Mitochondrial GWAS and association of nuclear - mitochondrial epistasis with BMI in T1DM patients.
GWAS
Mitochondria
Mitochondrial-nuclear interactions
Obesity
Journal
BMC medical genomics
ISSN: 1755-8794
Titre abrégé: BMC Med Genomics
Pays: England
ID NLM: 101319628
Informations de publication
Date de publication:
07 07 2020
07 07 2020
Historique:
received:
02
08
2019
accepted:
30
06
2020
entrez:
9
7
2020
pubmed:
9
7
2020
medline:
11
5
2021
Statut:
epublish
Résumé
BMI is a strong indicator of complications from type I diabetes, especially under intensive treatment. We have genotyped 435 type 1 diabetics using Illumina Infinium Omni Express Exome-8 v1.4 arrays and performed mitoGWAS on BMI. We identified additive interactions between mitochondrial and nuclear variants in genes associated with mitochondrial functioning MitoCarta2.0 and confirmed and refined the results on external cohorts: the Framingham Heart Study (FHS) and GTEx data. Linear mixed model analysis was performed using the GENESIS package in R/Bioconductor. We find a borderline significant association between the mitochondrial variant rs28357980, localized to MT-ND2, and BMI (β = - 0.69, p = 0.056). This BMI association was confirmed on 1889 patients from FHS cohort (β = - 0.312, p = 0.047). Next, we searched for additive interactions between mitochondrial and nuclear variants. MT-ND2 variants interacted with variants in the genes SIRT3, ATP5B, CYCS, TFB2M and POLRMT. TFB2M is a mitochondrial transcription factor and together with TFAM creates a transcription promoter complex for the mitochondrial polymerase POLRMT. We have found an interaction between rs3021088 in MT-ND2 and rs6701836 in TFB2M leading to BMI decrease (inter_pval = 0.0241), while interaction of rs3021088 in MT-ND2 and rs41542013 in POLRMT led to BMI increase (inter_pval = 0.0004). The influence of these interactions on BMI was confirmed in external cohorts. Here, we have shown that variants in the mitochondrial genome as well as additive interactions between mitochondrial and nuclear SNPs influence BMI in T1DM and general cohorts.
Sections du résumé
BACKGROUND
BMI is a strong indicator of complications from type I diabetes, especially under intensive treatment.
METHODS
We have genotyped 435 type 1 diabetics using Illumina Infinium Omni Express Exome-8 v1.4 arrays and performed mitoGWAS on BMI. We identified additive interactions between mitochondrial and nuclear variants in genes associated with mitochondrial functioning MitoCarta2.0 and confirmed and refined the results on external cohorts: the Framingham Heart Study (FHS) and GTEx data. Linear mixed model analysis was performed using the GENESIS package in R/Bioconductor.
RESULTS
We find a borderline significant association between the mitochondrial variant rs28357980, localized to MT-ND2, and BMI (β = - 0.69, p = 0.056). This BMI association was confirmed on 1889 patients from FHS cohort (β = - 0.312, p = 0.047). Next, we searched for additive interactions between mitochondrial and nuclear variants. MT-ND2 variants interacted with variants in the genes SIRT3, ATP5B, CYCS, TFB2M and POLRMT. TFB2M is a mitochondrial transcription factor and together with TFAM creates a transcription promoter complex for the mitochondrial polymerase POLRMT. We have found an interaction between rs3021088 in MT-ND2 and rs6701836 in TFB2M leading to BMI decrease (inter_pval = 0.0241), while interaction of rs3021088 in MT-ND2 and rs41542013 in POLRMT led to BMI increase (inter_pval = 0.0004). The influence of these interactions on BMI was confirmed in external cohorts.
CONCLUSIONS
Here, we have shown that variants in the mitochondrial genome as well as additive interactions between mitochondrial and nuclear SNPs influence BMI in T1DM and general cohorts.
Identifiants
pubmed: 32635923
doi: 10.1186/s12920-020-00752-7
pii: 10.1186/s12920-020-00752-7
pmc: PMC7341625
doi:
Substances chimiques
DNA, Mitochondrial
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
97Subventions
Organisme : Narodowe Centrum Nauki
ID : Nr 2013/11/D/NZ5/03219
Pays : International
Références
Nat Rev Mol Cell Biol. 2016 Apr;17(4):213-26
pubmed: 26956194
Nat Genet. 2010 Nov;42(11):937-48
pubmed: 20935630
Diabetes Care. 2001 Oct;24(10):1711-21
pubmed: 11574431
Nat Genet. 2012 Feb 19;44(3):307-11
pubmed: 22344219
Int J Oncol. 2015 Sep;47(3):1077-83
pubmed: 26179426
Am J Clin Nutr. 2019 Jan 1;109(1):29-42
pubmed: 30615110
Nature. 2016 Jul 28;535(7613):561-5
pubmed: 27383793
Am J Hum Genet. 2007 Sep;81(3):559-75
pubmed: 17701901
Nature. 2003 Dec 18;426(6968):789-96
pubmed: 14685227
Nat Genet. 2016 Oct;48(10):1279-83
pubmed: 27548312
Diabetes. 2013 Mar;62(3):672-8
pubmed: 23431006
Pediatr Diabetes. 2010 Feb;11(1):4-11
pubmed: 19473302
Mol Biotechnol. 2013 Jul;54(3):756-69
pubmed: 23208548
Hum Mol Genet. 2009 Sep 15;18(18):3502-7
pubmed: 19553259
Nat Commun. 2016 Dec 22;7:13889
pubmed: 28004827
Nat Genet. 2016 Oct;48(10):1284-1287
pubmed: 27571263
Dis Markers. 2008;25(3):131-9
pubmed: 19096125
Nucleic Acids Res. 2016 Sep 19;44(16):7817-29
pubmed: 27436287
Biochim Biophys Acta. 2010 Jun-Jul;1797(6-7):1099-104
pubmed: 20074547
Acta Neuropathol. 2012 Aug;124(2):199-208
pubmed: 22526016
J Biol Chem. 2008 Apr 18;283(16):10690-7
pubmed: 18281288
J Biol Chem. 2007 Feb 23;282(8):5171-9
pubmed: 17189252
Mol Aspects Med. 2013 Apr-Jun;34(2-3):465-84
pubmed: 23266187
PLoS Genet. 2014 Apr 17;10(4):e1004234
pubmed: 24743097
Diabetes. 2011 Jan;60(1):355-9
pubmed: 20980458
BMC Genet. 2012 Jul 24;13:63
pubmed: 22827487
PLoS One. 2014 Aug 25;9(8):e105116
pubmed: 25153900
Parkinsonism Relat Disord. 2009 Jul;15(6):468-70
pubmed: 18980857
Mol Med Rep. 2015 Nov;12(5):6976-84
pubmed: 26352605
Annu Rev Nurs Res. 2013;31:47-69
pubmed: 24894137
Endocrinology. 2012 Oct;153(10):4666-76
pubmed: 22919063
Oncotarget. 2015 Apr 20;6(11):8552-66
pubmed: 25839158
Genome Res. 2009 Jan;19(1):159-65
pubmed: 19037013
Mol Biol Rep. 2010 Jul;37(6):2743-8
pubmed: 19763879
BMB Rep. 2011 Jun;44(6):381-6
pubmed: 21699750
Mitochondrion. 2016 Sep;30:187-96
pubmed: 27503698
Nucleic Acids Res. 2016 Jan 4;44(D1):D1251-7
pubmed: 26450961
PLoS Genet. 2006 Dec;2(12):e190
pubmed: 17194218
Obesity (Silver Spring). 2008 Oct;16(10):2323-30
pubmed: 18719634
Free Radic Biol Med. 2017 Jan;102:174-187
pubmed: 27890640
Cell. 2012 Mar 16;148(6):1145-59
pubmed: 22424226
Diabetes Care. 2017 Dec;40(12):1756-1762
pubmed: 29138273
Diabetes Care. 2003 Oct;26(10):2871-5
pubmed: 14514594
FEBS J. 2017 Jan;284(2):196-210
pubmed: 27283924
Cell Death Dis. 2011 Oct 27;2:e222
pubmed: 22030538
Nat Genet. 2006 Aug;38(8):904-9
pubmed: 16862161
Genes Dev. 2009 Aug 1;23(15):1714-36
pubmed: 19651984
Genetics. 2014 Feb;196(2):413-25
pubmed: 24298061
Annu Rev Biochem. 2007;76:701-22
pubmed: 17227225
J Neurol Sci. 2015 Sep 15;356(1-2):55-60
pubmed: 26201854
Mol Metab. 2016 Feb 02;5(4):283-295
pubmed: 27069868
Bioinformatics. 2010 Nov 15;26(22):2867-73
pubmed: 20926424
Ann Epidemiol. 2018 Apr;28(4):249-257.e1
pubmed: 29501221
PLoS Genet. 2013 May;9(5):e1003520
pubmed: 23737753
Autophagy. 2017 May 4;13(5):779-780
pubmed: 28323521
Cold Spring Harb Perspect Biol. 2013 Nov 01;5(11):a021220
pubmed: 24186072
Nature. 2015 Feb 12;518(7538):197-206
pubmed: 25673413
Biomed Res Int. 2013;2013:631082
pubmed: 23936828
Ageing Res Rev. 2009 Jul;8(3):173-88
pubmed: 19491041
J Inherit Metab Dis. 2014 Jul;37(4):565-75
pubmed: 24797559