Abstract
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.
Highlights
Out of all 22q11.2DS cases identified from the Danish Cytogenetic Central Register, 209 individuals had a blood spot sample stored within the Danish Neonatal Screening Biobank (DNSB), which is a part of the Danish National Biobank
We evaluated the methylomes using further stratification of psychiatric diagnoses in which the psychiatric cohort was subcategorized into four main diagnosis groups: intellectual disability (ID, F70–79: intellectual disability, n = 23), behavioral disorders
Among 48 individuals with psychiatric diagnosis, 44 (~92%) had LRC22A–LRC22D deletion, 4 (~8%) had deletion within LRC22A–LRC22B or LRC22D–LCR22E region of 22q11.2, and none had LRC22C–LRC22D deletion. These results were concordant with PennCNV calls in single-nucleotide polymorphisms (SNPs) genotype data and support the use of 450 K DNA methylation data for detection of known CNVs
Summary
There is a strikingly increased risk of developing a mental disorder among individuals diagnosed with 22q11.2 deletion syndrome (DS) including mood disorders, anxiety disorders, attention deficit hyperactivity disorder (ADHD), autism spectrum disorder, as well as intellectual disability (ID) and schizophrenia (SZ).[1,2,3,4,5,6,7] It is the most common DS in humans that occurs at a population frequency ~ 1:3700 live births (Olsen et al, manuscript in preparation).[8,9,10,11] The syndrome is characterized by a hemizygous microdeletion of 1.5–3 Mb of chromosome 22 and is associated with a variety of clinical phenotypes including cardiac defects, hypocalcemia, cleft palate, dysfunction of the immune system as well as multiple mental disorders.[12,13,14,15]. The epigenome is dynamic, changing in early development, Genomic DNA was extracted from neonatal dried blood spots at the throughout life, and even during disease progression. Epigenetic profiles in neonatal blood samples may prove to be a useful tool to identify early on which 22q11.2 deletion carriers are at increased risk for mental disorder, allowing for early prediction and intervention, as well as improved understanding of the pathogenesis that underlies development of psychiatric phenotypes. Methylation data were further normalized with the use of withinarray Functional Normalization, which regresses out the variability explained by control probes included on the Infinium HumanMethylation450BeadChip array in order to remove the technical variation.[41] Normalization was performed with the first two principal components.[41] Normalization was followed by removal of probes with detP40.01 in at least 20% of samples, cross-reactive probes, probes targeting sex chromo-
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