Mapping methylation quantitative trait loci in cardiac tissues nominates risk loci and biological pathways in congenital heart disease.
Bayesian co-localization
Cardiac tissue
DNA methylation
Mendelian randomization
Quantitative trait loci
Journal
BMC genomic data
ISSN: 2730-6844
Titre abrégé: BMC Genom Data
Pays: England
ID NLM: 101775394
Informations de publication
Date de publication:
10 06 2021
10 06 2021
Historique:
received:
18
12
2020
accepted:
02
06
2021
entrez:
11
6
2021
pubmed:
12
6
2021
medline:
21
12
2021
Statut:
epublish
Résumé
Most congenital heart defects (CHDs) result from complex interactions among genetic susceptibilities, epigenetic modifications, and maternal environmental exposures. Characterizing the complex relationship between genetic, epigenetic, and transcriptomic variation will enhance our understanding of pathogenesis in this important type of congenital disorder. We investigated cis-acting effects of genetic single nucleotide polymorphisms (SNPs) on local DNA methylation patterns within 83 cardiac tissue samples and prioritized their contributions to CHD risk by leveraging results of CHD genome-wide association studies (GWAS) and their effects on cardiac gene expression. We identified 13,901 potential methylation quantitative trait loci (mQTLs) with a false discovery threshold of 5%. Further co-localization analyses and Mendelian randomization indicated that genetic variants near the HLA-DRB6 gene on chromosome 6 may contribute to CHD risk by regulating the methylation status of nearby CpG sites. Additional SNPs in genomic regions on chromosome 10 (TNKS2-AS1 gene) and chromosome 14 (LINC01629 gene) may simultaneously influence epigenetic and transcriptomic variations within cardiac tissues. Our results support the hypothesis that genetic variants may influence the risk of CHDs through regulating the changes of DNA methylation and gene expression. Our results can serve as an important source of information that can be integrated with other genetic studies of heart diseases, especially CHDs.
Sections du résumé
BACKGROUND
Most congenital heart defects (CHDs) result from complex interactions among genetic susceptibilities, epigenetic modifications, and maternal environmental exposures. Characterizing the complex relationship between genetic, epigenetic, and transcriptomic variation will enhance our understanding of pathogenesis in this important type of congenital disorder. We investigated cis-acting effects of genetic single nucleotide polymorphisms (SNPs) on local DNA methylation patterns within 83 cardiac tissue samples and prioritized their contributions to CHD risk by leveraging results of CHD genome-wide association studies (GWAS) and their effects on cardiac gene expression.
RESULTS
We identified 13,901 potential methylation quantitative trait loci (mQTLs) with a false discovery threshold of 5%. Further co-localization analyses and Mendelian randomization indicated that genetic variants near the HLA-DRB6 gene on chromosome 6 may contribute to CHD risk by regulating the methylation status of nearby CpG sites. Additional SNPs in genomic regions on chromosome 10 (TNKS2-AS1 gene) and chromosome 14 (LINC01629 gene) may simultaneously influence epigenetic and transcriptomic variations within cardiac tissues.
CONCLUSIONS
Our results support the hypothesis that genetic variants may influence the risk of CHDs through regulating the changes of DNA methylation and gene expression. Our results can serve as an important source of information that can be integrated with other genetic studies of heart diseases, especially CHDs.
Identifiants
pubmed: 34112112
doi: 10.1186/s12863-021-00975-2
pii: 10.1186/s12863-021-00975-2
pmc: PMC8194170
doi:
Substances chimiques
RNA, Long Noncoding
0
TNKS2 protein, human
EC 2.4.2.30
Tankyrases
EC 2.4.2.30
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
20Subventions
Organisme : NIDCR NIH HHS
ID : R03 DE024198
Pays : United States
Organisme : NHLBI NIH HHS
ID : K01 HL140333
Pays : United States
Organisme : NICHD NIH HHS
ID : R01 HD039054
Pays : United States
Organisme : NICHD NIH HHS
ID : R03 HD092854
Pays : United States
Références
Am J Hum Genet. 2010 Mar 12;86(3):411-9
pubmed: 20215007
Genet Epidemiol. 2016 May;40(4):304-14
pubmed: 27061298
Cold Spring Harb Perspect Biol. 2016 Sep 01;8(9):
pubmed: 27194046
Nat Genet. 2008 Jul;40(7):904-8
pubmed: 18568024
Nat Genet. 2013 Jul;45(7):818-21
pubmed: 23708190
Hum Mol Genet. 2015 Jan 1;24(1):265-73
pubmed: 25138779
PLoS One. 2011 Jan 24;6(1):e16506
pubmed: 21297937
Sci Adv. 2020 Sep 10;6(37):
pubmed: 32917697
Genome Res. 2002 Jun;12(6):996-1006
pubmed: 12045153
Genome Biol. 2014 Dec 03;15(12):503
pubmed: 25599564
Bioinformatics. 2014 May 15;30(10):1363-9
pubmed: 24478339
Mol Cell Proteomics. 2014 Feb;13(2):397-406
pubmed: 24309898
Nat Genet. 2020 Aug;52(8):769-777
pubmed: 32601476
Am J Hum Genet. 2016 May 5;98(5):934-955
pubmed: 27153397
Genome Res. 2010 Jul;20(7):883-9
pubmed: 20418490
Birth Defects Res A Clin Mol Teratol. 2011 Feb;91(2):69-76
pubmed: 21254366
PLoS One. 2015 Apr 13;10(4):e0123959
pubmed: 25875170
Genome Biol. 2017 Jun 19;18(1):120
pubmed: 28629478
Nat Commun. 2015 Aug 18;6:8082
pubmed: 26283027
Eur Heart J. 2018 Sep 7;39(34):3243-3249
pubmed: 29590334
PLoS Genet. 2017 Mar 9;13(3):e1006646
pubmed: 28278150
Am J Hum Genet. 2018 Nov 1;103(5):654-665
pubmed: 30401456
Elife. 2018 May 30;7:
pubmed: 29846171
Nature. 2009 Oct 1;461(7264):614-20
pubmed: 19759537
Genome Biol. 2014 Feb 20;15(2):R37
pubmed: 24555846
Zhonghua Fu Chan Ke Za Zhi. 2002 May;37(5):284-6
pubmed: 12133402
Birth Defects Res A Clin Mol Teratol. 2011 Dec;91(12):986-9
pubmed: 22140073
PLoS Genet. 2014 May 15;10(5):e1004383
pubmed: 24830394
Genet Epidemiol. 2013 Dec;37(8):802-13
pubmed: 24227294
Nature. 2017 Jan 5;541(7635):81-86
pubmed: 28002404
Biostatistics. 2009 Apr;10(2):327-34
pubmed: 19039033
Science. 1998 Nov 20;282(5393):1484-7
pubmed: 9822378
PLoS Genet. 2010 May 13;6(5):e1000952
pubmed: 20485568
Nat Genet. 2013 Jun;45(6):580-5
pubmed: 23715323
Am J Hum Genet. 2016 Jun 2;98(6):1114-1129
pubmed: 27236919
Nat Genet. 2003 Mar;33 Suppl:245-54
pubmed: 12610534
Bioinformatics. 2005 Jan 15;21(2):263-5
pubmed: 15297300
Genome Biol. 2014 May 29;15(5):R73
pubmed: 24887635
Nat Genet. 2013 Jul;45(7):822-4
pubmed: 23708191
Cell. 2011 Dec 9;147(6):1340-54
pubmed: 22153077
Hum Mol Genet. 2016 Jun 1;25(11):2331-2341
pubmed: 26965164
Eur J Epidemiol. 1992 Jul;8(4):503-8
pubmed: 1397216
Birth Defects Res. 2019 Nov 1;111(18):1329-1342
pubmed: 31654503
Hum Mol Genet. 2013 Apr 1;22(7):1473-81
pubmed: 23297363
EMBO Mol Med. 2018 Jan;10(1):107-120
pubmed: 29138229
Mol Cell Biol. 2006 Mar;26(6):2044-54
pubmed: 16507985
Am J Hum Genet. 2007 Sep;81(3):559-75
pubmed: 17701901
Circ Cardiovasc Genet. 2017 Jun;10(3):e001449
pubmed: 28468790
Images Paediatr Cardiol. 2000 Apr;2(2):17-23
pubmed: 22368579
Front Cell Dev Biol. 2014 May 05;2:15
pubmed: 25364722
Bioinformatics. 2017 Feb 15;33(4):558-560
pubmed: 28035024
Nat Rev Genet. 2012 May 29;13(7):484-92
pubmed: 22641018
Am J Obstet Gynecol. 2008 Sep;199(3):237.e1-9
pubmed: 18674752
JAMA Pediatr. 2014 Apr;168(4):371-7
pubmed: 24515445
Nature. 2010 Jul 8;466(7303):253-7
pubmed: 20613842
Bioinformatics. 2010 Mar 15;26(6):841-2
pubmed: 20110278
PLoS One. 2014 May 06;9(5):e96057
pubmed: 24800985
PLoS One. 2014 Sep 12;9(9):e107411
pubmed: 25215500
Nat Commun. 2019 Sep 25;10(1):4363
pubmed: 31554794