The schizophrenia associated BRD1 gene regulates behaviour, neurotransmission, and expression of schizophrenia risk enriched gene sets in mice
The schizophrenia-associated BRD1 gene encodes a transcriptional regulator whose comprehensive chromatin interactome is enriched with schizophrenia risk genes. However, the biology underlying the disease association of BRD1 remains speculative. In this study, we show that BRD1 schizophrenia risk alleles correlate with lower BRD1 mRNA levels in humans – and we demonstrate pathogenic consequences of reduced Brd1 expression with translational relevance to schizophrenia in genetically modified Brd1+/- mice.
About the study
The distal end of chromosome 22q is known to harbour genes implicated in brain functions as evident from patients with 22q13 deletion syndrome in whom intellectual disability, impaired learning as well as autism and bipolar disorder have been reported. The region seems to harbour a shared schizophrenia and bipolar disorder susceptibility locus and case-control studies have repeatedly found associations of the bromodomain containing 1 gene (BRD1) within this region, to both disorders. Notably, BRD1 features among the highest ranking schizophrenia associations in a recent large combined GWAS meta-analysis (11,185 cases and 10,768 control) and family-based replication study (6298 individuals), is located in a genome-wide significant schizophrenia risk locus identified using an Empirical Bayes statistical approach, and shows gene-wise significant association in the to date largest schizophrenia GWAS mega-analysis. Furthermore, a schizophrenia case with a disruptive nonsense mutation in BRD1 has recently been reported.
BRD1 encodes a transcriptional regulator protein involved in histone modification. We have recently identified hundreds of gene interaction partners of BRD1 and found that the BRD1 interaction network is enriched with schizophrenia risk genes as well as for pathways important for brain function. These findings propose the hypothesis that BRD1 may act as a central hub gene in schizophrenia etiopathogenesis and that modulation of BRD1 expression, similarly to what is observed in schizophrenia cases, may be conceived as a way to model the highly polygenic nature of the disorder.
In this manuscript we show that BRD1 schizophrenia risk alleles correlate with reduced BRD1 mRNA in humans and we demonstrate that, specifically, the rs1388880 promotor risk allele causes reduced transcriptional drive in vitro. Accordingly, we assessed the behavioural, molecular and neurochemical consequences of reduced Brd1 expression in genetically modified mice (Brd1+/- mice). We thereby find that Brd1+/- mice show schizophrenia-like behaviours, altered monoaminergic neurochemistry, and imbalanced excitatory/inhibitory signalling that involves loss of parvalbumin-immunoreactive interneurons. In line with BRD1 playing a role in chromatin remodelling, decreased Brd1 expression caused cortical and-subcortical transcriptomic changes that, to a high extent, affect schizophrenia risk loci and cluster in networks and pathways associated with mental disorders. Interestingly, we show that reduced Brd1 expression leads to altered GPCR-DARPP32-CREB signalling, which so far has received little attention in relation to schizophrenia.
Our study provides evidence translating the statistical association of a schizophrenia risk locus to disorder-relevant pathogenic effects in a genetic mouse model contributing novel insight into schizophrenia etiopathology.
The article “The schizophrenia associated BRD1 gene regulates behavior, neurotransmission, and expression of schizophrenia risk enriched gene sets in mice” was published online in Biological Psychiatry, September 15, 2016, [Epub ahead of print].
Facts about the study
- BRD1 schizophrenia risk alleles correlate with lower BRD1 mRNA levels in humans
- The rs1388880 BRD1 promotor risk allele display reduced transcriptional drive in vitro
- Genetically modified Brd1+/- mice have reduced Brd1 expression and show phenotypes with translational relevance to schizophrenia, including cognitive impairments, altered social behaviors and increased sensitivity towards psychostimulants.
- Brd1+/- mice show altered monoaminergic neurochemistry and imbalanced excitatory/inhibitory signalling that involves loss of parvalbumin-immunoreactive interneurons
- Brd1+/- mice display cortical and-subcortical gene expression changes that affect genes overall enriched for schizophrenia risk and, to a high extent, are located in established schizophrenia risk loci
Further information
Per Qvist, MSc, PhD, Postdoc, Department of Biomedicine, Aarhus University. Mobile: +45 50192006 Email: per.q@biomed.au.dk
Jane Hvarregaard Christensen, Msc, PhD, Associate Professor, Department of Biomedicine, Aarhus University. Mobile: +45 26526917 Email: jhc@biomed.au.dk