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PLoS Genet. 2014 Jul 31;10(7):e1004494. doi: 10.1371/journal.pgen.1004494. eCollection 2014.

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

Author information

1
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.
2
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.
3
Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
4
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
5
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.
6
Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
7
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.
8
Estonian Genome Center, University of Tartu, Tartu, Estonia.
9
Medical Systems Biology, Department of Pathology and Department of Microbiology & Immunology, The University of Melbourne, Parkville, Victoria, Australia.
10
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.
11
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.
12
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.
13
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.
14
Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, United States of America.
15
Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, United States of America.
16
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.
17
MediCity, University of Turku, Turku, Finland.
18
Department of Medical Microbiology and Immunology, University of Turku and National Institute for Health and Welfare, Turku, Finland.
19
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.
20
Division of Cardiology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
21
Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America.
22
Intermountain Heart Institute, Intermountain Medical Center, Salt Lake City, Utah, United States of America.
23
Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
24
Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
25
Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
26
Division of Cardiovascular Medicine, Radcliffe Department of Medicine, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
27
University of Verona School of Medicine, Department of Medicine, Verona, Italy.
28
Department of Epidemiology, University of Washington, Seattle, Washington, United States of America.
29
Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
30
Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
31
Department of Clinical Chemistry, Fimlab Laboratories, University of Tampere School of Medicine, Tampere, Finland.
32
Department of Medicine, University of Eastern Finland, Kuopio, Finland.
33
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.
34
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
35
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.
36
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.
37
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.
38
Department of Health, Functional Capacity and Welfare, National Institute for Health and Welfare, Helsinki, Finland.
39
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.
40
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.
41
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.

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.

PMID:
25078778
PMCID:
PMC4117444
DOI:
10.1371/journal.pgen.1004494
[Indexed for MEDLINE]
Free PMC Article
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