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Nat Commun. 2019 Nov 12;10(1):5121. doi: 10.1038/s41467-019-12958-0.

Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration.

Noordam R1, Bos MM2, Wang H3, Winkler TW4, Bentley AR5, Kilpeläinen TO6,7, de Vries PS8, Sung YJ9, Schwander K9, Cade BE3, Manning A10,11, Aschard H12,13, Brown MR8, Chen H8,14, Franceschini N15, Musani SK16, Richard M17, Vojinovic D18, Aslibekyan S19, Bartz TM20, de Las Fuentes L9,21, Feitosa M22, Horimoto AR23, Ilkov M24, Kho M25, Kraja A22, Li C26, Lim E27, Liu Y28, Mook-Kanamori DO29,30, Rankinen T31, Tajuddin SM32, van der Spek A18, Wang Z8, Marten J33, Laville V13, Alver M34,35, Evangelou E36,37, Graff ME15, He M38, Kühnel B39,40, Lyytikäinen LP41,42, Marques-Vidal P43, Nolte IM44, Palmer ND45, Rauramaa R46, Shu XO47, Snieder H44, Weiss S48, Wen W47, Yanek LR49, Adolfo C16, Ballantyne C50,51, Bielak L25, Biermasz NR52,53, Boerwinkle E8,54, Dimou N37, Eiriksdottir G24, Gao C55, Gharib SA56, Gottlieb DJ3,11,57, Haba-Rubio J58, Harris TB59, Heikkinen S60,61, Heinzer R58, Hixson JE8, Homuth G48, Ikram MA18,62, Komulainen P46, Krieger JE23, Lee J3, Liu J63, Lohman KK64, Luik AI18, Mägi R34, Martin LW65, Meitinger T66, Metspalu A34,35, Milaneschi Y65, Nalls MA67,68, O'Connell J69,70, Peters A40,71, Peyser P25, Raitakari OT72,73, Reiner AP63, Rensen PCN52,53, Rice TK9, Rich SS74, Roenneberg T75, Rotter JI76, Schreiner PJ77, Shikany J78, Sidney SS79, Sims M16, Sitlani CM80, Sofer T3,81, Strauch K82,83, Swertz MA84, Taylor KD76, Uitterlinden AG18,85, van Duijn CM18,86, Völzke H87, Waldenberger M39,40,71, Wallance RB88, van Dijk KW52,53,89, Yu C38, Zonderman AB90, Becker DM49, Elliott P35,91,92,93, Esko T34,94, Gieger C39,95, Grabe HJ96, Lakka TA46,61,97, Lehtimäki T41,42, North KE15, Penninx BWJH98, Vollenweider P43, Wagenknecht LE99, Wu T38, Xiang YB100, Zheng W47, Arnett DK101, Bouchard C31, Evans MK32, Gudnason V24,102, Kardia S25, Kelly TN103, Kritchevsky SB104, Loos RJF105,106, Pereira AC23, Province M22, Psaty BM107,108, Rotimi C5, Zhu X109, Amin N18, Cupples LA27,110, Fornage M17, Fox EF111, Guo X76, Gauderman WJ112, Rice K113, Kooperberg C63, Munroe PB114,115, Liu CT27, Morrison AC8, Rao DC9, van Heemst D2, Redline S116,117.

Author information

1
Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands. r.noordam@lumc.nl.
2
Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
3
Division of Sleep and Circadian Disorders, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA.
4
Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.
5
Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
6
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark.
7
Department of Environmental Medicine and Public Health, The Icahn School of Medicine at Mount Sinai, New York, New York, USA.
8
Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
9
Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA.
10
Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, USA.
11
Department of Medicine, Harvard Medical School, Boston, MA, USA.
12
Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
13
Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur, Paris, France.
14
Center for Precision Health, School of Public Health & School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, USA.
15
Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
16
Jackson Heart Study, Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
17
Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA.
18
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
19
Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.
20
Cardiovascular Health Research Unit, Biostatistics and Medicine, University of Washington, Seattle, WA, USA.
21
Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
22
Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
23
Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor), University of São Paulo Medical School, São Paulo, SP, Brazil.
24
Icelandic Heart Association, Kopavogur, Iceland.
25
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
26
Epidemiology and Biostatistics, University of Georgia at Athens College of Public Health, Athens, GA, USA.
27
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
28
Public Health Sciences, Epidemiology and Prevention, Wake Forest University Health Sciences, Winston-Salem, NC, USA.
29
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, Netherlands.
30
Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, Netherlands.
31
Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA.
32
Health Disparities Research Section, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
33
Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
34
Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.
35
Department of Biotechnology, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
36
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
37
Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.
38
Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
39
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
40
Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
41
Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland.
42
Department of Clinical Chemistry, Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
43
Medicine, Internal Medicine, Lausanne University Hospital, Lausanne, Switzerland.
44
University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, The Netherlands.
45
Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
46
Foundation for Research in Health Exercise and Nutrition, Kuopio Research Institute of Exercise Medicine, Kuopio, Finland.
47
Division of Epidemiology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
48
Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
49
Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
50
Section of Cardiovascular Research, Baylor College of Medicine, Houston, TX, USA.
51
Houston Methodist Debakey Heart and Vascular Center, Houston, TX, USA.
52
Department of Internal Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.
53
Einthoven Laboratory for Experimental Vascular Medicine, Leiden, The Netherlands.
54
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
55
Molecular Genetics and Genomics Program, Wake Forest School of Medicine, Winston-Salem, NC, USA.
56
Computational Medicine Core, Center for Lung Biology, UW Medicine Sleep Center, Medicine, University of Washington, Seattle, WA, USA.
57
VA Boston Healthcare System, Boston, MA, USA.
58
Medicine, Sleep Laboratory, Lausanne University Hospital, Lausanne, Switzerland.
59
Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
60
Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland.
61
Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio Campus, Finland.
62
Department of Radiology and Nuclear Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
63
Fred Hutchinson Cancer Research Center, University of Washington School of Public Health, Seattle, WA, USA.
64
Public Health Sciences, Biostatistical Sciences, Wake Forest University Health Sciences, Winston-Salem, NC, USA.
65
Cardiology, School of Medicine and Health Sciences, George Washington University, Washington, D.C., USA.
66
Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
67
Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
68
Data Tecnica International, Glen Echo, MD, USA.
69
Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA.
70
Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
71
DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Neuherberg, Germany.
72
Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
73
University of Turku, Turku, Finland.
74
Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
75
Institute of Medical Psychology, Ludwig-Maximilians-Universitat Munchen, Munich, Germany.
76
Genomic Outcomes, Department of Pediatrics, Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Torrance, CC, USA.
77
Division of Epidemiology & Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA.
78
Division of Preventive Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
79
Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.
80
Cardiovascular Health Research Unit, Medicine, University of Washington, Seattle, WA, USA.
81
Institute of Human Genetics, Technische Universität München, Munich, Germany.
82
Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
83
Institute for Medical Informatics Biometry and Epidemiology, Ludwig-Maximilians-Universitat Munchen, Munich, Germany.
84
University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
85
Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
86
Nuffield Department of Population Health, University of Oxford, Oxford, UK.
87
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
88
Department of Epidemiology, University of Iowa College of Public Health, Iowa City, IA, USA.
89
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
90
Behavioral Epidemiology Section, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
91
MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
92
National Institute of Health Research Imperial College London Biomedical Research Centre, London, UK.
93
UK-DRI Dementia Research Institute at Imperial College London, London, UK.
94
Broad Institute of the Massachusetts Institute of Technology and Harvard University, Boston, MA, USA.
95
German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
96
Department Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
97
Department of Clinical Phsiology and Nuclear Medicine, Kuopia University Hospital, Kuopio, Finland.
98
Department of Psychiatry, Amsterdam Neuroscience and Amsterdam Public Health Research Institute, Amsterdam UMC, Vrije Universiteit, Amsterdam, The Netherlands.
99
Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
100
SKLORG & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P. R. China.
101
Dean's Office, University of Kentucky College of Public Health, Lexington, KS, USA.
102
Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
103
Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA.
104
Sticht Center for Healthy Aging and Rehabilitation, Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
105
The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, NY, USA.
106
The Mindich Child Health Development Institute, The Icahn School of Medicine at Mount Sinai, New York, NY, USA.
107
Cardiovascular Health Research Unit, Epidemiology, Medicine and Health Services, University of Washington, Seattle, WA, USA.
108
Kaiser Permanente Washington, Health Research Institute, Seattle, WA, USA.
109
Department of Population Quantitative and Health Sciences, Case Western Reserve University, Cleveland, OH, USA.
110
NHLBI Framingham Heart Study, Framingham, MA, USA.
111
Cardiology, Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
112
Biostatistics, Preventive Medicine, University of Southern California, Los Angeles, CA, USA.
113
Department of Biostatistics, University of Washington, Seattle, WA, USA.
114
Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
115
NIHR Barts Cardiovascular Biomedical Research Centre, Queen Mary University of London, London, London, UK.
116
Division of Sleep and Circadian Disorders, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA. sredline@bwh.harvard.edu.
117
Division of Pulmonary Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. sredline@bwh.harvard.edu.

Abstract

Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles.

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