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

Elaine T. Lim, Peter Würtz, Aki S. Havulinna, Priit Palta, Taru Tukiainen, Karola Rehnström, Tõnu Esko, Reedik Mägi, Michael Inouye, Tuuli Lappalainen, Yingleong Chan, Rany M. Salem, Monkol Lek, Jason Flannick, Xueling Sim, Alisa Manning, Claes Ladenvall, Suzannah Bumpstead, Eija Hämäläinen, Kristiina AaltoMikael Maksimow, Marko Salmi, Stefan Blankenberg, Diego Ardissino, Svati Shah, Benjamin Horne, Ruth McPherson, Gerald K. Hovingh, Muredach P. Reilly, Hugh Watkins, Anuj Goel, Martin Farrall, Domenico Girelli, Alex P. Reiner, Nathan O. Stitziel, Sekar Kathiresan, Stacey Gabriel, Jeffrey C. Barrett, Terho Lehtimäki, Markku Laakso, Leif Groop, Jaakko Kaprio, Markus Perola, Mark I. McCarthy, Michael Boehnke, David M. Altshuler, Cecilia M. Lindgren, Joel N. Hirschhorn, Andres Metspalu, Nelson B. Freimer, Tanja Zeller, Sirpa Jalkanen, Seppo Koskinen, Olli Raitakari, Richard Durbin, Daniel G. MacArthur, Veikko Salomaa, Samuli Ripatti, Mark J. Daly, Aarno Palotie

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220 Scopus citations


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.

Original languageEnglish
Article numbere1004494
JournalPLoS genetics
Issue number7
StatePublished - Jul 2014


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