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Am J Hum Genet. 2019 Jan 3;104(1):112-138. doi: 10.1016/j.ajhg.2018.12.001. Epub 2018 Dec 27.

Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits.

Kraja AT1, Liu C2, Fetterman JL3, Graff M4, Have CT5, Gu C6, Yanek LR7, Feitosa MF8, Arking DE9, Chasman DI10, Young K4, Ligthart S11, Hill WD12, Weiss S13, Luan J14, Giulianini F15, Li-Gao R16, Hartwig FP17, Lin SJ8, Wang L8, Richardson TG18, Yao J19, Fernandez EP11, Ghanbari M11, Wojczynski MK8, Lee WJ20, Argos M21, Armasu SM22, Barve RA23, Ryan KA24, An P8, Baranski TJ25, Bielinski SJ26, Bowden DW27, Broeckel U28, Christensen K29, Chu AY15, Corley J12, Cox SR12, Uitterlinden AG30, Rivadeneira F30, Cropp CD31, Daw EW8, van Heemst D32, de Las Fuentes L33, Gao H34, Tzoulaki I35, Ahluwalia TS36, de Mutsert R16, Emery LS37, Erzurumluoglu AM38, Perry JA24, Fu M24, Forouhi NG14, Gu Z39, Hai Y19, Harris SE40, Hemani G18, Hunt SC41, Irvin MR42, Jonsson AE5, Justice AE43, Kerrison ND14, Larson NB26, Lin KH44, Love-Gregory LD45, Mathias RA46, Lee JH47, Nauck M48, Noordam R32, Ong KK14, Pankow J49, Patki A50, Pattie A12, Petersmann A48, Qi Q51, Ribel-Madsen R52, Rohde R4, Sandow K19, Schnurr TM5, Sofer T53, Starr JM54, Taylor AM12, Teumer A55, Timpson NJ18, de Haan HG16, Wang Y4, Weeke PE56, Williams C8, Wu H57, Yang W58, Zeng D59, Witte DR60, Weir BS37, Wareham NJ14, Vestergaard H61, Turner ST62, Torp-Pedersen C63, Stergiakouli E18, Sheu WH64, Rosendaal FR16, Ikram MA11, Franco OH65, Ridker PM10, Perls TT66, Pedersen O5, Nohr EA67, Newman AB68, Linneberg A69, Langenberg C14, Kilpeläinen TO5, Kardia SLR70, Jørgensen ME36, Jørgensen T71, Sørensen TIA72, Homuth G13, Hansen T5, Goodarzi MO73, Deary IJ12, Christensen C74, Chen YI19, Chakravarti A75, Brandslund I76, Bonnelykke K77, Taylor KD19, Wilson JG78, Rodriguez S18, Davies G12, Horta BL79, Thyagarajan B80, Rao DC6, Grarup N5, Davila-Roman VG33, Hudson G81, Guo X19, Arnett DK82, Hayward C83, Vaidya D7, Mook-Kanamori DO84, Tiwari HK50, Levy D85, Loos RJF86, Dehghan A34, Elliott P34, Malik AN87, Scott RA14, Becker DM7, de Andrade M22, Province MA8, Meigs JB88, Rotter JI19, North KE89.

Author information

1
Division of Statistical Genomics, Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St Louis, MO 63110, USA. Electronic address: aldikraja@wustl.edu.
2
Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
3
Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA.
4
Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27516, USA.
5
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark.
6
Division of Biostatistics, Washington University School of Medicine, St Louis, MO 63110, USA.
7
GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
8
Division of Statistical Genomics, Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St Louis, MO 63110, USA.
9
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
10
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
11
Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3015 CE, the Netherlands.
12
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK.
13
Interfaculty Institute for Genetics and Functional Genomics, University Medicine and University of Greifswald, Greifswald 17475, Germany.
14
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, UK.
15
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
16
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands.
17
Postgraduate Program in Epidemiology, Federal University of Pelotas, Pelotas 96020-220, Brazil; MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, University of Bristol, Bristol BS8 2BN, UK.
18
MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, University of Bristol, Bristol BS8 2BN, UK.
19
Institute for Translational Genomics and Population Sciences, LABioMed and Department of Pediatrics, at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
20
Department of Medical Research, Taichung Veterans General Hospital, Taichung 407, Taiwan; Department of Social Work, Tunghai University, Taichung 407, Taiwan.
21
Department of Epidemiology and Biostatistics, University of Illinois at Chicago, Chicago, IL 60612, USA.
22
Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
23
Department of Genetics, Washington University School of Medicine, St Louis, MO 63110, USA.
24
School of Medicine, Division of Endocrinology, Diabetes and Nutrition, and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
25
Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA.
26
Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
27
Center for Diabetes Research, Wake Forest School of Medicine, Cincinnati, OH 45206, USA.
28
Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
29
The Danish Aging Research Center, University of Southern Denmark, Odense 5000, Denmark.
30
Department of Internal Medicine, Erasmus Medical Center, 3000 CA Rotterdam, the Netherlands.
31
Samford University McWhorter School of Pharmacy, Birmingham, Alabama, Translational Genomics Research Institute (TGen), Phoenix, AZ 35229, USA.
32
Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands.
33
Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.
34
Department of Biostatistics and Epidemiology, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK.
35
Department of Biostatistics and Epidemiology, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK; Department of Hygiene and Epidemiology, University of Ioannina, Ioannina 45110, Greece.
36
Steno Diabetes Center Copenhagen, Copenhagen 2820, Denmark.
37
Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
38
Department of Health Sciences, University of Leicester, Leicester LE1 7RH, UK.
39
Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
40
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Centre for Genomic and Experimental Medicine, Medical Genetics Section, University of Edinburgh, Edinburgh EH4 2XU, UK.
41
Department of Internal Medicine, University of Utah, Salt Lake City, UT 84132, USA; Department of Genetic Medicine, Weill Cornell Medicine, PO Box 24144, Doha, Qatar.
42
Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
43
Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27516, USA; Biomedical and Translational Informatics, Geisinger Health, Danville, PA 17822, USA.
44
Department of Ophthalmology, Taichung Veterans General Hospital, Taichung 407, Taiwan.
45
Genomics & Pathology Services, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
46
GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; GeneSTAR Research Program, Divisions of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
47
Taub Institute for Research on Alzheimer disease and the Aging Brain, Columbia University Medical Center, New York, NY 10032, USA.
48
Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald 17475, Germany.
49
University of Minnesota School of Public Health, Division of Epidemiology and Community Health, Minneapolis, MN 55454, USA.
50
Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
51
Department of Epidemiology & Population Health, Albert Einstein School of Medicine, Bronx, NY 10461, USA.
52
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark; Department of Endocrinology, Diabetes and Metabolism, Rigshospitalet, Copenhagen University Hospital, 2100 Copenhagen, Denmark; The Danish Diabetes Academy, 5000 Odense, Denmark.
53
Department of Biostatistics, University of Washington, Seattle, WA 98195, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
54
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK; Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh EH8 9JZ, UK.
55
Institute for Community Medicine, University Medicine Greifswald, 17475 Greifswald, Germany.
56
Department of Cardiology, The Heart Centre, Rigshospitalet, University of Copenhagen, Copenhagen 2100, Denmark.
57
Computer Science and Networking, Wentworth Institute of Technology, Boston, MA 02115, USA.
58
Genome Technology Access Center, Washington University School of Medicine, St Louis, MO 63110, USA.
59
Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
60
Department of Public Health, Section of Epidemiology, Aarhus University, Denmark, Danish Diabetes Academy, Odense University Hospital, 5000 Odense, Denmark.
61
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark; Steno Diabetes Center Copenhagen, Copenhagen 2820, Denmark.
62
Division of Nephrology and Hypertension, Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN 55902, USA.
63
Department of Health Science and Technology, Aalborg University Hospital, Aalborg 9220, Denmark.
64
Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan; Institute of Medical Technology, National Chung-Hsing University, Taichung 402, Taiwan; School of Medicine, National Defense Medical Center, Taipei 114, Taiwan; School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.
65
Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3015 CE, the Netherlands; Institute of Social and Preventive Medicine (ISPM), University of Bern, 3012 Bern, Switzerland.
66
Department of Medicine, Geriatrics Section, Boston University School of Medicine and Boston Medical Center, Boston, MA 02118, USA.
67
Research Unit for Gynecology and Obstetrics, Department of Clinical Research, University of Southern Denmark, 5000 Odense, Denmark.
68
Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
69
Department of Clinical Experimental Research, Rigshospitalet, Copenhagen 2200, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark; The Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, The Capital Region, Copenhagen 2000, Denmark.
70
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.
71
Research Centre for Prevention and Health, Glostrup Hospital, Glostrup 2600, Denmark; Department of Public Health, Faculty of Health Sciences, University of Copenhagen, Copenhagen 1014, Denmark; Faculty of Medicine, Aalborg University, Aalborg 9100, Denmark.
72
Novo Nordisk Foundation Center for Basic Metabolic Research (Section of Metabolic Genetics) and Department of Public Health (Section on Epidemiology), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200N, Denmark.
73
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
74
Department of Internal Medicine, Section of Endocrinology, Vejle Lillebaelt Hospital, 7100 Vejle, Denmark.
75
Center for Complex Disease Genomics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
76
Department of Clinical Biochemistry, Vejle Hospital, 7100 Vejle, Denmark; Institute of Regional Health Research, University of Southern Denmark, 5000 Odense C, Denmark.
77
Copenhagen Prospective Studies on Asthma in Childhood, Copenhagen University Hospital, Gentofte & Naestved 2820, Denmark; Health Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
78
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
79
Postgraduate Program in Epidemiology, Federal University of Pelotas, Pelotas 96020-220, Brazil.
80
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
81
Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
82
University of Kentucky, College of Public Health, Lexington, KY 40508, USA.
83
MRC Human Genetics Unit, University of Edinburgh, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh EH4 2XU, UK.
84
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands; Department of Public Health and Primary Care, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
85
The Framingham Heart Study, Framingham, MA, USA; The Population Sciences Branch, NHLBI/NIH, Bethesda, MD 20892, USA.
86
Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Genetics of Obesity and Related Traits Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
87
King's College London, Department of Diabetes, School of Life Course, Faculty of Life Sciences and Medicine, London SE1 1NN, UK.
88
Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Division of General Internal Medicine, Massachusetts General Hospital, Boston 02114, MA, USA; Program in Medical and Population Genetics, Broad Institute, Boston, MA 02142, USA.
89
Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27516, USA. Electronic address: kari_north@unc.edu.

Abstract

Mitochondria (MT), the major site of cellular energy production, are under dual genetic control by 37 mitochondrial DNA (mtDNA) genes and numerous nuclear genes (MT-nDNA). In the CHARGEmtDNA+ Consortium, we studied genetic associations of mtDNA and MT-nDNA associations with body mass index (BMI), waist-hip-ratio (WHR), glucose, insulin, HOMA-B, HOMA-IR, and HbA1c. This 45-cohort collaboration comprised 70,775 (insulin) to 170,202 (BMI) pan-ancestry individuals. Validation and imputation of mtDNA variants was followed by single-variant and gene-based association testing. We report two significant common variants, one in MT-ATP6 associated (p ≤ 5E-04) with WHR and one in the D-loop with glucose. Five rare variants in MT-ATP6, MT-ND5, and MT-ND6 associated with BMI, WHR, or insulin. Gene-based meta-analysis identified MT-ND3 associated with BMI (p ≤ 1E-03). We considered 2,282 MT-nDNA candidate gene associations compiled from online summary results for our traits (20 unique studies with 31 dataset consortia's genome-wide associations [GWASs]). Of these, 109 genes associated (p ≤ 1E-06) with at least 1 of our 7 traits. We assessed regulatory features of variants in the 109 genes, cis- and trans-gene expression regulation, and performed enrichment and protein-protein interactions analyses. Of the identified mtDNA and MT-nDNA genes, 79 associated with adipose measures, 49 with glucose/insulin, 13 with risk for type 2 diabetes, and 18 with cardiovascular disease, indicating for pleiotropic effects with health implications. Additionally, 21 genes related to cholesterol, suggesting additional important roles for the genes identified. Our results suggest that mtDNA and MT-nDNA genes and variants reported make important contributions to glucose and insulin metabolism, adipocyte regulation, diabetes, and cardiovascular disease.

KEYWORDS:

BMI; HOMA-B; HOMA-IR; HbA1c; MT-nDNA candidate genes; glucose; insulin; mitochondria; mtDNA; waist-to-hip ratio

PMID:
30595373
PMCID:
PMC6323610
[Available on 2019-07-03]
DOI:
10.1016/j.ajhg.2018.12.001

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