Effects of cis-regulatory variation differ across regions of the adult human brain

Centre for the Cellular Basis of Behaviour, Department of Neuroscience, The James Black Centre, Institute of Psychiatry,King’s College London, 125 Coldharbour Lane, London, UK.
Human Molecular Genetics (Impact Factor: 6.39). 11/2010; 19(22):4490-6. DOI: 10.1093/hmg/ddq380
Source: PubMed


Cis-regulatory variation is considered to be an important determinant of human phenotypic variability, including susceptibility to complex disease. Recent studies have shown that the effects of cis-regulatory polymorphism on gene expression can differ widely between tissues. In the present study, we tested whether the effects of cis-regulatory variation can also differ between regions of the adult human brain. We used relative allelic expression to measure cis-effects on the RNA expression of five candidate genes for neuropsychiatric illness (ZNF804A, NOS1, RGS4, AKT1 and TCF4) across multiple discrete brain regions within individual subjects. For all five genes, we observed significant differences in allelic expression between brain regions in several individual subjects, suggesting regional differences in the effects of cis-regulatory polymorphism to be a common phenomenon. As well as highlighting an important caveat for studies of regulatory polymorphism in the brain, our findings indicate that it is possible to delineate brain areas in which cis-regulatory variants are active. This may provide important insights into the fundamental biology of neuropsychiatric phenotypes with which such variants are associated.

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    • "In healthy adults, ZNF804A is widely expressed in neurons from multiple regions, including the hippocampus (Bernstein et al., 2014), but the expression patterns of this gene in schizophrenia are not well known. The rs1344706 risk allele is associated with allelic expression imbalance of ZNF804A in adult dorsolateral prefrontal cortex samples (Guella et al., 2014), and there are variable cis-effects across different areas of the adult brain, particularly in the hippocampus (Buonocore et al., 2010). It would be interesting to investigate whether rs1344706 carriers have altered ZNF804A expression selectively in the CA1 region of the hippocampus during adolescence, as our results suggest that there is a transient upregulation of Zfp804a at this neurodevelopmental stage. "
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    ABSTRACT: The zinc finger protein ZNF804A rs1344706 variant is a replicated genome-wide significant risk variant for schizophrenia and bipolar disorder. While its association with altered brain structure and cognition in patients and healthy risk allele carriers is well documented, the characteristics and function of the gene in the brain remains poorly understood. Here, we used in situ hybridization to determine mRNA expression levels of the ZNF804A rodent homologue, Zfp804a, across multiple postnatal neurodevelopmental time points in the rat brain. We found changes in Zfp804a expression in the rat hippocampus, frontal cortex, and thalamus across postnatal neurodevelopment. Zfp804a mRNA peaked at postnatal day (P) 21 in hippocampal CA1 and DG regions and was highest in the lower cortical layers of frontal cortex at P1, possibly highlighting a role in developmental migration. Using immunofluorescence, we found that Zfp804a mRNA and ZFP804A co-localized with neurons and not astrocytes. In primary cultured cortical neurons, we found that Zfp804a expression was significantly increased when neurons were exposed to glutamate [20μM], but this increase was blocked by the N-methyl-d-aspartate receptor (NMDAR) antagonist MK-801. Expression of Comt, Pde4b, and Drd2, genes previously shown to be regulated by ZNF804A overexpression, was also significantly changed in an NMDA-dependent manner. Our results describe, for the first time, the unique postnatal neurodevelopmental expression of Zfp804a in the rodent brain and demonstrate that glutamate potentially plays an important role in the regulation of this psychiatric susceptibility gene. These are critical steps toward understanding the biological function of ZNF804A in the mammalian brain. Copyright © 2015 Elsevier B.V. All rights reserved.
    Schizophrenia Research 07/2015; 168(1). DOI:10.1016/j.schres.2015.06.023 · 3.92 Impact Factor
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    • "* Parts of these clusters are also significant at p < 0.05, family-wise error corrected. Schultz et al. 2014), as is the regional pattern of physiological expression (Buonocore et al. 2010). Also, recent studies suggest an indirect action of ZNF804A by modulating the gene expression of other risk genes (Girgenti et al. 2012). "
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    ABSTRACT: Background: Genetic variation in the gene encoding ZNF804A, a risk gene for schizophrenia, has been shown to affect brain functional endophenotypes of the disorder, while studies of white matter structure have been inconclusive. Method: We analysed effects of ZNF804A single nucleotide polymorphism rs1344706 on grey and white matter using voxel-based morphometry (VBM) in high-resolution T1-weighted magnetic resonance imaging scans of 62 schizophrenia patients and 54 matched healthy controls. Results: We found a significant (p < 0.05, family-wise error corrected for multiple comparisons) interaction effect of diagnostic group x genotype for local grey matter in the left orbitofrontal and right and left lateral temporal cortices, where patients and controls showed diverging effects of genotype. Analysing the groups separately (at p < 0.001, uncorrected), variation in rs1344706 showed effects on brain structure within the schizophrenia patients in several areas including the left and right inferior temporal, right supramarginal/superior temporal, right and left inferior frontal, left frontopolar, right and left dorsolateral/ventrolateral prefrontal cortices, and the right thalamus, as well as effects within the healthy controls in left lateral temporal, right anterior insula and left orbitofrontal cortical areas. We did not find effects of genotype of regional white matter in either of the two cohorts. Conclusions: Our findings demonstrate effects of ZNF804A genetic variation on brain structure, with diverging regional effects in schizophrenia patients and healthy controls in frontal and temporal brain areas. These effects, however, might be dependent on the impact of other (genetic or non-genetic) disease factors.
    Psychological Medicine 05/2014; 45(01):1-10. DOI:10.1017/S0033291714001159 · 5.94 Impact Factor
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    • "SNPs can occur in coding and non-coding regions of the genome. While the vast majority of SNPs located in non-coding regions of the genome were believed to be silent, new evidence suggests that SNPs coincident with cis-regulatory elements play a critical role in defining human diversity and disease by regulating the nature and timing of gene expression (Pastinen et al., 2006; Dimas et al., 2009; Buonocore et al., 2010). "
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    ABSTRACT: MicroRNAs are master regulators of gene expression and control many biological pathways such as cell growth, differentiation and apoptosis. Deregulation of microRNA expression and activity results in a myriad of diseases including cancer. Recently, several reports have indicated that single nucleotide polymorphisms (SNPs) in microRNAs and microRNA-target sites impact microRNA biology and associate with cancer risk, treatment response and outcome. In this review we will describe these findings and discuss the possible future of utilizing these SNPs as diagnostic and prognostic markers in the clinic.
    Pharmacology [?] Therapeutics 09/2012; 137(1). DOI:10.1016/j.pharmthera.2012.08.016 · 9.72 Impact Factor
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