Abstract
Childhood psychotic symptoms are associated with increased rates of schizophrenia, other psychiatric disorders, and suicide attempts in adulthood; thus, elucidating early risk indicators is crucial to target prevention efforts. There is considerable discordance for psychotic symptoms between monozygotic twins, indicating that child-specific non-genetic factors must be involved. Epigenetic processes may constitute one of these factors and have not yet been investigated in relation to childhood psychotic symptoms. Therefore, this study explored whether differences in DNA methylation at age 10 were associated with monozygotic twin discordance for psychotic symptoms at age 12. The Environmental Risk (E-Risk) Longitudinal Twin Study cohort of 2,232 children (1,116 twin pairs) was assessed for age-12 psychotic symptoms and 24 monozygotic twin pairs discordant for symptoms were identified for methylomic comparison. Children provided buccal samples at ages 5 and 10. DNA was bisulfite modified and DNA methylation was quantified using the Infinium HumanMethylation450 array. Differentially methylated positions (DMPs) associated with psychotic symptoms were subsequently tested in post-mortem prefrontal cortex tissue from adult schizophrenia patients and age-matched controls. Site-specific DNA methylation differences were observed at age 10 between monozygotic twins discordant for age-12 psychotic symptoms. Similar DMPs were not found at age 5. The top-ranked psychosis-associated DMP (cg23933044), located in the promoter of the C5ORF42 gene, was also hypomethylated in post-mortem prefrontal cortex brain tissue from schizophrenia patients compared to unaffected controls. These data tentatively suggest that epigenetic variation in peripheral tissue is associated with childhood psychotic symptoms and may indicate susceptibility to schizophrenia and other mental health problems.
Highlights
Psychotic symptoms are reported by approximately 1 in 20 children at around 12 years of age[1] and include paranoid thoughts, hearing or seeing things that others do not, and believing that others can read one‘s mind or vice versa
Investigating top-ranked age-10 Differentially methylated positions (DMPs) in schizophrenia post-mortem brain tissue We examined DNA methylation at the top-ranked age-10 DMPs identified in our twin study in prefrontal cortex (PFC) samples from two independent cohorts of adult schizophrenia patients and matched non-psychiatric control samples
Changes in DNA methylation between ages 5 and 10 in discordant MZ twins we examined CpG sites characterized by psychosis-associated intra-individual changes in DNA methylation between ages 5 and 10
Summary
Psychotic symptoms are reported by approximately 1 in 20 children at around 12 years of age[1] and include paranoid thoughts, hearing or seeing things that others do not, and believing that others can read one‘s mind or vice versa. These symptoms often occur in children without a diagnosable illness but tend to be distressing[2] and are highly predictive of schizophrenia, other psychiatric disorders, and suicide attempts in adulthood,[3] as well as self-harm[1] and suicide attempts[4] in adolescence. Epigenetic variation identified in post-mortem brain tissue has been associated with several neuropsychiatric conditions, including schizophrenia and other psychotic disorders in adults.[7,8,9,10] DNA methylation differences in peripheral tissue have been found in individuals with schizophrenia compared to unaffected controls.[11,12,13]
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