Format

Send to

Choose Destination
Nature. 2019 Aug;572(7769):323-328. doi: 10.1038/s41586-019-1457-z. Epub 2019 Jul 31.

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

Author information

1
Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
2
McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO, USA.
3
Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
4
Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA.
5
Center for Neurobehavioral Genetics, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA.
6
Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
7
Quantitative and Computational Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA.
8
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
9
National Institute for Health and Welfare, Helsinki, Finland.
10
Department of Biomedical Data Science, Stanford University, Stanford, CA, USA.
11
Department of Public Health, University of Helsinki, Helsinki, Finland.
12
Helsinki Institute for Information Technology HIIT and Department of Mathematics and Statistics, University of Helsinki, Helsinki, Finland.
13
Department of Genetics, Washington University School of Medicine, St Louis, MO, USA.
14
The Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
15
Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA.
16
USTAR Center for Genetic Discovery and Department of Human Genetics, University of Utah, Salt Lake City, UT, USA.
17
Federal State Institution "National Medical Research Center for Preventive Medicine" of the Ministry of Healthcare of the Russian Federation, Moscow, Russia.
18
Departments of Epidemiology and Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
19
Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland.
20
Department of Public Health Solutions, National Institute for Health and Welfare, Helsinki, Finland.
21
Folkhälsan Research Center, Helsinki, Finland.
22
Department of General Practice and Primary Health Care, University of Helsinki, Helsinki and Helsinki University Hospital, Helsinki, Finland.
23
Systems Epidemiology, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.
24
Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, University of Oulu, Oulu, Finland.
25
NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
26
Population Health Science, Bristol Medical School, University of Bristol, Bristol, UK.
27
Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.
28
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.
29
Biocenter Oulu, University of Oulu, Oulu, Finland.
30
Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.
31
Unit of Primary Health Care, Oulu University Hospital, Oulu, Finland.
32
Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
33
Department of Life Sciences, College of Health and Life Sciences, Brunel University London, London, UK.
34
Northern Finland Birth Cohorts, Faculty of Medicine, University of Oulu, Oulu, Finland.
35
Medical and Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
36
Department of Obstetrics and Gynecology, Tampere University Hospital and University of Tampere, Faculty of Medicine and Life Sciences, Tampere, Finland.
37
Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
38
Department of Statistics, Stanford University, Stanford, CA, USA.
39
Analytical and Translational Genetics Unit (ATGU), Psychiatric & Neurodevelopmental Genetics Unit, Departments of Psychiatry and Neurology, Massachusetts General Hospital, Boston, MA, USA.
40
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
41
Department of Medicine, Kuopio University Hospital, Kuopio, Finland.
42
Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, USA. boehnke@umich.edu.
43
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.

Abstract

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.

PMID:
31367044
PMCID:
PMC6697530
[Available on 2020-01-31]
DOI:
10.1038/s41586-019-1457-z

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center