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.
authors: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America; Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America; Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Elaine T
authors: ET
authors: Lim
authors: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland; Computational Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland.
authors: Peter
authors: P
authors: Würtz
authors: Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
authors: Aki S
authors: AS
authors: Havulinna
authors: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors: Priit
authors: P
authors: Palta
authors: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America; Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Taru
authors: T
authors: Tukiainen
authors: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors: Karola
authors: K
authors: Rehnström
authors: Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America; Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America; Estonian Genome Center, University of Tartu, Tartu, Estonia; Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Children's Hospital Boston, Boston, Massachusetts, United States of America.
authors: Tõnu
authors: T
authors: Esko
authors: Estonian Genome Center, University of Tartu, Tartu, Estonia.
authors: Reedik
authors: R
authors: Mägi
authors: Medical Systems Biology, Department of Pathology and Department of Microbiology & Immunology, The University of Melbourne, Parkville, Victoria, Australia.
authors: Michael
authors: M
authors: Inouye
authors: Department of Genetics, Stanford University, Stanford, California, United States of America; Stanford Center for Computational, Evolutionary and Human Genomics, Stanford, California, United States of America.
authors: Tuuli
authors: T
authors: Lappalainen
authors: Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America; Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts, United States of America; Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Children's Hospital Boston, Boston, Massachusetts, United States of America.
authors: Yingleong
authors: Y
authors: Chan
authors: Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America; Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Children's Hospital Boston, Boston, Massachusetts, United States of America.
authors: Rany M
authors: RM
authors: Salem
authors: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America; Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Monkol
authors: M
authors: Lek
authors: Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America; Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Jason
authors: J
authors: Flannick
authors: Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, United States of America.
authors: Xueling
authors: X
authors: Sim
authors: Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America.
authors: Alisa
authors: A
authors: Manning
authors: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; Lund University Diabetes Center, Department of Clinical Sciences, Diabetes & Endocrinology, Skåne University Hospital, Lund University, Malmö, Sweden.
authors: Claes
authors: C
authors: Ladenvall
authors: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors: Suzannah
authors: S
authors: Bumpstead
authors: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors: Eija
authors: E
authors: Hämäläinen
authors: MediCity, University of Turku, Turku, Finland.
authors: Kristiina
authors: K
authors: Aalto
authors: MediCity, University of Turku, Turku, Finland.
authors: Mikael
authors: M
authors: Maksimow
authors: Department of Medical Microbiology and Immunology, University of Turku and National Institute for Health and Welfare, Turku, Finland.
authors: Marko
authors: M
authors: Salmi
authors: University Heart Centre Hamburg, Clinic for General and Interventional Cardiology, Hamburg, Germany; DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.
authors: Stefan
authors: S
authors: Blankenberg
authors: Division of Cardiology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
authors: Diego
authors: D
authors: Ardissino
authors: Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America.
authors: Svati
authors: S
authors: Shah
authors: Intermountain Heart Institute, Intermountain Medical Center, Salt Lake City, Utah, United States of America.
authors: Benjamin
authors: B
authors: Horne
authors: Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors: Ruth
authors: R
authors: McPherson
authors: Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
authors: Gerald K
authors: GK
authors: Hovingh
authors: Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors: Muredach P
authors: MP
authors: Reilly
authors: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors: Hugh
authors: H
authors: Watkins
authors: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors: Anuj
authors: A
authors: Goel
authors: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors: Martin
authors: M
authors: Farrall
authors: University of Verona School of Medicine, Department of Medicine, Verona, Italy.
authors: Domenico
authors: D
authors: Girelli
authors: Department of Epidemiology, University of Washington, Seattle, Washington, United States of America.
authors: Alex P
authors: AP
authors: Reiner
authors: Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors: Nathan O
authors: NO
authors: Stitziel
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors: Sekar
authors: S
authors: Kathiresan
authors: Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America.
authors: Stacey
authors: S
authors: Gabriel
authors: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors: Jeffrey C
authors: JC
authors: Barrett
authors: Department of Clinical Chemistry, Fimlab Laboratories, University of Tampere School of Medicine, Tampere, Finland.
authors: Terho
authors: T
authors: Lehtimäki
authors: Department of Medicine, University of Eastern Finland, Kuopio, Finland.
authors: Markku
authors: M
authors: Laakso
authors: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; Lund University Diabetes Center, Department of Clinical Sciences, Diabetes & Endocrinology, Skåne University Hospital, Lund University, Malmö, Sweden.
authors: Leif
authors: L
authors: Groop
authors: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; University of Helsinki, Hjelt Institute, Dept of Public Health, Helsinki, Finland; National Institute for Health and Welfare, Dept of Mental Health and Substance Abuse Services, Helsinki, Finland.
authors: Jaakko
authors: J
authors: Kaprio
authors: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
authors: Markus
authors: M
authors: Perola
authors: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Headington, Oxford, United Kingdom; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Oxford NIHR Biomedical Research Centre, Churchill Hospital, Headington, Oxford, United Kingdom.
authors: Mark I
authors: MI
authors: McCarthy
authors: Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, United States of America.
authors: Michael
authors: M
authors: Boehnke
authors: Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America; Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: David M
authors: DM
authors: Altshuler
authors: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors: Cecilia M
authors: CM
authors: Lindgren
authors: Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America; Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Children's Hospital Boston, Boston, Massachusetts, United States of America.
authors: Joel N
authors: JN
authors: Hirschhorn
authors: Estonian Genome Center, University of Tartu, Tartu, Estonia.
authors: Andres
authors: A
authors: Metspalu
authors: University of California Los Angeles Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California, United States of America.
authors: Nelson B
authors: NB
authors: Freimer
authors: University Heart Centre Hamburg, Clinic for General and Interventional Cardiology, Hamburg, Germany; DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.
authors: Tanja
authors: T
authors: Zeller
authors: Department of Medical Microbiology and Immunology, University of Turku and National Institute for Health and Welfare, Turku, Finland.
authors: Sirpa
authors: S
authors: Jalkanen
authors: Department of Health, Functional Capacity and Welfare, National Institute for Health and Welfare, Helsinki, Finland.
authors: Seppo
authors: S
authors: Koskinen
authors: Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland; Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
authors: Olli
authors: O
authors: Raitakari
authors: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors: Richard
authors: R
authors: Durbin
authors: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America; Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Daniel G
authors: DG
authors: MacArthur
authors: Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
authors: Veikko
authors: V
authors: Salomaa
authors: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland; Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom; University of Helsinki, Hjelt Institute, Dept of Public Health, Helsinki, Finland; Department of Biometry, Hjelt Institute, University of Helsinki, Helsinki, Finland.
authors: Samuli
authors: S
authors: Ripatti
authors: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America; Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Mark J
authors: MJ
authors: Daly
authors: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors: Aarno
authors: A
authors: Palotie
mesh_terms: D059472:Exome / Q000235:genetics; D005260:Female; D005387:Finland; D018703:Founder Effect; D005787:Gene Frequency; D030342:Genetic Diseases, Inborn; D040961:Genetic Drift; D014644:Genetic Variation; D005828:Genetics, Population; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D010641:Phenotype; D044465:White People