7 · 2021: 7 · 2020: 4 · 2019: 5 · 2018: 5 · 2017: 5 · 2016: 3
- FWCI
- 1.75
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Tampere University Institutional Repository (Tampere University) (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by)
- Lund University Publications (Lund University) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Tampere University Institutional Repository (Tampere University) (submittedVersion)
- STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
- Apollo (cc-by)
- WOS
- Funders
- Foundation for Cardiovascular Research
- Wellcome Trust (139635, FP7/2007–2013, 251704, 090367, 261433, 085545, 098381, 086596, 086596/Z/08/Z, 201413, 242167)
- National Institute for Health and Care Research (NF-SI-0611-10099)
- European Commission (313010, 278913, 2007–2013, SF0180142s08, 265240, FP7 2007-2013, 261123, 261433, 201413, FP7/2007, 242167, 098381)
- Academy of Finland (263401, 263 278, 265 240, 141 054, 255847, 250422, 265240, 263278, 139635, 251217)
- Sydäntutkimussäätiö
- Tartu Ülikool (SP1GVARENG)
- National Institutes of Health (FP7/2007-2013, 5rc2dk088389-02, 1rc2hl103010-01, HEALTH-F2-2011, DK062370)
- Abbott Diagnostics
- Medical Research Council
- National Health and Medical Research Council (637400)
- European Regional Development Fund (FP7/2007‐2013, 2007 – 2013, 3.2.0304.11-0312)
- National Heart, Lung, and Blood Institute (HL 102923, RC2HL102925, HL-102924, HL-102925, RC2HL102926, RC2HL102923, UC2HL102924, RC2HL-103010, RFA-HL-12-007, UC2HL102925, HL 103010, R01HL113315, UC2HL102923, UC2HL103010, RC2HL102924, UC2HL102926, HL-102926)
- National Institute of Diabetes and Digestive and Kidney Diseases (U01DK085584, U01DK062370, RC2-DK088389, U01DK085545, R56DK062370, DK-085584, DK-062370, R01DK075787, P30DK020572, R01DK062370)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and phenotypic traits in livestock
- Keywords
- loss-of-function mutations, founder populations, Finnish population, low-frequency variants, rare variants, complex diseases, lipoprotein(a), cardiovascular disease, Mendelian randomization, gene knockout, population genetic history, exome sequencing
- MeSH terms
- Female, Finland, Gene Frequency, Genetics, Population, Humans, Male, Phenotype, Genetic Variation, Founder Effect, Genetic Diseases, Inborn, Genetic Drift, White People, Genome-Wide Association Study, Exome
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