University of Leicester
Browse
AJHG-D-18-00438_R3.pdf (4.94 MB)

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

Download (4.94 MB)
journal contribution
posted on 2019-02-15, 12:36 authored by A Erzurumluoglu, AT Kraja, C Liu, JL Fetterman, M Graff, CT Have, et al
Mitochondria (MT), the major site of cellular energy production, are under dual genetic control by 37 mitochondrial DNA (mtDNA) genes and numerous nuclear genes (MTnDNA). 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 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 (GWAS)). Of these, 109 genes associated (P≤1E-06) with at least one 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.

Funding

A.E. Justice is supported by a K99/R00 from the National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI) (5K99HL130580-02 and 5R00HL130580-04). G. Hudson has received funding support by Wellcome Trust Centre for Mitochondrial Research, Grant Code G906919. J.I.R., X.G., Y.-D.I.C., K.D.T., Y.H., K.S., and J.Y. have received NIH support for research related to mitochondria.

History

Citation

American Journal of Human Genetics, Volume 104, Issue 1, 3 January 2019, pp 112-138

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Health Sciences

Version

  • AM (Accepted Manuscript)

Published in

American Journal of Human Genetics

Publisher

Elsevier (Cell Press)

issn

0002-9297

eissn

1537-6605

Acceptance date

2018-12-06

Copyright date

2019

Available date

2019-02-15

Publisher version

https://www.sciencedirect.com/science/article/pii/S000292971830452X

Language

en

Usage metrics

    University of Leicester Publications

    Categories

    Keywords

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC