Differential inflammatory profiles in carriers of reciprocal 22q11.2 copy number variants

• Published in: Psychoneuroendocrinology 2024-11, Vol.169, p.107135, Article 107135
• Main Authors: O’Hora, Kathleen P., Amir, Carolyn M., Chiem, Emily, Schleifer, Charles H., Grigoryan, Vardui, Kushan-Wells, Leila, Chiang, Jessica J., Cole, Steven, Irwin, Michael R., Bearden, Carrie E.
• Format: Article
• Language: English
• Subjects: 22q11.2 CNV; Adolescent; Adult; Child; Chromosomes, Human, Pair 22 - genetics; Cytokines; Cytokines - blood; Cytokines - genetics; DiGeorge syndrome; DiGeorge Syndrome - genetics; DNA Copy Number Variations - genetics; Female; Heterozygote; Humans; Inflammation; Inflammation - blood; Inflammation - genetics; Interferon-gamma - blood; Interferon-gamma - genetics; Interleukin-10 - blood; Interleukin-10 - genetics; Interleukin-6 - blood; Interleukin-6 - genetics; Interleukin-8 - blood; Interleukin-8 - genetics; Male; Psychosis; Psychotic Disorders - genetics; Sleep; Sleep Wake Disorders - genetics; Tumor Necrosis Factor-alpha - blood; Tumor Necrosis Factor-alpha - genetics; Young Adult
• ISSN: 0306-4530; 1873-3360; 1873-3360
• DOI: 10.1016/j.psyneuen.2024.107135

Genetic copy number variants (CNVs; i.e., a deletion or duplication) at the 22q11.2 locus confer increased risk of neuropsychiatric disorders and immune dysfunction. Inflammatory profiles of 22q11.2 CNV carriers can shed light on gene-immune relationships that may be related to neuropsychiatric symptoms. However, little is known about inflammation and its relationship to clinical phenotypes in 22q11.2 CNV carriers. Here, we investigate differences in peripheral inflammatory markers in 22q11.2 CNV carriers and explore their relationship with psychosis risk symptoms and sleep disturbance. Blood samples and clinical assessments were collected from 22q11.2 deletion (22qDel) carriers (n=45), 22q11.2 duplication (22qDup) carriers (n=29), and typically developing (TD) control participants (n=92). Blood plasma levels of pro-inflammatory cytokines, including interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ), and anti-inflammatory cytokine interleukin-10 (IL-10) were measured using a MesoScale Discovery multiplex immunoassay. Plasma levels of C-reactive protein (CRP) were measured using Enzyme-linked Immunosorbent Assay (ELISA). Linear mixed effects models controlling for age, sex, and body mass index were used to: a) examine group differences in inflammatory markers between 22qDel, 22qDup, and TD controls, b) test differences in inflammatory markers between 22qDel carriers with psychosis risk symptoms (22qDelPS+) and those without (22qDelPS-), and c) conduct an exploratory analysis testing the effect of sleep disturbance on inflammation in 22qDel and 22qDup carriers. A false discovery rate correction was used to correct for multiple comparisons. 22qDup carriers exhibited significantly elevated levels of IL-8 relative to TD controls (q0.13). 22qDelPS+ exhibited increased levels of IL-8 relative to both 22qDelPS- (q=0.02) and TD controls (p=0.002). There were no relationships between sleep and inflammatory markers that survived FDR correction (q>0.14). Our results suggest that CNVs at the 22q11.2 locus may have differential effects on inflammatory processes related to IL-8, a key mediator of inflammation produced by macrophages and microglia. Further, these IL-8-mediated inflammatory processes may be related to psychosis risk symptoms