Exome sequencing of Finnish isolates enhances rare-variant association power.

Alleles Cholesterol, HDL / genetics Cluster Analysis Endpoint Determination Finland Genetic Association Studies / methods Genetic Predisposition to Disease / genetics Genetic Variation / genetics Geographic Mapping Humans Multifactorial Inheritance / genetics Quantitative Trait Loci / genetics Reproducibility of Results Exome Sequencing

Journal

Nature
ISSN: 1476-4687
Titre abrégé: Nature
Pays: England
ID NLM: 0410462

Informations de publication

Date de publication:
08 2019
Historique:
received: 05 11 2018
accepted: 02 07 2019
pubmed: 2 8 2019
medline: 18 12 2019
entrez: 2 8 2019
Statut: ppublish

Résumé

Exome-sequencing studies have generally been underpowered to identify deleterious alleles with a large effect on complex traits as such alleles are mostly rare. Because the population of northern and eastern Finland has expanded considerably and in isolation following a series of bottlenecks, individuals of these populations have numerous deleterious alleles at a relatively high frequency. Here, using exome sequencing of nearly 20,000 individuals from these regions, we investigate the role of rare coding variants in clinically relevant quantitative cardiometabolic traits. Exome-wide association studies for 64 quantitative traits identified 26 newly associated deleterious alleles. Of these 26 alleles, 19 are either unique to or more than 20 times more frequent in Finnish individuals than in other Europeans and show geographical clustering comparable to Mendelian disease mutations that are characteristic of the Finnish population. We estimate that sequencing studies of populations without this unique history would require hundreds of thousands to millions of participants to achieve comparable association power.

Identifiants

DOI: 10.1038/s41586-019-1457-z PMID: 31367044 PMC: PMC6697530
pubmed: 31367044
doi: 10.1038/s41586-019-1457-z
pii: 10.1038/s41586-019-1457-z
pmc: PMC6697530
mid: EMS83607
doi:

Substances chimiques

Cholesterol, HDL 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

323-328

Subventions

Organisme : NIDDK NIH HHS
ID : R56 DK062370
Pays : United States
Organisme : NINDS NIH HHS
ID : T32 NS048004
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK062370
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1 HG008853
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL113315
Pays : United States
Organisme : NIMH NIH HHS
ID : U01 MH105578
Pays : United States
Organisme : Medical Research Council
ID : MR/S019669/1
Pays : United Kingdom
Organisme : NHGRI NIH HHS
ID : R01 HG006695
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK056341
Pays : United States
Organisme : NINDS NIH HHS
ID : P30 NS062691
Pays : United States
Organisme : NIDDK NIH HHS
ID : U01 DK062370
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL131961
Pays : United States
Organisme : NHGRI NIH HHS
ID : U54 HG003079
Pays : United States

Commentaires et corrections

Type : ErratumIn

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Auteurs

Adam E Locke (AE)

Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO, USA.
Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, USA.

Karyn Meltz Steinberg (KM)

McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO, USA.
Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA.

Charleston W K Chiang (CWK)

Center for Neurobehavioral Genetics, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA.
Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Quantitative and Computational Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA.

Susan K Service (SK)

Center for Neurobehavioral Genetics, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA.

Aki S Havulinna (AS)

Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
National Institute for Health and Welfare, Helsinki, Finland.

Laurel Stell (L)

Department of Biomedical Data Science, Stanford University, Stanford, CA, USA.

Matti Pirinen (M)

Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
Department of Public Health, University of Helsinki, Helsinki, Finland.
Helsinki Institute for Information Technology HIIT and Department of Mathematics and Statistics, University of Helsinki, Helsinki, Finland.

Haley J Abel (HJ)

McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO, USA.
Department of Genetics, Washington University School of Medicine, St Louis, MO, USA.

Colby C Chiang (CC)

McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO, USA.

Robert S Fulton (RS)

McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO, USA.
Department of Genetics, Washington University School of Medicine, St Louis, MO, USA.

Anne U Jackson (AU)

Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, USA.

Chul Joo Kang (CJ)

McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO, USA.

Krishna L Kanchi (KL)

McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO, USA.

Daniel C Koboldt (DC)

McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO, USA.
The Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA.

David E Larson (DE)

McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO, USA.
Department of Genetics, Washington University School of Medicine, St Louis, MO, USA.

Joanne Nelson (J)

McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO, USA.

Thomas J Nicholas (TJ)

McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO, USA.
USTAR Center for Genetic Discovery and Department of Human Genetics, University of Utah, Salt Lake City, UT, USA.

Arto Pietilä (A)

National Institute for Health and Welfare, Helsinki, Finland.

Vasily Ramensky (V)

Center for Neurobehavioral Genetics, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA.
Federal State Institution "National Medical Research Center for Preventive Medicine" of the Ministry of Healthcare of the Russian Federation, Moscow, Russia.

Debashree Ray (D)

Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
Departments of Epidemiology and Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.

Laura J Scott (LJ)

Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, USA.

Heather M Stringham (HM)

Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, USA.

Jagadish Vangipurapu (J)

Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland.

Ryan Welch (R)

Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, USA.

Pranav Yajnik (P)

Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, USA.

Xianyong Yin (X)

Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, USA.

Johan G Eriksson (JG)

Department of Public Health Solutions, National Institute for Health and Welfare, Helsinki, Finland.
Folkhälsan Research Center, Helsinki, Finland.
Department of General Practice and Primary Health Care, University of Helsinki, Helsinki and Helsinki University Hospital, Helsinki, Finland.

Mika Ala-Korpela (M)

Systems Epidemiology, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.
Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, University of Oulu, Oulu, Finland.
NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
Population Health Science, Bristol Medical School, University of Bristol, Bristol, UK.
Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.
Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Faculty of Medicine, Nursing and Health Sciences, The Alfred Hospital, Monash University, Melbourne, Victoria, Australia.

Marjo-Riitta Järvelin (MR)

Biocenter Oulu, University of Oulu, Oulu, Finland.
Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.
Unit of Primary Health Care, Oulu University Hospital, Oulu, Finland.
Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
Department of Life Sciences, College of Health and Life Sciences, Brunel University London, London, UK.

Minna Männikkö (M)

Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.
Northern Finland Birth Cohorts, Faculty of Medicine, University of Oulu, Oulu, Finland.

Hannele Laivuori (H)

Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
Medical and Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Department of Obstetrics and Gynecology, Tampere University Hospital and University of Tampere, Faculty of Medicine and Health Technology, Tampere, Finland.

Susan K Dutcher (SK)

McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO, USA.
Department of Genetics, Washington University School of Medicine, St Louis, MO, USA.

Nathan O Stitziel (NO)

McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO, USA.
Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.

Richard K Wilson (RK)

McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO, USA.
The Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA.

Ira M Hall (IM)

Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO, USA.

Chiara Sabatti (C)

Department of Biomedical Data Science, Stanford University, Stanford, CA, USA.
Department of Statistics, Stanford University, Stanford, CA, USA.

Aarno Palotie (A)

Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
Analytical and Translational Genetics Unit (ATGU), Psychiatric & Neurodevelopmental Genetics Unit, Departments of Psychiatry and Neurology, Massachusetts General Hospital, Boston, MA, USA.
Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Veikko Salomaa (V)

National Institute for Health and Welfare, Helsinki, Finland.

Markku Laakso (M)

Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland.
Department of Medicine, Kuopio University Hospital, Kuopio, Finland.

Samuli Ripatti (S)

Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
Department of Public Health, University of Helsinki, Helsinki, Finland.
Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Michael Boehnke (M)

Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, USA. boehnke@umich.edu.

Nelson B Freimer (NB)

Center for Neurobehavioral Genetics, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA. nfreimer@mednet.ucla.edu.

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Classifications MeSH

questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Gènes › Allèles › Exome sequencing of Finnish isolates enhances...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Lipoprotéines › Lipoprotéines HDL › Cholestérol HDL › Exome sequencing of Finnish isolates enhances...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Statistiques comme sujet › Analyse de regroupements › Exome sequencing of Finnish isolates enhances...
questionsmedicales.fr › Techniques d'investigation › Détermination du point final › Exome sequencing of Finnish isolates enhances...
questionsmedicales.fr › Régions géographiques › Europe › Pays nordiques et scandinaves › Finlande › Exome sequencing of Finnish isolates enhances...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Études d'associations génétiques › Exome sequencing of Finnish isolates enhances...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Prédisposition génétique à une maladie › Exome sequencing of Finnish isolates enhances...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Exome sequencing of Finnish isolates enhances...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Statistiques comme sujet › Analyse spatiale › Cartographie géographique › Exome sequencing of Finnish isolates enhances...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Exome sequencing of Finnish isolates enhances...
questionsmedicales.fr › Phénomènes génétiques › Modes de transmission héréditaire › Hérédité multifactorielle › Exome sequencing of Finnish isolates enhances...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Locus génétiques › Locus de caractère quantitatif › Exome sequencing of Finnish isolates enhances...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Méthodologie en recherche épidémiologique › Reproductibilité des résultats › Exome sequencing of Finnish isolates enhances...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Analyse de séquence › Analyse de séquence d'ADN › Séquençage du génome entier › Séquençage de l'exome › Exome sequencing of Finnish isolates enhances...