Distribution and medical impact of loss-of-function variants in the Finnish founder population.
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Authors
Lim, Elaine T
Würtz, Peter
Havulinna, Aki S
Palta, Priit
Tukiainen, Taru
Rehnström, Karola
Esko, Tõnu
Mägi, Reedik
Lappalainen, Tuuli
Chan, Yingleong
Salem, Rany M
Lek, Monkol
Flannick, Jason
Sim, Xueling
Manning, Alisa
Ladenvall, Claes
Bumpstead, Suzannah
Hämäläinen, Eija
Aalto, Kristiina
Maksimow, Mikael
Salmi, Marko
Blankenberg, Stefan
Ardissino, Diego
Shah, Svati
Horne, Benjamin
McPherson, Ruth
Hovingh, Gerald K
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
MacArthur, Daniel G
Salomaa, Veikko
Ripatti, Samuli
Daly, Mark J
Palotie, Aarno
Sequencing Initiative Suomi (SISu) Project
Publication Date
2014-07Journal Title
PLoS Genet
ISSN
1553-7390
Publisher
Public Library of Science (PLoS)
Volume
10
Issue
7
Pages
e1004494
Language
eng
Type
Article
Physical Medium
Electronic-eCollection
Metadata
Show full item recordCitation
Lim, E. T., Würtz, P., Havulinna, A. S., Palta, P., Tukiainen, T., Rehnström, K., Esko, T., et al. (2014). Distribution and medical impact of loss-of-function variants in the Finnish founder population.. PLoS Genet, 10 (7), e1004494. https://doi.org/10.1371/journal.pgen.1004494
Abstract
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.
Keywords
Sequencing Initiative Suomi (SISu) Project, Humans, Genetic Diseases, Inborn, Genetics, Population, Founder Effect, Gene Frequency, Genetic Drift, Phenotype, European Continental Ancestry Group, Finland, Female, Male, Genetic Variation, Genome-Wide Association Study, Exome
Identifiers
External DOI: https://doi.org/10.1371/journal.pgen.1004494
This record's URL: https://www.repository.cam.ac.uk/handle/1810/280086
Rights
Attribution 4.0 International (CC BY 4.0)
Licence URL: https://creativecommons.org/licenses/by/4.0/
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