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Associations of mitochondrial and nuclear mitochondrial variants and genes with seven metabolic traits

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Title: Associations of mitochondrial and nuclear mitochondrial variants and genes with seven metabolic traits
Authors: Kraja, AT
Liu, C
Fetterman, JL
Graff, M
Have, CT
Gu, C
Yanek, LR
Feitosa, MF
Arking, DE
Chasman, D
Young, K
Ligthart, S
Hill, WD
Weiss, S
Luan, J
Giulianini, F
Li-Gao, R
Hartwig, FP
Lin, SJ
Wang, L
Richardson, TG
Yao, J
Fernandez, EP
Ghanbari, M
Wojczynski, MK
Lee, W-J
Argos, M
Armasu, SM
Barve, RA
Ryan, KA
An, P
Baranski, TJ
Bielinski, SJ
Bowden, DW
Broeckel, U
Christensen, K
Chu, AY
Corley, J
Cox, SR
Uitterlinden, AG
Rivadeneira, F
Cropp, CD
Daw, EW
Van Heemst, D
De las Fuentes, L
Gao, H
Tzoulaki, I
Ahluwalia, TS
De Mutsert, R
Emery, LS
Erzurumluoglu, AM
Perry, JA
Fu, M
Forouhi, NG
Gu, Z
Hai, Y
Harris, SE
Hemani, G
Hunt, SC
Irvin, MR
Jonsson, AE
Justice, AE
Kernson, ND
Larson, NB
Lin, K-H
Love-Gregory, LD
Mathias, RA
Lee, JH
Nauck, M
Noordam, R
Ong, KK
Pankow, J
Patki, A
Pattie, A
Petersmann, A
Qi, Q
Ribel-Madsen, R
Rohde, R
Sandow, K
Schnurr, TM
Sofer, T
Starr, JM
Taylor, AM
Teumer, A
Timpson, NJ
De Haan, HG
Wang, Y
Weeke, PE
Williams, C
Wu, H
Yang, W
Zeng, D
Witte, DR
Weir, BS
Wareham, NJ
Vestergaard, H
Turner, ST
Torp-Pedersen, C
Stergiakouli, E
Sheu, WH-H
Rosendaal, FR
Ikram, MA
Franco, OH
Ridker, PM
Perls, TT
Pedersen, O
Nohr, EA
Newman, AB
Linneberg, A
Langenberg, C
Kilpelainen, TO
Kardia, SLR
Jorgensen, ME
Jorgensen, T
Sorensen, TIA
Homuth, G
Hansen, T
Goodarzi, MO
Deary, IJ
Christensen, C
Chen, Y-DI
Chakravarti, A
Brandslund, I
Bonnelykke, K
Taylor, KD
Wilson, JG
Rodriguez, S
Davies, G
Horta, BL
Thyagarajan, B
Rao, DC
Grarup, N
Davila-Roman, VG
Hudson, G
Guo, X
Arnett, DK
Hayward, C
Vaidya, D
Mook-Kanamori, DO
Tiwari, HK
Levy, D
Loos, RJF
Dehghan, A
Elliott, P
Malik, AN
Scott, RA
Becker, DM
De Andrade, M
Province, MA
Meigs, JB
Rotter, J
North, KE
Item Type: Journal Article
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.
Issue Date: 3-Jan-2019
Date of Acceptance: 6-Dec-2018
URI: http://hdl.handle.net/10044/1/66677
DOI: https://dx.doi.org/10.1016/j.ajhg.2018.12.001
ISSN: 0002-9297
Publisher: Elsevier (Cell Press)
Start Page: 112
End Page: 138
Journal / Book Title: American Journal of Human Genetics
Volume: 104
Issue: 1
Copyright Statement: © 2019 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Sponsor/Funder: Home Office
Medical Research Council (MRC)
Medical Research Council (MRC)
Medical Research Council (MRC)
National Institute for Health Research
Imperial College Healthcare NHS Trust- BRC Funding
UK DRI Ltd
Funder's Grant Number: 7370192
MR/L01632X/1
MR/L01632X/1
MR/L01341X/1
RTJ6219303-1
RDF03
N/A
Keywords: Science & Technology
Life Sciences & Biomedicine
Genetics & Heredity
GENOME-WIDE ASSOCIATION
BODY-MASS INDEX
DNA COPY NUMBER
SUSCEPTIBILITY LOCI
ATHEROSCLEROSIS RISK
INDIVIDUALS REVEAL
PERIPHERAL-BLOOD
COMMON VARIANTS
GLYCEMIC TRAITS
ADIPOSE-TISSUE
BMI
HOMA-B
HOMA-IR
HbA1c
MT-nDNA candidate genes
glucose
insulin
mitochondria
mtDNA
waist-to-hip ratio
06 Biological Sciences
11 Medical And Health Sciences
Publication Status: Published
Online Publication Date: 2018-12-27
Appears in Collections:Faculty of Medicine
Epidemiology, Public Health and Primary Care



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