Identification of genetic variants influencing methylation in brain with pleiotropic effects on psychiatric disorders.
Allele-specific methylation
Comorbid disorders
DNA methylation
Gene expression
Psychiatric disorders
Journal
Progress in neuro-psychopharmacology & biological psychiatry
ISSN: 1878-4216
Titre abrégé: Prog Neuropsychopharmacol Biol Psychiatry
Pays: England
ID NLM: 8211617
Informations de publication
Date de publication:
08 03 2022
08 03 2022
Historique:
received:
01
04
2021
revised:
06
10
2021
accepted:
06
10
2021
pubmed:
13
10
2021
medline:
25
2
2022
entrez:
12
10
2021
Statut:
ppublish
Résumé
Psychiatric disorders affect 29% of the global population at least once in the lifespan, and genetic studies have proved a shared genetic basis among them, although the underlying molecular mechanisms remain largely unknown. DNA methylation plays an important role in complex disorders and, remarkably, enrichment of common genetic variants influencing allele-specific methylation (ASM) has been reported among variants associated with specific psychiatric disorders. In the present study we assessed the contribution of ASM to a set of eight psychiatric disorders by combining genetic, epigenetic and expression data. We interrogated a list of 3896 ASM tagSNPs in the brain in the summary statistics of a cross-disorder GWAS meta-analysis of eight psychiatric disorders from the Psychiatric Genomics Consortium, including more than 162,000 cases and 276,000 controls. We identified 80 SNPs with pleiotropic effects on psychiatric disorders that show an opposite directional effect on methylation and gene expression. These SNPs converge on eight candidate genes: ZSCAN29, ZSCAN31, BTN3A2, DDAH2, HAPLN4, ARTN, FAM109B and NAGA. ZSCAN29 shows the broadest pleiotropic effects, showing associations with five out of eight psychiatric disorders considered, followed by ZSCAN31 and BTN3A2, associated with three disorders. All these genes overlap with CNVs related to cognitive phenotypes and psychiatric traits, they are expressed in the brain, and seven of them have previously been associated with specific psychiatric disorders, supporting our results. To sum up, our integrative functional genomics analysis identified eight psychiatric disease risk genes that impact a broad list of disorders and highlight an etiologic role of SNPs that influence DNA methylation and gene expression in the brain.
Identifiants
pubmed: 34637873
pii: S0278-5846(21)00213-X
doi: 10.1016/j.pnpbp.2021.110454
pmc: PMC10501479
mid: NIHMS1929221
pii:
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
110454Subventions
Organisme : NIMH NIH HHS
ID : R00 MH101367
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH119243
Pays : United States
Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Références
Neuroimmunomodulation. 2018;25(5-6):246-270
pubmed: 30517945
Nat Commun. 2017 Oct 24;8(1):1011
pubmed: 29066808
Nat Commun. 2018 May 8;9(1):1825
pubmed: 29739930
Cell. 2019 Dec 12;179(7):1469-1482.e11
pubmed: 31835028
Nat Commun. 2018 May 29;9(1):2098
pubmed: 29844566
Curr Med Chem. 2016;23(24):2680-2691
pubmed: 27450675
Nature. 2015 Feb 19;518(7539):317-30
pubmed: 25693563
Cell. 2017 Jun 15;169(7):1177-1186
pubmed: 28622505
Cell. 2019 May 2;177(4):1022-1034.e6
pubmed: 31051098
Nat Genet. 2019 May;51(5):793-803
pubmed: 31043756
Science. 2012 Sep 7;337(6099):1190-5
pubmed: 22955828
Clin Exp Immunol. 2019 Sep;197(3):294-307
pubmed: 31125426
Mol Psychiatry. 2011 Jan;16(1):59-66
pubmed: 20048749
PLoS Genet. 2012;8(3):e1002555
pubmed: 22396665
Am J Hum Genet. 2009 Apr;84(4):524-33
pubmed: 19344873
Elife. 2016 May 10;5:
pubmed: 27162171
Am J Hum Genet. 2010 Mar 12;86(3):411-9
pubmed: 20215007
Epigenetics Chromatin. 2019 Oct 8;12(1):60
pubmed: 31594537
Science. 2018 Jun 22;360(6395):
pubmed: 29930110
Nat Genet. 2013 Oct;45(10):1150-9
pubmed: 23974872
Nat Genet. 2019 Mar;51(3):431-444
pubmed: 30804558
Nucleic Acids Res. 2016 Jan 4;44(D1):D877-81
pubmed: 26657631
PLoS One. 2013;8(1):e53092
pubmed: 23326387
Biochim Biophys Acta Mol Basis Dis. 2019 Aug 1;1865(8):1949-1967
pubmed: 30500433
Neuron. 2002 Jul 18;35(2):267-82
pubmed: 12160745
J Psychiatr Res. 2008 Oct;42(14):1145-53
pubmed: 18313696
Nat Genet. 2018 Jul;50(7):920-927
pubmed: 29942085
Neuron. 1998 Dec;21(6):1291-302
pubmed: 9883723
Nat Genet. 2018 May;50(5):668-681
pubmed: 29700475
Prog Neuropsychopharmacol Biol Psychiatry. 2016 Apr 3;66:97-103
pubmed: 26654950
Nat Genet. 2019 Jan;51(1):63-75
pubmed: 30478444
Science. 2020 Sep 11;369(6509):1318-1330
pubmed: 32913098
Nature. 2014 Jul 24;511(7510):421-7
pubmed: 25056061
Am J Psychiatry. 2019 Mar 1;176(3):217-227
pubmed: 30818990
Bioinformatics. 2019 Oct 1;35(19):3576-3583
pubmed: 30850848
Epigenetics. 2010 Oct 1;5(7):578-82
pubmed: 20716955
J Clin Cell Immunol. 2016 Dec;7(6):
pubmed: 28180029
Mol Psychiatry. 2018 May;23(5):1181-1188
pubmed: 28761083
PLoS Genet. 2010 May 13;6(5):e1000952
pubmed: 20485568
Nat Genet. 2013 Jun;45(6):580-5
pubmed: 23715323
Cold Spring Harb Perspect Biol. 2014 May 01;6(5):a019133
pubmed: 24789823
Eur J Immunol. 2011 Dec;41(12):3443-54
pubmed: 21918970
Physiol Rev. 2018 Jan 1;98(1):477-504
pubmed: 29351513
Nat Neurosci. 2016 Jan;19(1):48-54
pubmed: 26619357
Am J Psychiatry. 2017 Sep 1;174(9):850-858
pubmed: 28494655
Mol Psychiatry. 2019 Mar;24(3):409-420
pubmed: 29317742
Int J Epidemiol. 2014 Apr;43(2):476-93
pubmed: 24648481
Schizophr Res. 2015 Mar;162(1-3):124-37
pubmed: 25667193
Nature. 2015 Oct 1;526(7571):68-74
pubmed: 26432245
Annu Rev Public Health. 2018 Apr 1;39:309-333
pubmed: 29328878
Am J Hum Genet. 2016 May 5;98(5):956-962
pubmed: 27087318
Nat Genet. 2008 Sep;40(9):1053-5
pubmed: 18677311
Nature. 2008 Nov 6;456(7218):18-21
pubmed: 18987709
Mol Psychiatry. 2016 Sep;21(9):1244-50
pubmed: 26728569
Transl Psychiatry. 2019 Oct 3;9(1):242
pubmed: 31582733
Biochem J. 1999 Oct 1;343 Pt 1:209-14
pubmed: 10493931
Front Physiol. 2015 May 11;6:139
pubmed: 26029110
Psychiatr Genet. 2019 Oct;29(5):132-141
pubmed: 31464994
Nat Genet. 2011 Oct 30;43(12):1228-31
pubmed: 22037552
Nature. 2015 Apr 9;520(7546):224-9
pubmed: 25607358