Sensitivity to gene dosage and gene expression affects genes with copy number variants observed among neuropsychiatric diseases.
Copy number variants
Gene dosage sensitivity
Gene expression sensitivity
Neuropsychiatric diseases
Ohnolog
Two-round whole-genome duplication
Journal
BMC medical genomics
ISSN: 1755-8794
Titre abrégé: BMC Med Genomics
Pays: England
ID NLM: 101319628
Informations de publication
Date de publication:
29 03 2020
29 03 2020
Historique:
received:
25
10
2018
accepted:
24
02
2020
entrez:
1
4
2020
pubmed:
1
4
2020
medline:
11
5
2021
Statut:
epublish
Résumé
Copy number variants (CNVs) have been reported to be associated with diseases, traits, and evolution. However, it is hard to determine which gene should have priority as a target for further functional experiments if a CNV is rare or a singleton. In this study, we attempted to overcome this issue by using two approaches: by assessing the influences of gene dosage sensitivity and gene expression sensitivity. Dosage sensitive genes derived from two-round whole-genome duplication in previous studies. In addition, we proposed a cross-sectional omics approach that utilizes open data from GTEx to assess the effect of whole-genome CNVs on gene expression. Affymetrix Genome-Wide SNP Array 6.0 was used to detect CNVs by PennCNV and CNV Workshop. After quality controls for population stratification, family relationship and CNV detection, 287 patients with narcolepsy, 133 patients with essential hypersomnia, 380 patients with panic disorders, 164 patients with autism, 784 patients with Alzheimer disease and 1280 healthy individuals remained for the enrichment analysis. Overall, significant enrichment of dosage sensitive genes was found across patients with narcolepsy, panic disorders and autism. Particularly, significant enrichment of dosage-sensitive genes in duplications was observed across all diseases except for Alzheimer disease. For deletions, less or no enrichment of dosage-sensitive genes with deletions was seen in the patients when compared to the healthy individuals. Interestingly, significant enrichments of genes with expression sensitivity in brain were observed in patients with panic disorder and autism. While duplications presented a higher burden, deletions did not cause significant differences when compared to the healthy individuals. When we assess the effect of sensitivity to genome dosage and gene expression at the same time, the highest ratio of enrichment was observed in the group including dosage-sensitive genes and genes with expression sensitivity only in brain. In addition, shared CNV regions among the five neuropsychiatric diseases were also investigated. This study contributed the evidence that dosage-sensitive genes are associated with CNVs among neuropsychiatric diseases. In addition, we utilized open data from GTEx to assess the effect of whole-genome CNVs on gene expression. We also investigated shared CNV region among neuropsychiatric diseases.
Sections du résumé
BACKGROUND
Copy number variants (CNVs) have been reported to be associated with diseases, traits, and evolution. However, it is hard to determine which gene should have priority as a target for further functional experiments if a CNV is rare or a singleton. In this study, we attempted to overcome this issue by using two approaches: by assessing the influences of gene dosage sensitivity and gene expression sensitivity. Dosage sensitive genes derived from two-round whole-genome duplication in previous studies. In addition, we proposed a cross-sectional omics approach that utilizes open data from GTEx to assess the effect of whole-genome CNVs on gene expression.
METHODS
Affymetrix Genome-Wide SNP Array 6.0 was used to detect CNVs by PennCNV and CNV Workshop. After quality controls for population stratification, family relationship and CNV detection, 287 patients with narcolepsy, 133 patients with essential hypersomnia, 380 patients with panic disorders, 164 patients with autism, 784 patients with Alzheimer disease and 1280 healthy individuals remained for the enrichment analysis.
RESULTS
Overall, significant enrichment of dosage sensitive genes was found across patients with narcolepsy, panic disorders and autism. Particularly, significant enrichment of dosage-sensitive genes in duplications was observed across all diseases except for Alzheimer disease. For deletions, less or no enrichment of dosage-sensitive genes with deletions was seen in the patients when compared to the healthy individuals. Interestingly, significant enrichments of genes with expression sensitivity in brain were observed in patients with panic disorder and autism. While duplications presented a higher burden, deletions did not cause significant differences when compared to the healthy individuals. When we assess the effect of sensitivity to genome dosage and gene expression at the same time, the highest ratio of enrichment was observed in the group including dosage-sensitive genes and genes with expression sensitivity only in brain. In addition, shared CNV regions among the five neuropsychiatric diseases were also investigated.
CONCLUSIONS
This study contributed the evidence that dosage-sensitive genes are associated with CNVs among neuropsychiatric diseases. In addition, we utilized open data from GTEx to assess the effect of whole-genome CNVs on gene expression. We also investigated shared CNV region among neuropsychiatric diseases.
Identifiants
pubmed: 32223758
doi: 10.1186/s12920-020-0699-9
pii: 10.1186/s12920-020-0699-9
pmc: PMC7104509
doi:
Substances chimiques
Genetic Markers
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
55Subventions
Organisme : Japan Agency for Medical Research and Development
ID : AMED-17km0405205h0002
Pays : International
Références
BMC Bioinformatics. 2010 Feb 04;11:74
pubmed: 20132550
Nature. 2009 May 28;459(7246):569-73
pubmed: 19404257
Proc Natl Acad Sci U S A. 2010 May 18;107(20):9270-4
pubmed: 20439718
PLoS Comput Biol. 2013;9(5):e1003073
pubmed: 23696728
Ann Rheum Dis. 2008 Mar;67(3):409-13
pubmed: 17604289
Science. 2015 Sep 11;349(6253):aab3761
pubmed: 26249230
BMC Bioinformatics. 2014 Feb 21;15:50
pubmed: 24555668
Brain. 2006 Nov;129(Pt 11):2977-83
pubmed: 16921174
Nature. 2000 Sep 14;407(6801):189-94
pubmed: 11001057
Nature. 2016 Aug 11;536(7615):205-9
pubmed: 27487209
Proc Natl Acad Sci U S A. 2014 Jan 7;111(1):361-6
pubmed: 24368850
Am J Hum Genet. 2006 Sep;79(3):439-48
pubmed: 16909382
Nat Commun. 2013;4:2283
pubmed: 23917329
Nat Genet. 2015 Mar;47(3):296-303
pubmed: 25621458
PLoS Comput Biol. 2015 Jul 16;11(7):e1004394
pubmed: 26181593
Nat Genet. 2017 Feb;49(2):274-281
pubmed: 27992416
J Alzheimers Dis. 2014;41(4):1031-8
pubmed: 24762945
J Clin Invest. 1985 Dec;76(6):2078-83
pubmed: 3865934
Neurosci Res. 2014 Feb;79:22-33
pubmed: 24211644
Science. 2005 Mar 4;307(5714):1434-40
pubmed: 15637236
Nat Genet. 2009 Jun;41(6):708-11
pubmed: 19412176
Arch Neurol. 2002 Oct;59(10):1553-62
pubmed: 12374492
Nat Rev Genet. 2015 Mar;16(3):172-83
pubmed: 25645873
Tissue Antigens. 1984 Nov;24(5):316-9
pubmed: 6597978
Nature. 2016 Aug 17;536(7616):285-91
pubmed: 27535533
Science. 1920 Oct 22;52(1347):388-90
pubmed: 17829955
Nat Genet. 2014 May;46(5):492-7
pubmed: 24686848
Lancet. 2000 Jan 1;355(9197):39-40
pubmed: 10615891
Genet Med. 2015 May;17(5):405-24
pubmed: 25741868
Biol Psychiatry. 2013 Nov 1;74(9):656-63
pubmed: 23726511
Nat Genet. 2013 Jun;45(6):580-5
pubmed: 23715323
Nat Genet. 2015 Feb;47(2):115-25
pubmed: 25581432
J Hum Genet. 2014 May;59(5):235-40
pubmed: 24694762
Am J Hum Genet. 2009 Feb;84(2):148-61
pubmed: 19166990
Science. 2007 Feb 9;315(5813):848-53
pubmed: 17289997
Nat Genet. 2008 Jan;40(1):23-5
pubmed: 18059266
Genome Res. 2007 Nov;17(11):1665-74
pubmed: 17921354
Neurobiol Aging. 2012 Feb;33(2):426.e13-21
pubmed: 21193246
Nat Genet. 2016 Oct;48(10):1107-11
pubmed: 27533299
Nat Genet. 2011 Aug 14;43(9):838-46
pubmed: 21841781
Genet Test Mol Biomarkers. 2014 Jun;18(6):375-6
pubmed: 24896853
Nature. 2003 Jul 10;424(6945):194-7
pubmed: 12853957
Brain Behav Immun. 2015 Oct;49:148-55
pubmed: 25986216
PeerJ. 2013 Apr 16;1:e66
pubmed: 23646285
J Hum Genet. 2010 Mar;55(3):137-41
pubmed: 20094064
Nat Genet. 2009 Apr;41(4):424-9
pubmed: 19270705
Hum Genet. 2010 Sep;128(3):269-80
pubmed: 20549515
Nucleic Acids Res. 2009 Jan;37(Database issue):D832-6
pubmed: 19015121
Nat Genet. 2006 Jan;38(1):24-6
pubmed: 16369530
Genet Med. 2016 May;18(5):421-30
pubmed: 26312828
PLoS One. 2010 Sep 08;5(9):e12538
pubmed: 20838618
J Hum Genet. 2016 Oct;61(10):873-878
pubmed: 27305985
PLoS Comput Biol. 2014 Jul 31;10(7):e1003754
pubmed: 25080083
Transl Psychiatry. 2012 Nov 13;2:e186
pubmed: 23149450
PLoS Med. 2015 Mar 31;12(3):e1001779
pubmed: 25826379
Nat Genet. 2011 Jan;43(1):66-71
pubmed: 21170044
Mol Biol Evol. 2017 Sep 1;34(9):2396-2407
pubmed: 28666362
Hum Genome Var. 2015 Nov 26;2:15050
pubmed: 27081555
Lancet. 1984 Nov 24;2(8413):1178-80
pubmed: 6150235
Nature. 2003 Dec 18;426(6968):789-96
pubmed: 14685227
Brief Funct Genomics. 2015 Sep;14(5):352-7
pubmed: 25922366
Biol Psychiatry. 2012 Oct 15;72(8):651-4
pubmed: 22795968
Am J Med Genet B Neuropsychiatr Genet. 2010 Oct 5;153B(7):1336-41
pubmed: 20552680
Mol Psychiatry. 2016 May;21(5):665-79
pubmed: 26390831
Front Neurol. 2015 May 26;6:107
pubmed: 26074864
Exp Ther Med. 2016 Sep;12(3):1293-1298
pubmed: 27602061
Bioinformatics. 2016 Nov 1;32(21):3298-3305
pubmed: 27402902
Nat Commun. 2018 Apr 10;9(1):1366
pubmed: 29636450
Nature. 2006 Nov 23;444(7118):444-54
pubmed: 17122850
Transl Psychiatry. 2015 Feb 03;5:e501
pubmed: 25646590
Neuropsychopharmacology. 2013 Aug;38(9):1648-54
pubmed: 23463151
Immunogenetics. 2000 Nov;52(1-2):12-8
pubmed: 11132147