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

Brain, Behavior, & Immunity - Health (Dec 2021)

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

Affiliations

Amy Lin: Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Neuroscience Interdepartmental Program, University of California at Los Angeles, Los Angeles, CA, USA
Jennifer K. Forsyth: Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department of Psychology, University of Washington, WA, USA
Gil D. Hoftman: Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA
Leila Kushan-Wells: Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA
Maria Jalbrzikowski: Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
Deepika Dokuru: Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA
Giovanni Coppola: Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA
Ania Fiksinski: Wilhelmina Children's Hospital & University Medical Center Utrecht, Brain Center, the Netherlands; Maastricht University, Department of Psychiatry and Neuropsychology, Division of Mental Health, MHeNS, the Netherlands
Janneke Zinkstok: Department of Psychiatry and Brain Center, University Medical Center Utrecht, the Netherlands
Jacob Vorstman: Program in Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, Canada; Department of Psychiatry, University of Toronto, Toronto, Canada
Daniel Nachun: Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department of Pathology, Stanford University, Stanford, CA, USA
Carrie E. Bearden: Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department of Psychology, University of California, Los Angeles, Los Angeles, CA, USA; Corresponding author. UCLA Semel Institute for Neuroscience and Human Behavior, 760 Westwood Plaza, Rm A7-436, Los Angeles, CA, 90095, USA.

Journal volume & issue: Vol. 18
p. 100386

Abstract

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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.

Published in Brain, Behavior, & Immunity - Health

ISSN: 2666-3546 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/brain-behavior-and-immunity-health

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