LAUSR

Background 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. While 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. Methods Subjects with 22q11.2 deletion were selected from The Danish Cytogenetic Central Register. DNA methylation was measured genome-wide with the use of Infinium HumanMethylation450 BeadChip from neonatal dried blood spots in a cohort of 164 individuals with 22q11.2DS, including 48 diagnosed with a psychiatric disorder. Epigenome-Wide Association Study (EWAS) was performed to determine differential DNA methylation among 22q11.2 deletion carriers diagnosed with mental disorder compared to carriers with no current or past mental disorder diagnosis. Most associated sites were used for Gene Ontology pathway enrichment analysis. Moreover, we evaluated four sub-classes of most commonly observed psychiatric diagnoses (intellectual disability: F70-79, behavioral disorders: F90-98, disorders of psychological development: F80-89 and schizophrenia spectrum disorders: F20-29) in the cohort and compared their methylome profiles to the non-psychiatric controls. Regression models, adjusted for sex, type of 22q11.2 deletion, and age of the blood spot card, were used for all EWAS analyses to identify differentially methylated sites. Results Among several CpG sites with p-value Discussion 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. Differentially methylated sites were located in genes enriched in those involved in neurogenesis, nervous development, and neuron projection development, what supports previous studies that suggested mental disorders to have an early neurodevelopmental component.