Genes regulated by BCL11B during T-cell development are enriched for de novo mutations found in schizophrenia patients.
Animals
Databases, Genetic
Female
Gene Expression
/ genetics
Gene Expression Regulation
/ genetics
Genetic Predisposition to Disease
/ genetics
Genome-Wide Association Study
/ methods
Humans
Male
Mice
Mutation
/ genetics
Mutation, Missense
/ genetics
Repressor Proteins
/ genetics
Schizophrenia
/ genetics
T-Lymphocytes
/ metabolism
Transcription Factors
/ genetics
Tumor Suppressor Proteins
/ genetics
Exome Sequencing
/ methods
ChIP-seq
RNA-seq
de novo mutation
immune system
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:
09 2020
09 2020
Historique:
received:
20
12
2019
revised:
20
04
2020
accepted:
28
05
2020
pubmed:
31
7
2020
medline:
15
5
2021
entrez:
31
7
2020
Statut:
ppublish
Résumé
While abnormal neurodevelopment contributes to schizophrenia (SCZ) risk, there is also evidence to support a role for immune dysfunction in SCZ. BCL11B, associated with SCZ in genome-wide association study (GWAS), is a transcription factor that regulates the differentiation and development of cells in the central nervous and immune systems. Here, we use functional genomics data from studies of BCL11B to investigate the contribution of neuronal and immune processes to SCZ pathophysiology. We identified the gene targets of BCL11B in brain striatal cells (n = 223 genes), double negative 4 (DN4) developing T cells (n = 114 genes) and double positive (DP) developing T cells (n = 518 genes) using an integrated analysis of RNA-seq and ChIP-seq data. No gene-set was enriched for genes containing common variants associated with SCZ but the DP gene-set was enriched for genes containing missense de novo mutations (DNMs; p = .001) using data from 3,447 SCZ trios. Post hoc analysis revealed the enrichment to be stronger for DP genes negatively regulated by BCL11B. Biological processes enriched for genes negatively regulated by BCL11B in DP gene-set included immune system development and cytokine signaling. These analyses, leveraging a GWAS-identified SCZ risk gene and data on gene expression and transcription factor binding, indicate that DNMs in immune pathways contribute to SCZ risk.
Identifiants
pubmed: 32729240
doi: 10.1002/ajmg.b.32811
doi:
Substances chimiques
BCL11B protein, human
0
Repressor Proteins
0
Transcription Factors
0
Tumor Suppressor Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
370-379Informations de copyright
© 2020 Wiley Periodicals LLC.
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