Differential DNA methylation at birth associated with mental disorder in individuals with 22q11.2 deletion syndrome

Abstract

Individuals with 22q11.2 deletion syndrome (DS) have an increased risk of comorbid mental disorders including schizophrenia, attention deficit hyperactivity disorder, depression, as well as intellectual disability. Although most 22q11.2 deletion carriers have the long 3-Mb form of the hemizygous deletion, there remains a large variation in the development and progression of psychiatric disorders, which suggests that alternative factors contribute to the pathogenesis. In this study we investigated whether neonatal DNA methylation signatures in individuals with the 22q11.2 deletion associate with mental disorder later in life. DNA methylation was measured genome-wide from neonatal dried blood spots in a cohort of 164 individuals with 22q11.2DS, including 48 individuals diagnosed with a psychiatric disorder. Among several CpG sites with P-value<10−6, we identified cg23546855 (P-value=2.15 × 10−7) mapping to STK32C to be associated with a later psychiatric diagnosis. Pathway analysis of the top findings resulted in the identification of several Gene Ontology pathways to be significantly enriched (P-value<0.05 after Benjamini–Hochberg correction); among them are the following: neurogenesis, neuron development, neuron projection development, astrocyte development, axonogenesis and axon guidance. In addition, we identified differentially methylated CpG sites in LRP2BP (P-value=5.37 × 10−8) to be associated with intellectual disability (F70–79), in TOP1 (P-value=1.86 × 10−7) with behavioral disorders (F90–98), in NOSIP (P-value=5.12 × 10−8) with disorders of psychological development (F80–89) and in SEMA4B (P-value=4.02 × 10−7) with schizophrenia spectrum disorders (F20–29). In conclusion, our study suggests an association of DNA methylation differences at birth with development of mental disorder later in life in 22q11.2DS individuals.

Nosip functions during vertebrate eye and cranial cartilage development

“…Additionally, mutations in any of these genes were linked to human patients showing eye phenotypes such as anophthalmia, microphthalmia and coloboma (Deml et al, 2016;Lequeux et al, 2008;London et al, 2009;Ragge et al, 2005;Zhang et al, 2009). Special attention should be paid to the fact that NOSIP has recently been associated with psychological disorders including schizophrenia (Lin et al, 2017;Starnawska et al, 2017). Special attention should be paid to the fact that NOSIP has recently been associated with psychological disorders including schizophrenia (Lin et al, 2017;Starnawska et al, 2017).…”

“…Nosip, belongs to the family of E3-ubiquitin ligases containing an U-box domain (Friedman et al, 2003). Recently, Nosip has been associated with various human diseases, including mental disorders (Lin et al, 2017;Starnawska et al, 2017) and Hirschsprung`s disease (Tomuschat et al, 2017). Nosip monoubiquitylates the catalytic subunit of the protein phosphatase 2A (PP2A), whereas the knockout of Nosip in mice results in an increased PP2A activity (Hoffmeister et al, 2014).…”

A Mini Review on the Contribution of the Anterior Cingulate Cortex in the Risk of Psychosis in 22q11.2 Deletion Syndrome

“…For instance, two recent investigations showed that preterm birth can be a risk factor of schizophrenia in 22q11DS ( 8 , 10 ). In addition, it has been reported that the DNA methylation status differs in the patients with 22q11DS that develop mental disorders ( 12 ), thus suggesting a role of the environment and epigenetic factors in the risk of psychosis.…”

Exploring the Role of Fallopian Ciliated Cells in the Pathogenesis of High-Grade Serous Ovarian Cancer

“…Despite these predictions, there is no direct evidence of LRP2BP function. Indirect evidences associate LRP2BP with several diseases such as osteoporosis in an ovariectomized mouse model [ 130 ], intellectual disability [ 131 ], and atherosclerosis [ 132 ].…”