Transcriptomic profiling of whole blood in 22q11.2 reciprocal copy number variants reveals that cell proportion highly impacts gene expression

22q11.2 reciprocal copy number variants (CNVs) offer a powerful quasi-experimental “reverse-genetics” paradigm to elucidate how gene dosage (i.e., deletions and duplications) disrupts the transcriptome to cause further downstream effects. Clinical profiles of 22q11.2 CNV carriers indicate that disru...

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Autores principales:	Amy Lin, Jennifer K. Forsyth, Gil D. Hoftman, Leila Kushan-Wells, Maria Jalbrzikowski, Deepika Dokuru, Giovanni Coppola, Ania Fiksinski, Janneke Zinkstok, Jacob Vorstman, Daniel Nachun, Carrie E. Bearden
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	22q11.2 Copy number variation Transcriptome Differential expression Whole blood Cell type composition Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/7bbf0d5c64de4d89987d58b825e1a27b
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spelling	oai:doaj.org-article:7bbf0d5c64de4d89987d58b825e1a27b2021-11-20T05:14:15ZTranscriptomic profiling of whole blood in 22q11.2 reciprocal copy number variants reveals that cell proportion highly impacts gene expression2666-354610.1016/j.bbih.2021.100386https://doaj.org/article/7bbf0d5c64de4d89987d58b825e1a27b2021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2666354621001897https://doaj.org/toc/2666-354622q11.2 reciprocal copy number variants (CNVs) offer a powerful quasi-experimental “reverse-genetics” paradigm to elucidate how gene dosage (i.e., deletions and duplications) disrupts the transcriptome to cause further downstream effects. Clinical profiles of 22q11.2 CNV carriers indicate that disrupted gene expression causes alterations in neuroanatomy, cognitive function, and psychiatric disease risk. However, interpreting transcriptomic signal in bulk tissue requires careful consideration of potential changes in cell composition. We first characterized transcriptomic dysregulation in peripheral blood from reciprocal 22q11.2 CNV carriers using differential expression analysis and weighted gene co-expression network analysis (WGCNA) to identify modules of co-expressed genes. We also assessed for group differences in cell composition and re-characterized transcriptomic differences after accounting for cell type proportions and medication usage. Finally, to explore whether CNV-related transcriptomic changes relate to downstream phenotypes associated with 22q11.2 CNVs, we tested for associations of gene expression with neuroimaging measures and behavioral traits, including IQ and psychosis or ASD diagnosis. 22q11.2 deletion carriers (22qDel) showed widespread expression changes at the individual gene as well as module eigengene level compared to 22q11.2 duplication carriers (22qDup) and controls. 22qDup showed increased expression of 5 genes within the 22q11.2 locus, and CDH6 located outside of the locus. Downregulated modules in 22qDel implicated altered immune and inflammatory processes. Celltype deconvolution analyses revealed significant differences between CNV and control groups in T-cell, mast cell, and macrophage proportions; differential expression of individual genes between groups was substantially attenuated after adjusting for cell composition. Individual gene, module eigengene, and cell proportions were not significantly associated with psychiatric or neuroanatomic traits. Our findings suggest broad immune-related dysfunction in 22qDel and highlight the importance of understanding differences in cell composition when interpreting transcriptomic changes in clinical populations. Results also suggest novel directions for future investigation to test whether 22q11.2 CNV effects on macrophages have implications for brain-related microglial function that may contribute to psychiatric phenotypes in 22q11.2 CNV carriers.Amy LinJennifer K. ForsythGil D. HoftmanLeila Kushan-WellsMaria JalbrzikowskiDeepika DokuruGiovanni CoppolaAnia FiksinskiJanneke ZinkstokJacob VorstmanDaniel NachunCarrie E. BeardenElsevierarticle22q11.2Copy number variationTranscriptomeDifferential expressionWhole bloodCell type compositionNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENBrain, Behavior, & Immunity - Health, Vol 18, Iss , Pp 100386- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	22q11.2 Copy number variation Transcriptome Differential expression Whole blood Cell type composition Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	22q11.2 Copy number variation Transcriptome Differential expression Whole blood Cell type composition Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Amy Lin Jennifer K. Forsyth Gil D. Hoftman Leila Kushan-Wells Maria Jalbrzikowski Deepika Dokuru Giovanni Coppola Ania Fiksinski Janneke Zinkstok Jacob Vorstman Daniel Nachun Carrie E. Bearden Transcriptomic profiling of whole blood in 22q11.2 reciprocal copy number variants reveals that cell proportion highly impacts gene expression
description	22q11.2 reciprocal copy number variants (CNVs) offer a powerful quasi-experimental “reverse-genetics” paradigm to elucidate how gene dosage (i.e., deletions and duplications) disrupts the transcriptome to cause further downstream effects. Clinical profiles of 22q11.2 CNV carriers indicate that disrupted gene expression causes alterations in neuroanatomy, cognitive function, and psychiatric disease risk. However, interpreting transcriptomic signal in bulk tissue requires careful consideration of potential changes in cell composition. We first characterized transcriptomic dysregulation in peripheral blood from reciprocal 22q11.2 CNV carriers using differential expression analysis and weighted gene co-expression network analysis (WGCNA) to identify modules of co-expressed genes. We also assessed for group differences in cell composition and re-characterized transcriptomic differences after accounting for cell type proportions and medication usage. Finally, to explore whether CNV-related transcriptomic changes relate to downstream phenotypes associated with 22q11.2 CNVs, we tested for associations of gene expression with neuroimaging measures and behavioral traits, including IQ and psychosis or ASD diagnosis. 22q11.2 deletion carriers (22qDel) showed widespread expression changes at the individual gene as well as module eigengene level compared to 22q11.2 duplication carriers (22qDup) and controls. 22qDup showed increased expression of 5 genes within the 22q11.2 locus, and CDH6 located outside of the locus. Downregulated modules in 22qDel implicated altered immune and inflammatory processes. Celltype deconvolution analyses revealed significant differences between CNV and control groups in T-cell, mast cell, and macrophage proportions; differential expression of individual genes between groups was substantially attenuated after adjusting for cell composition. Individual gene, module eigengene, and cell proportions were not significantly associated with psychiatric or neuroanatomic traits. Our findings suggest broad immune-related dysfunction in 22qDel and highlight the importance of understanding differences in cell composition when interpreting transcriptomic changes in clinical populations. Results also suggest novel directions for future investigation to test whether 22q11.2 CNV effects on macrophages have implications for brain-related microglial function that may contribute to psychiatric phenotypes in 22q11.2 CNV carriers.
format	article
author	Amy Lin Jennifer K. Forsyth Gil D. Hoftman Leila Kushan-Wells Maria Jalbrzikowski Deepika Dokuru Giovanni Coppola Ania Fiksinski Janneke Zinkstok Jacob Vorstman Daniel Nachun Carrie E. Bearden
author_facet	Amy Lin Jennifer K. Forsyth Gil D. Hoftman Leila Kushan-Wells Maria Jalbrzikowski Deepika Dokuru Giovanni Coppola Ania Fiksinski Janneke Zinkstok Jacob Vorstman Daniel Nachun Carrie E. Bearden
author_sort	Amy Lin
title	Transcriptomic profiling of whole blood in 22q11.2 reciprocal copy number variants reveals that cell proportion highly impacts gene expression
title_short	Transcriptomic profiling of whole blood in 22q11.2 reciprocal copy number variants reveals that cell proportion highly impacts gene expression
title_full	Transcriptomic profiling of whole blood in 22q11.2 reciprocal copy number variants reveals that cell proportion highly impacts gene expression
title_fullStr	Transcriptomic profiling of whole blood in 22q11.2 reciprocal copy number variants reveals that cell proportion highly impacts gene expression
title_full_unstemmed	Transcriptomic profiling of whole blood in 22q11.2 reciprocal copy number variants reveals that cell proportion highly impacts gene expression
title_sort	transcriptomic profiling of whole blood in 22q11.2 reciprocal copy number variants reveals that cell proportion highly impacts gene expression
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/7bbf0d5c64de4d89987d58b825e1a27b
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Transcriptomic profiling of whole blood in 22q11.2 reciprocal copy number variants reveals that cell proportion highly impacts gene expression

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