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 Aalto; Mikael 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 A 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 Daly; Aarno Palotie

doi:10.1371/journal.pgen.1004494

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 A 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 Daly, Aarno Palotie

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	e1004494
Journal	PLoS Genetics
Volume	10
Issue number	7
DOIs	https://doi.org/10.1371/journal.pgen.1004494
Publication status	Published - 2014

Subject classification (UKÄ)

Endocrinology and Diabetes

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1371/journal.pgen.1004494

http://www.ncbi.nlm.nih.gov/pubmed/25078778?dopt=Abstract

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Lim, E. T., Würtz, P., Havulinna, A. S., Palta, P., Tukiainen, T., Rehnström, K., Esko, T., Mägi, R., Inouye, M., Lappalainen, T., Chan, Y., Salem, R. M., Lek, M., Flannick, J., Sim, X., Manning, A., Ladenvall, C., Bumpstead, S., Hämäläinen, E., ... Palotie, A. (2014). Distribution and Medical Impact of Loss-of-Function Variants in the Finnish Founder Population. PLoS Genetics, 10(7), Article e1004494. https://doi.org/10.1371/journal.pgen.1004494

@article{8743af47dbae42368657348ec9a939d3,

title = "Distribution and Medical Impact of Loss-of-Function Variants in the Finnish Founder Population.",

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.",

author = "Lim, {Elaine T} and Peter W{\"u}rtz and Havulinna, {Aki S} and Priit Palta and Taru Tukiainen and Karola Rehnstr{\"o}m and T{\~o}nu Esko and Reedik M{\"a}gi and Michael Inouye and Tuuli Lappalainen and Yingleong Chan and Salem, {Rany M} and Monkol Lek and Jason Flannick and Xueling Sim and Alisa Manning and Claes Ladenvall and Suzannah Bumpstead and Eija H{\"a}m{\"a}l{\"a}inen and Kristiina Aalto and Mikael Maksimow and Marko Salmi and Stefan Blankenberg and Diego Ardissino and Svati Shah and Benjamin Horne and Ruth McPherson and Hovingh, {Gerald K} and Reilly, {Muredach P} and Hugh Watkins and Anuj Goel and Martin Farrall and Domenico Girelli and Reiner, {Alex P} and Stitziel, {Nathan O} and Sekar Kathiresan and Stacey Gabriel and Barrett, {Jeffrey C} and Terho Lehtim{\"a}ki and Markku Laakso and Leif Groop and Jaakko Kaprio and Markus Perola and McCarthy, {Mark I} and Michael Boehnke and Altshuler, {David M} and Lindgren, {Cecilia A} and Hirschhorn, {Joel N} and Andres Metspalu and Freimer, {Nelson B} and Tanja Zeller and Sirpa Jalkanen and Seppo Koskinen and Olli Raitakari and Richard Durbin and MacArthur, {Daniel G} and Veikko Salomaa and Samuli Ripatti and Mark Daly and Aarno Palotie",

year = "2014",

doi = "10.1371/journal.pgen.1004494",

language = "English",

volume = "10",

journal = "PLoS Genetics",

issn = "1553-7404",

publisher = "Public Library of Science (PLoS)",

number = "7",

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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, CA, Hirschhorn, JN, Metspalu, A, Freimer, NB, Zeller, T, Jalkanen, S, Koskinen, S, Raitakari, O, Durbin, R, MacArthur, DG, Salomaa, V, Ripatti, S, Daly, M & Palotie, A 2014, 'Distribution and Medical Impact of Loss-of-Function Variants in the Finnish Founder Population.', PLoS Genetics, vol. 10, no. 7, e1004494. https://doi.org/10.1371/journal.pgen.1004494

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 A

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

AU - Palotie, Aarno

PY - 2014

Y1 - 2014

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.

U2 - 10.1371/journal.pgen.1004494

DO - 10.1371/journal.pgen.1004494

M3 - Article

SN - 1553-7404

VL - 10

JO - PLoS Genetics

JF - PLoS Genetics

IS - 7

M1 - e1004494

ER -

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

Abstract

Subject classification (UKÄ)

UN SDGs

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