Integrated genome-wide methylation and expression analyses reveal functional predictors of response to antidepressants

Abstract

Major depressive disorder (MDD) is primarily treated with antidepressants, yet many patients fail to respond adequately, and identifying antidepressant response biomarkers is thus of clinical significance. Some hypothesis-driven investigations of epigenetic markers for treatment response have been previously made, but genome-wide approaches remain unexplored. Healthy participants (n = 112) and MDD patients (n = 211) between 18–60 years old were recruited for an 8-week trial of escitalopram treatment. Responders and non-responders were identified using differential Montgomery-Åsberg Depression Rating Scale scores before and after treatment. Genome-wide DNA methylation and gene expression analyses were assessed using the Infinium MethylationEPIC Beadchip and HumanHT-12 v4 Expression Beadchip, respectively, on pre-treatment peripheral blood DNA and RNA samples. Differentially methylated positions (DMPs) located in regions of differentially expressed genes between responders (n = 82) and non-responders (n = 95) were identified, and technically validated using a targeted sequencing approach. Three DMPs located in the genes CHN2 (cg23687322, p = 0.00043 and cg06926818, p = 0.0014) and JAK2 (cg08339825, p = 0.00021) were the most significantly associated with mRNA expression changes and subsequently validated. Replication was then conducted with non-responders (n = 76) and responders (n = 71) in an external cohort that underwent a similar antidepressant trial. One CHN2 site (cg06926818; p = 0.03) was successfully replicated. Our findings indicate that differential methylation at CpG sites upstream of the CHN2 and JAK2 TSS regions are possible peripheral predictors of antidepressant treatment response. Future studies can provide further insight on robustness of our candidate biomarkers, and greater characterization of functional components.

Whole-blood expression of inflammasome- and glucocorticoid-related mRNAs correctly separates treatment-resistant depressed patients from drug-free and responsive patients in the BIODEP study

“…Only STAT1 is increased in the present study, in both drug-free and TRD patients, suggesting that the upregulation of the other three genes is only visible after pharmacological inflammation induced by IFN-alpha, or in brain tissue. Although this is the first study measuring STAT1 in the blood of depressed patients, the above-mentioned studies in the NESDA cohort 20 and in non-responders to citalopram 25 found an upregulation of, respectively, STAT3 and JAK2 mRNAs, and another study found STAT3 cell signalling alterations in depression 71 .…”

“…Two studies using RNAseq have found differential regulation of type I interferon-related pathways 23,24 , with one study also showing enrichment for several other pathways involving immune function 23 . Finally, a very recent study has used genome-wide DNA methylation and gene expression analyses in patients prospectively-defined as responders and non-responders to an 8-week trial of escitalopram treatment 25 , and found two genes that exhibited increases in both DNA methylation and mRNA expression in non-responders: CHN2, which could affect hippocampal neurogenesis, and JAK2, which activates both innate and adaptive immunity.…”

Association between childhood maltreatment, psychopathology and DNA methylation of genes involved in stress regulation: Evidence from a study in Borderline Personality Disorder

“…[23,52,59,60]. We believe that studies reporting methylation patterns beneath a certain methodological detection threshold need to be interpreted with caution and warrant replication [17,43,[61][62][63]. Another shortcoming of the present study relates to the sample, which was exclusively female.…”

Drug Response-Related DNA Methylation Changes in Schizophrenia, Bipolar Disorder, and Major Depressive Disorder

“…Responders and non-responders had two CpG sites on genes PPFIA4 and HS3ST1 that were differently methylated ( q < 0.05). Another study compared the DNAm changes in blood between responders and non-responders with 8 weeks of escitalopram treatment for 177 MDD patients, using the EPIC assays ( Ju et al, 2019 ). They identified 303 ( p < 0.05) sites with nominally significant differences between responders and non-responders, but none were significantly different after correction for multiple comparisons.…”

“…Positional effects are emerging when the same sample in different physical positions on the array and could bias methylation levels and lead to false findings. From our review, we observed that only one study did the batch effects correction ( Ju et al, 2019 ), and none of these studies corrected for positional effects according to the method description in those papers. We cannot rule out the possibility that the data were properly processed but failed to be reported in the papers, but not reporting such details at least indicated the lack of attention to the serious issues.…”