A screen of 1,049 schizophrenia and 30 Alzheimer's-associated variants for regulatory potential.
Alleles
Alzheimer Disease
/ genetics
Cell Line, Tumor
Gene Expression
/ genetics
Gene Expression Regulation
/ genetics
Gene Frequency
/ genetics
Genetic Predisposition to Disease
Genetic Variation
/ genetics
Genome-Wide Association Study
/ methods
Haplotypes
Humans
K562 Cells
Linkage Disequilibrium
Polymorphism, Single Nucleotide
/ genetics
Quantitative Trait Loci
Schizophrenia
/ genetics
Alzheimer's
association
gene regulation
reporter assays
schizophrenia
Journal
American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics
ISSN: 1552-485X
Titre abrégé: Am J Med Genet B Neuropsychiatr Genet
Pays: United States
ID NLM: 101235742
Informations de publication
Date de publication:
01 2020
01 2020
Historique:
received:
05
06
2019
revised:
19
08
2019
accepted:
20
08
2019
pubmed:
11
9
2019
medline:
5
1
2021
entrez:
11
9
2019
Statut:
ppublish
Résumé
Recent genome-wide association studies (GWAS) identified numerous schizophrenia (SZ) and Alzheimer's disease (AD) associated loci, most outside protein-coding regions and hypothesized to affect gene transcription. We used a massively parallel reporter assay to screen, 1,049 SZ and 30 AD variants in 64 and nine loci, respectively for allele differences in driving reporter gene expression. A library of synthetic oligonucleotides assaying each allele five times was transfected into K562 chronic myelogenous leukemia lymphoblasts and SK-SY5Y human neuroblastoma cells. One hundred forty eight variants showed allelic differences in K562 and 53 in SK-SY5Y cells, on average 2.6 variants per locus. Nine showed significant differences in both lines, a modest overlap reflecting different regulatory landscapes of these lines that also differ significantly in chromatin marks. Eight of nine were in the same direction. We observe no preference for risk alleles to increase or decrease expression. We find a positive correlation between the number of SNPs in linkage disequilibrium and the proportion of functional SNPs supporting combinatorial effects that may lead to haplotype selection. Our results prioritize future functional follow up of disease associated SNPs to determine the driver GWAS variant(s), at each locus and enhance our understanding of gene regulation dynamics.
Identifiants
pubmed: 31503409
doi: 10.1002/ajmg.b.32761
pmc: PMC7233147
mid: NIHMS1586876
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
61-73Subventions
Organisme : NIMH NIH HHS
ID : P50 MH094268
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH113215
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007814
Pays : United States
Organisme : NIMH NIH HHS
ID : R56 MH113215
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH106522
Pays : United States
Informations de copyright
© 2019 Wiley Periodicals, Inc.
Références
Nat Genet. 2018 Sep;50(9):1327-1334
pubmed: 30127527
Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9362-7
pubmed: 19474294
PLoS One. 2016 Jun 08;11(6):e0157086
pubmed: 27276213
Nature. 2009 Sep 10;461(7261):199-205
pubmed: 19741700
Nat Biotechnol. 2012 Feb 26;30(3):271-7
pubmed: 22371084
Nucleic Acids Res. 2011 Mar;39(4):1576-85
pubmed: 20972222
Nature. 2009 Oct 8;461(7265):747-53
pubmed: 19812666
PLoS One. 2012;7(4):e36351
pubmed: 22558445
Nat Genet. 2013 Dec;45(12):1452-8
pubmed: 24162737
Am J Hum Genet. 2017 Jul 6;101(1):5-22
pubmed: 28686856
Genomics. 2015 Sep;106(3):159-164
pubmed: 26072433
Cell Rep. 2015 Apr 28;11(4):618-29
pubmed: 25892229
Biostatistics. 2007 Jan;8(1):118-27
pubmed: 16632515
Nat Rev Genet. 2009 Mar;10(3):184-94
pubmed: 19223927
BMC Genomics. 2019 Mar 12;20(1):209
pubmed: 30866806
Genome Res. 2013 May;23(5):800-11
pubmed: 23512712
Bioinformatics. 2008 Dec 15;24(24):2938-9
pubmed: 18974171
Nature. 2014 Jul 24;511(7510):421-7
pubmed: 25056061
Genome Res. 2014 Jan;24(1):1-13
pubmed: 24196873
Nat Genet. 2018 Mar;50(3):381-389
pubmed: 29483656
Bioinformatics. 2016 May 15;32(10):1555-6
pubmed: 26794315
Science. 2012 Sep 7;337(6099):1190-5
pubmed: 22955828
Genome Res. 2012 Sep;22(9):1748-59
pubmed: 22955986
Biol Psychiatry. 2015 Jun 1;77(11):e43-51
pubmed: 25592863
Transl Psychiatry. 2015 Oct 13;5:e656
pubmed: 26460480
Genomics. 2015 Sep;106(3):145-150
pubmed: 26072434
Neurochem Int. 2010 Dec;57(7):691-704
pubmed: 20813145