Article open access publication

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

American Journal of Human Genetics, Elsevier, ISSN 1537-6605

Volume 104, 1, 2019

DOI:10.1016/j.ajhg.2018.12.001, Dimensions: pub.1110926855, PMC: PMC6323610, PMID: 30595373,

Authors

Yao, Jie (16)
Lee, Wen-Jane (17) (18)
An, Ping (1)
Gao, He (26)
Tzoulaki, Ioanna (26) (27)
Fu, Mao (21)
Hai, Yang (16)
Hunt, Steven C. (32) (33)
Justice, Anne E. (4) (35)
Qi, Qibin (38)
Ribel-Madsen, Rasmus (5) (39) (40)
Sofer, Tamar (8) (29)
Yang, Wei (1)
Sheu, Wayne Huey-Herng (18) (46) (47) (48)
Franco, Oscar H. (9) (49)
Ridker, Paul M. (7) (8)
Linneberg, Allan (5) (51) (52)
Jørgensen, Torben (5) (52) (54)
Brandslund, Ivan (24) (57)
Rao, D.C. (1)
Levy, Daniel (63) (64)
Meigs, James B. (8) (67) (68)

* Corresponding author

Affiliations

Organisations

  1. (1) Washington University in St. Louis, grid.4367.6
  2. (2) Boston University, grid.189504.1
  3. (3) Boston University School of Medicine, grid.475010.7
  4. (4) University of North Carolina System, grid.410711.2
  5. (5) University of Copenhagen, grid.5254.6, KU
  6. (6) Johns Hopkins University, grid.21107.35
  7. (7) Brigham and Women's Hospital, grid.62560.37
  8. (8) Harvard University, grid.38142.3c
  9. (9) Erasmus University Medical Center, grid.5645.2
  10. (10) University of Edinburgh, grid.4305.2
  11. (11) University of Greifswald, grid.5603.0
  12. (12) University of Cambridge, grid.5335.0
  13. (13) Leiden University Medical Center, grid.10419.3d
  14. (14) Federal University of Pelotas, grid.411221.5
  15. (15) University of Bristol, grid.5337.2
  16. (16) Harbor–UCLA Medical Center, grid.239844.0
  17. (17) Tunghai University, grid.265231.1
  18. (18) Taichung Veterans General Hospital, grid.410764.0
  19. (19) University of Illinois at Chicago, grid.185648.6
  20. (20) Mayo Clinic, grid.66875.3a
  21. (21) University of Maryland, Baltimore, grid.411024.2
  22. (22) New York University, grid.137628.9
  23. (23) Medical College of Wisconsin, grid.30760.32
  24. (24) University of Southern Denmark, grid.10825.3e, SDU
  25. (25) Samford University, grid.263055.7
  26. (26) Imperial College London, grid.7445.2
  27. (27) University of Ioannina, grid.9594.1
  28. (28) Steno Diabetes Center, grid.419658.7, Capital Region
  29. (29) University of Washington, grid.34477.33
  30. (30) University of Leicester, grid.9918.9
  31. (31) Cornell University, grid.5386.8
  32. (32) Department of Genetic Medicine, Weill Cornell Medicine, PO Box 24144, Doha, Qatar
  33. (33) University of Utah, grid.223827.e
  34. (34) University of Alabama at Birmingham, grid.265892.2
  35. (35) Biomedical and Translational Informatics, Geisinger Health, Danville, PA 17822, USA
  36. (36) Columbia University Medical Center, grid.239585.0
  37. (37) University of Minnesota, grid.17635.36
  38. (38) Albert Einstein College of Medicine, grid.251993.5
  39. (39) Danish Diabetes Academy, grid.484078.7
  40. (40) Department of Endocrinology, Diabetes and Metabolism, Rigshospitalet, Copenhagen University Hospital, 2100 Copenhagen, Denmark
  41. (41) Department of Cardiology, The Heart Centre, Rigshospitalet, University of Copenhagen, Copenhagen 2100, Denmark
  42. (42) Wentworth Institute of Technology, grid.422596.e
  43. (43) University of North Carolina at Chapel Hill, grid.10698.36
  44. (44) Aarhus University, grid.7048.b, AU
  45. (45) Aalborg Hospital, grid.27530.33, North Denmark Region
  46. (46) National Chung Hsing University, grid.260542.7
  47. (47) National Defense Medical Center, grid.260565.2
  48. (48) National Yang Ming University, grid.260770.4
  49. (49) University of Bern, grid.5734.5
  50. (50) University of Pittsburgh, grid.21925.3d
  51. (51) Bispebjerg Hospital, grid.411702.1, Capital Region
  52. (52) Rigshospitalet, grid.475435.4, Capital Region
  53. (53) University of Michigan, grid.214458.e
  54. (54) Aalborg University, grid.5117.2, AAU
  55. (55) Cedars-Sinai Medical Center, grid.50956.3f
  56. (56) Sygehus Lillebælt, grid.459623.f, Southern Denmark Region
  57. (57) Vejle Sygehus, grid.417271.6, Southern Denmark Region
  58. (58) Copenhagen Prospective Studies on Asthma in Childhood, Copenhagen University Hospital, Gentofte Naestved 2820, Denmark
  59. (59) University of Mississippi Medical Center, grid.410721.1
  60. (60) Wellcome Centre for Mitochondrial Research, grid.450004.5
  61. (61) University of Kentucky, grid.266539.d
  62. (62) MRC Human Genetics Unit, University of Edinburgh, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh EH4 2XU, UK
  63. (63) National Heart Lung and Blood Institute, grid.279885.9
  64. (64) The Framingham Heart Study, Framingham, MA, USA; The Population Sciences Branch, NHLBI/NIH, Bethesda, MD 20892, USA
  65. (65) Icahn School of Medicine at Mount Sinai, grid.59734.3c
  66. (66) King's College London, grid.13097.3c
  67. (67) Broad Institute, grid.66859.34
  68. (68) Massachusetts General Hospital, grid.32224.35

Description

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.

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University of Copenhagen

University of Southern Denmark

Aarhus University

Aalborg University

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Times Cited: 22

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