Distribution and medical impact of loss-of-function variants in the Finnish founder population
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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; 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; Durbin, Richard; MacArthur, Daniel G; Salomaa, Veikko; Ripatti, Samuli; Daly, Mark J; Palotie, Aarno; Sequencing Initiative Suomi (SISu) Project.
In: PLOS GENET, Vol. 10, No. 7, 07.2014, p. e1004494.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Distribution and medical impact of loss-of-function variants in the Finnish founder population
AU - Lim, Elaine T
AU - Würtz, Peter
AU - Havulinna, Aki S
AU - Palta, Priit
AU - Tukiainen, Taru
AU - Rehnström, Karola
AU - Esko, Tõnu
AU - Mägi, Reedik
AU - Inouye, Michael
AU - Lappalainen, Tuuli
AU - Chan, Yingleong
AU - Salem, Rany M
AU - Lek, Monkol
AU - Flannick, Jason
AU - Sim, Xueling
AU - Manning, Alisa
AU - Ladenvall, Claes
AU - Bumpstead, Suzannah
AU - Hämäläinen, Eija
AU - Aalto, Kristiina
AU - Maksimow, Mikael
AU - Salmi, Marko
AU - Blankenberg, Stefan
AU - Ardissino, Diego
AU - Shah, Svati
AU - Horne, Benjamin
AU - McPherson, Ruth
AU - Hovingh, Gerald K
AU - Reilly, Muredach P
AU - Watkins, Hugh
AU - Goel, Anuj
AU - Farrall, Martin
AU - Girelli, Domenico
AU - Reiner, Alex P
AU - Stitziel, Nathan O
AU - Kathiresan, Sekar
AU - Gabriel, Stacey
AU - Barrett, Jeffrey C
AU - Lehtimäki, Terho
AU - Laakso, Markku
AU - Groop, Leif
AU - Kaprio, Jaakko
AU - Perola, Markus
AU - McCarthy, Mark I
AU - Boehnke, Michael
AU - Altshuler, David M
AU - Lindgren, Cecilia M
AU - Hirschhorn, Joel N
AU - Metspalu, Andres
AU - Freimer, Nelson B
AU - Zeller, Tanja
AU - Jalkanen, Sirpa
AU - Koskinen, Seppo
AU - Raitakari, Olli
AU - Durbin, Richard
AU - MacArthur, Daniel G
AU - Salomaa, Veikko
AU - Ripatti, Samuli
AU - Daly, Mark J
AU - Palotie, Aarno
AU - Sequencing Initiative Suomi (SISu) Project
PY - 2014/7
Y1 - 2014/7
N2 - 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.
AB - 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.
KW - European Continental Ancestry Group
KW - Exome/genetics
KW - Female
KW - Finland
KW - Founder Effect
KW - Gene Frequency
KW - Genetic Diseases, Inborn
KW - Genetic Drift
KW - Genetic Variation
KW - Genetics, Population
KW - Genome-Wide Association Study
KW - Humans
KW - Male
KW - Phenotype
U2 - 10.1371/journal.pgen.1004494
DO - 10.1371/journal.pgen.1004494
M3 - SCORING: Journal article
C2 - 25078778
VL - 10
SP - e1004494
JO - PLOS GENET
JF - PLOS GENET
SN - 1553-7404
IS - 7
ER -