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Distribution and medical impact of loss-of-function variants in the Finnish founder population.

Publication ,  Journal Article
Lim, ET; Würtz, P; Havulinna, AS; Palta, P; Tukiainen, T; Rehnström, K; Esko, T; Mägi, R; Inouye, M; Lappalainen, T; Chan, Y; Salem, RM ...
Published in: PLoS Genet
July 2014

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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Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

July 2014

Volume

10

Issue

7

Start / End Page

e1004494

Location

United States

Related Subject Headings

  • White People
  • Phenotype
  • Male
  • Humans
  • Genome-Wide Association Study
  • Genetics, Population
  • Genetic Variation
  • Genetic Drift
  • Genetic Diseases, Inborn
  • Gene Frequency
 

Citation

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Lim, E. T., Würtz, P., Havulinna, A. S., Palta, P., Tukiainen, T., Rehnström, K., … Sequencing Initiative Suomi (SISu) Project, . (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
Lim, Elaine T., Peter Würtz, Aki S. Havulinna, Priit Palta, Taru Tukiainen, Karola Rehnström, Tõnu Esko, et al. “Distribution and medical impact of loss-of-function variants in the Finnish founder population.PLoS Genet 10, no. 7 (July 2014): e1004494. https://doi.org/10.1371/journal.pgen.1004494.
Lim ET, Würtz P, Havulinna AS, Palta P, Tukiainen T, Rehnström K, et al. Distribution and medical impact of loss-of-function variants in the Finnish founder population. PLoS Genet. 2014 Jul;10(7):e1004494.
Lim, Elaine T., et al. “Distribution and medical impact of loss-of-function variants in the Finnish founder population.PLoS Genet, vol. 10, no. 7, July 2014, p. e1004494. Pubmed, doi:10.1371/journal.pgen.1004494.
Lim ET, Würtz P, Havulinna AS, Palta P, Tukiainen T, Rehnström K, Esko T, Mägi R, Inouye M, Lappalainen T, Chan Y, Salem RM, 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 GK, Reilly MP, Watkins H, Goel A, Farrall M, Girelli D, Reiner AP, Stitziel NO, Kathiresan S, Gabriel S, Barrett JC, Lehtimäki T, Laakso M, Groop L, Kaprio J, Perola M, McCarthy MI, Boehnke M, Altshuler DM, Lindgren CM, Hirschhorn JN, Metspalu A, Freimer NB, Zeller T, Jalkanen S, Koskinen S, Raitakari O, Durbin R, MacArthur DG, Salomaa V, Ripatti S, Daly MJ, Palotie A, Sequencing Initiative Suomi (SISu) Project. Distribution and medical impact of loss-of-function variants in the Finnish founder population. PLoS Genet. 2014 Jul;10(7):e1004494.

Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

July 2014

Volume

10

Issue

7

Start / End Page

e1004494

Location

United States

Related Subject Headings

  • White People
  • Phenotype
  • Male
  • Humans
  • Genome-Wide Association Study
  • Genetics, Population
  • Genetic Variation
  • Genetic Drift
  • Genetic Diseases, Inborn
  • Gene Frequency