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 o10 − 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 o 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

“…Thus, a sequence analysis of the NOSIP gene in human patients showing those eye abnormalities would be of high interest. 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). Whether those patients also have eye or craniofacial defects should be examined in the future.…”

“…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).…”

Epigenetic‐genetic chromatin footprinting identifies novel and subject‐specific genes active in prefrontal cortex neurons

“…S8F, I). Interestingly, the DNA methylation state of NUP210L has recently been linked to psychologic development disorders (60), and the common SNPs in this region are associated with mathematical abilities (61) and intelligence (62). Thus, the consequences of abnormal NUP210L activation found in the brain of some individuals warrants further investigation.…”

STK32A is a dual-specificity AGC kinase with a preference for acidic substrates

“…In a study of monozygotic twins a differentially methylated position in STK32C was found to be associated with adolescent depression [17]. An SNP within STK32C was also linked to risk of psychiatric disorders in Down Syndrome patients [18].…”