Macare C1, Ruggeri B1, Yun L2, Ruegg J3, Jia T1, Sarkysian D4, Syvaenen AC3, Ekstroem T3, Bakalkin G4, Schumann G1 and the IMAGEN consortium.
1MRC-SGDP Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College, London, UK
2Fudan University, Shanghai, PR China;
3Karolinska Institute, Stockholm, Sweden,
4Uppsala University, Uppsala, Sweden.
Early stressful negative life events (SLEs) are linked to various mental health problems. To functionally characterize pathways between the experience of SLEs and mental health outcomes, we carried out an epigenome-wide association study (EWAS) analysis to measure the association between the frequency of SLEs with differentially methylated regions (DMRs) in n=1287 14 year-old adolescents of the IMAGEN study. Using Illumina 450 chips and the bump-hunting method, we identified a genome-wide-significant DMR in the Sterile-α-motif-pointed-domain-epithelial-specific transcription factor (SPDEF) gene which was positively associated with SLEs (p(fwe-corrected)=.018). We independently replicated the results with pyrosequencing analyses (r=.12, p(one-tailed)=.033,df=239). To functionally characterize the epigenetic mark of SLEs on risk for psychopathology, we assessed the association between a key region of emotion processing, the amygdala, and the methylation level in the DMRs in SPDEF. The blood-oxygen-level-dependent (BOLD) response in the amygdala was significantly associated with methylation level (r(partial)=-.073, p=.037, df=818). Frequency of SLEs was associated with cigarette smoking, which in turn was also associated with the BOLD response in the left amygdala during emotion processing. Our results indicate a novel epigenetic mechanism by which environmental insults may mediate brain activity and behavior. Here, we will present the most up-to-date findings of this study.