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Nat Genet. 2015 Jun;47(6):589-97. doi: 10.1038/ng.3300. Epub 2015 May 11.

The impact of low-frequency and rare variants on lipid levels.

Author information

1
1] Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. [2] National Institute for Health and Welfare, Helsinki, Finland.
2
1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. [2] Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
3
Estonian Genome Center, University of Tartu, Tartu, Estonia.
4
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
5
Department of Life Sciences and Biotechnology, Genetic Section, University of Ferrara, Ferrara, Italy.
6
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
7
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
8
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
9
1] Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. [2] Molecular Epidemiology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden. [3] Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
10
Department of Biological Psychology, EMGO Institute for Health and Care Research, VU University and VU University Medical Center, Amsterdam, the Netherlands.
11
1] Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands. [2] Centre for Medical Systems Biology, Leiden, the Netherlands.
12
Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Skåne University Hospital, Malmö, Sweden.
13
1] Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, the Netherlands. [2] Netherlands Consortium for Healthy Ageing, Leiden, the Netherlands.
14
1] Estonian Genome Center, University of Tartu, Tartu, Estonia. [2] Division of Endocrinology, Children's Hospital, Boston, Massachusetts, USA. [3] Center for Basic and Translational Obesity Research, Children's Hospital, Boston, Massachusetts, USA. [4] Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [5] Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
15
Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
16
1] Department of Cardiovascular Sciences, University of Leicester, Leicester, UK. [2] National Institute for Health Research (NIHR) Leicester Cardiovascular Disease Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
17
1] Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, Lübeck, Germany. [2] Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), partner site Hamburg, Lübeck and Kiel, Germany.
18
Department of Epidemiology and Biostatistics, Medical Research Council (MRC) Health Protection Agency (HPA), Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
19
1] Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, the Netherlands. [2] Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
20
1] Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. [2] German Center for Diabetes Research (DZD), Neuherberg, Germany. [3] Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
21
Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
22
National Institute for Health and Welfare, Helsinki, Finland.
23
1] Deutsches Herzzentrum München, Technische Universität München, Munich, Germany. [2] Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), partner site Munich Heart Alliance, Munich, Germany.
24
Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands.
25
1] Population, Policy and Practice, University College London Institute of Child Health, London, UK. [2] South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia. [3] School of Population Health, University of South Australia, Adelaide, South Australia, Australia. [4] Sansom Institute, University of South Australia, Adelaide, South Australia, Australia.
26
Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
27
Department of Clinical Chemistry, Fimlab Laboratories and School of Medicine, University of Tampere, Tampere, Finland.
28
1] Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Skåne University Hospital, Malmö, Sweden. [2] Steno Diabetes Center, Gentofte, Denmark.
29
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
30
1] Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. [2] Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), partner site Munich Heart Alliance, Munich, Germany. [3] Department of Medicine I, University Hospital Großhadern, Ludwig Maximilians Universität, Munich, Germany. [4] Chair of Genetic Epidemiology, Institute of Medical Informatics, Biometry and Epidemiology, Ludwig Maximilians Universität, Munich, Germany.
31
Department of Psychiatry, VU University Medical Center, Amsterdam, the Netherlands.
32
1] Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. [2] National Institute for Health and Welfare, Helsinki, Finland. [3] Estonian Genome Center, University of Tartu, Tartu, Estonia. [4] Diabetes and Obesity Research Program, University of Helsinki, Helsinki, Finland.
33
1] Division of Endocrinology, Children's Hospital, Boston, Massachusetts, USA. [2] Center for Basic and Translational Obesity Research, Children's Hospital, Boston, Massachusetts, USA. [3] Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
34
1] Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. [2] Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. [3] Deutsches Herzzentrum München, Technische Universität München, Munich, Germany.
35
European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, UK.
36
Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, UK.
37
1] Department of Medicine, University of Turku, Turku, Finland. [2] Division of Medicine, Turku University Hospital, Turku, Finland.
38
1] Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. [2] National Institute for Health and Welfare, Helsinki, Finland. [3] Department of Public Health, University of Helsinki, Helsinki, Finland.
39
Department of Medical Sciences, Uppsala University, Akademiska Sjukhuset, Uppsala, Sweden.
40
1] Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. [2] Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. [3] Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
41
1] Estonian Genome Center, University of Tartu, Tartu, Estonia. [2] Institute of Molecular and Cell Biology of the University of Tartu, Tartu, Estonia.
42
1] Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. [2] Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Skåne University Hospital, Malmö, Sweden.
43
1] National Institute for Health and Welfare, Helsinki, Finland. [2] Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland. [3] Folkhälsan Research Centre, Helsinki, Finland. [4] Unit of Primary Health Care, Helsinki University Hospital, Helsinki, Finland.
44
Population, Policy and Practice, University College London Institute of Child Health, London, UK.
45
1] Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland. [2] Department of Clinical Physiology and Nuclear Medicine, University of Turku and Turku University Hospital, Turku, Finland.
46
1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. [2] Molecular Epidemiology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden. [3] Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
47
1] National Institute for Health and Welfare, Helsinki, Finland. [2] [3] Institute of Health Sciences, University of Oulu, Oulu, Finland. [4] Biocenter Oulu, University of Oulu, Oulu, Finland. [5] Unit of Primary Care, Oulu University Hospital, Oulu, Finland.
48
1] deCODE Genetics/Amgen, Inc., Reykjavik, Iceland. [2] Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
49
1] Anatomy, Institute of Biomedicine, University of Helsinki, Helsinki, Finland. [2] Minerva Foundation Institute for Medical Research, Helsinki, Finland.
50
1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. [2] Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
51
1] Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. [2] Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [3] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [4] Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts, USA. [5] Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.
52
1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. [2] Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK. [3] Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK.
53
1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. [2] Estonian Genome Center, University of Tartu, Tartu, Estonia. [3] Department of Biostatistics, University of Liverpool, Liverpool, UK.
54
Department of Genomics of Common Disease, School of Public Health, Imperial College London, Hammersmith Hospital, London, UK.
55
1] Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. [2] Department of Public Health, University of Helsinki, Helsinki, Finland. [3] Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.

Abstract

Using a genome-wide screen of 9.6 million genetic variants achieved through 1000 Genomes Project imputation in 62,166 samples, we identify association to lipid traits in 93 loci, including 79 previously identified loci with new lead SNPs and 10 new loci, 15 loci with a low-frequency lead SNP and 10 loci with a missense lead SNP, and 2 loci with an accumulation of rare variants. In six loci, SNPs with established function in lipid genetics (CELSR2, GCKR, LIPC and APOE) or candidate missense mutations with predicted damaging function (CD300LG and TM6SF2) explained the locus associations. The low-frequency variants increased the proportion of variance explained, particularly for low-density lipoprotein cholesterol and total cholesterol. Altogether, our results highlight the impact of low-frequency variants in complex traits and show that imputation offers a cost-effective alternative to resequencing.

PMID:
25961943
PMCID:
PMC4757735
DOI:
10.1038/ng.3300
[Indexed for MEDLINE]
Free PMC Article

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