The HLA Complex Group 9 Gene Modification Study in Major Psychosis

Epigenetic mechanisms can offer new insights into the non-Mendelian features of complex psychiatric disorders. The first epigenome-wide scan in major psychosis, conducted by our group, identified DNA modification differences at HLA complex group 9 (non-protein coding) gene (HCG9) in the post-mortem brain samples of individuals affected with schizophrenia (SCZ) and bipolar disorder (BPD). In this thesis we present results from bisulfite pyrosequencing based fine mapping of a ~700 bp region of HCG9 in 1,402 DNA samples from post-mortem brain, germline (sperm), and peripheral white blood cells (WBC) of SCZ and BPD patients as well as unaffected controls. We observed significant differences in CpG modification between BPD samples and controls across all tissues and demonstrated the utility of WBC DNA modification density as an epigenetic marker for BPD. We further extended our analysis to full length HCG9 with bisulfite padlock probe-based deep sequencing in SCZ, BPD and control post-mortem brain samples. We identified significant differences in CpH modification between sense and anti-sense DNA strands and between major psychosis patients and controls. Next, we characterized genome-wide distribution of 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) in neural and non-neural tissue from mice and humans. 5-hmC has been recently found to be abundant in brain but its function is poorly understood. We assayed 5-hmC by using glucosylation coupled with restriction enzyme digestion and microarray analysis. We detected enrichment of 5-hmC in genes with synapse-related functions and tissue-specific differential distribution of 5-mC and 5-hmC at the exon-intron boundary. This boundary change was mainly due to 5-hmC in the brain but due to 5-mC in non-neural tissue. Our study suggests a new role for 5-hmC in RNA splicing and synaptic function in the brain. Finally, we determined 5-mC and 5-hmC modification density at HCG9 CpG6 in post-mortem brain tissue and WBCs of SCZ, BPD and control samples. Consistent with our previous report, we identified significant differences between the major psychosis group and controls, which were due to 5-hmC but not 5-mC as it was previously assumed.

Department dc:contributor.department

Pharmacology

Year dc:date.issued

2015

Author dc:creator

• Pal, Mrinal

Advisor dc:contributor.advisor

• Petronis, Arturas

• bipolar disorder
• bisulfite sequencing
• DNA modification
• epigenetics
• micorarray
• schizophrenia

Handle dc:identifier.uri

http://hdl.handle.net/1807/71602

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/71602