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

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*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.

Original languageEnglish
Pages (from-to)100386
JournalBrain, Behavior, & Immunity - Health
Publication statusPublished - Dec 2021

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