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Distribution and Medical Impact of Loss-of-Function Variants in the Finnish Founder Population.

Lim, Elaine T; Würtz, Peter; Havulinna, Aki S; Palta, Priit; Tukiainen, Taru; Rehnström, Karola; Esko, Tõnu; Mägi, Reedik; Inouye, Michael and Lappalainen, Tuuli, et al. (2014) In PLoS Genetics 10(7).
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... (More)
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. (Less)
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PLoS Genetics
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7
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Public Library of Science
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  • pmid:25078778
  • wos:000339902600042
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1553-7404
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10.1371/journal.pgen.1004494
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English
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8743af47-dbae-4236-8657-348ec9a939d3 (old id 4615846)
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@article{8743af47-dbae-4236-8657-348ec9a939d3,
  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&lt;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.},
  articleno    = {e1004494},
  author       = {Lim, Elaine T and Würtz, Peter and Havulinna, Aki S and Palta, Priit and Tukiainen, Taru and Rehnström, Karola and Esko, Tõnu and Mägi, Reedik and Inouye, Michael and Lappalainen, Tuuli and Chan, Yingleong and Salem, Rany M and Lek, Monkol and Flannick, Jason and Sim, Xueling and Manning, Alisa and Ladenvall, Claes and Bumpstead, Suzannah and Hämäläinen, Eija and Aalto, Kristiina and Maksimow, Mikael and Salmi, Marko and Blankenberg, Stefan and Ardissino, Diego and Shah, Svati and Horne, Benjamin and McPherson, Ruth and Hovingh, Gerald K and Reilly, Muredach P and Watkins, Hugh and Goel, Anuj and Farrall, Martin and Girelli, Domenico and Reiner, Alex P and Stitziel, Nathan O and Kathiresan, Sekar and Gabriel, Stacey and Barrett, Jeffrey C and Lehtimäki, Terho and Laakso, Markku and Groop, Leif and Kaprio, Jaakko and Perola, Markus and McCarthy, Mark I and Boehnke, Michael and Altshuler, David M and Lindgren, Cecilia A and Hirschhorn, Joel N and Metspalu, Andres and Freimer, Nelson B and Zeller, Tanja and Jalkanen, Sirpa and Koskinen, Seppo and Raitakari, Olli and Durbin, Richard and MacArthur, Daniel G and Salomaa, Veikko and Ripatti, Samuli and Daly, Mark and Palotie, Aarno},
  issn         = {1553-7404},
  language     = {eng},
  number       = {7},
  publisher    = {Public Library of Science},
  series       = {PLoS Genetics},
  title        = {Distribution and Medical Impact of Loss-of-Function Variants in the Finnish Founder Population.},
  url          = {http://dx.doi.org/10.1371/journal.pgen.1004494},
  volume       = {10},
  year         = {2014},
}