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

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 -