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Panic disorder (PD) affects about four million Europeans, with women affected twice as likely as men, causing substantial suffering and high economic costs. The etiopathogenesis of PD remains largely unknown, but both genetic and environmental factors contribute to risk. An epigenome-wide association study (EWAS) was conducted to compare medication-free PD patients (n = 89) with healthy controls (n = 76) stratified by gender. Replication was sought in an independent sample (131 cases, 169 controls) and functional analyses were conducted in a third sample (N = 71). DNA methylation was assessed in whole blood using the Infinium HumanMethylation450 BeadChip. One genome-wide association surviving FDR of 5% (cg07308824, P = 1.094 × 10-7, P-adj = 0.046) was identified in female PD patients (N = 49) compared to controls (N = 48). The same locus, located in an enhancer region of the HECA gene, was also hypermethylated in female PD patients in the replication sample (P = 0.035) and the significance of the association improved in the meta-analysis (P-adj = 0.004). Methylation at this CpG site was associated with HECA mRNA expression in another independent female sample (N = 71) both at baseline (P = 0.046) and after induction by dexamethasone (P = 0.029). Of 15 candidates, 5 previously reported as associated with PD or anxiety traits also showed differences in DNA methylation after gene-wise correction and included SGK1, FHIT, ADCYAP1, HTR1A, HTR2A. Our study examines epigenome-wide differences in peripheral blood for PD patients. Our results point to possible sex-specific methylation changes in the HECA gene for PD but overall highlight that this disorder is not associated with extensive changes in DNA methylation in peripheral blood.

Increasing age is tightly linked to decreased thickness of the human neocortex. The biological mechanisms that mediate this effect are hitherto unknown. The DNA methylome, as part of the epigenome, contributes significantly to age-related phenotypic changes. Here, we identify an epigenetic signature that is associated with cortical thickness (P=3.86 × 10 -8 ) and memory performance in 533 healthy young adults. The epigenetic effect on cortical thickness was replicated in a sample comprising 596 participants with major depressive disorder and healthy controls. The epigenetic signature mediates partially the effect of age on cortical thickness (P<0.001). A multilocus genetic score reflecting genetic variability of this signature is associated with memory performance (P=0.0003) in 3,346 young and elderly healthy adults. The genomic location of the contributing methylation sites points to the involvement of specific immune system genes. The decomposition of blood methylome-wide patterns bears considerable potential for the study of brain-related traits.

DNA methylation likely plays a role in the regulation of human stress reactivity. Here we show that in a genome-wide analysis of blood DNA methylation in 85 healthy individuals, a locus in the Kit ligand gene (KITLG; cg27512205) showed the strongest association with cortisol stress reactivity (P=5.8 × 10(-6)). Replication was obtained in two independent samples using either blood (N=45, P=0.001) or buccal cells (N=255, P=0.004). KITLG methylation strongly mediates the relationship between childhood trauma and cortisol stress reactivity in the discovery sample (32% mediation). Its genomic location, a CpG island shore within an H3K27ac enhancer mark, and the correlation between methylation in the blood and prefrontal cortex provide further evidence that KITLG methylation is functionally relevant for the programming of stress reactivity in the human brain. Our results extend preclinical evidence for epigenetic regulation of stress reactivity to humans and provide leads to enhance our understanding of the neurobiological pathways underlying stress vulnerability.

Our understanding of major depressive disorder (MDD) has focused on the influence of genetic variation and environmental risk factors. Growing evidence suggests the additional role of epigenetic mechanisms influencing susceptibility for complex traits. DNA sequence within discordant monozygotic twin (MZT) pairs is virtually identical; thus, they represent a powerful design for studying the contribution of epigenetic factors to disease liability. The aim of this study was to investigate whether specific methylation profiles in white blood cells could contribute to the aetiology of MDD. Participants were drawn from the Queensland Twin Registry and comprised 12 MZT pairs discordant for MDD and 12 MZT pairs concordant for no MDD and low neuroticism. Bisulphite treatment and genome-wide interrogation of differentially methylated CpG sites using the Illumina Human Methylation 450 BeadChip were performed in WBC-derived DNA. No overall difference in mean global methylation between cases and their unaffected co-twins was found; however, the differences in females was significant (P=0.005). The difference in variance across all probes between affected and unaffected twins was highly significant (P<2.2 × 10⁻¹⁶), with 52.4% of probes having higher variance in cases (binomial P-value<2.2 × 10⁻¹⁶). No significant differences in methylation were observed between discordant MZT pairs and their matched concordant MZT (permutation minimum P=0.11) at any individual probe. Larger samples are likely to be needed to identify true associations between methylation differences at specific CpG sites.