Profiling placental DNA methylation associated with maternal SSRI treatment during pregnancy
Amy M Inkster, Chaini Konwar, Maria S Peñaherrera, Ursula Brain, Almas Khan, E Magda Price, Johanna Schuetz, Élodie Portales-Casamar, Amber Burt, Carmen J Marsit, Cathy Vaillancourt, Tim F Oberlander
Selective serotonin reuptake inhibitors (SSRIs), used to treat prenatal maternal depression, have been associated with neurobehavioral disturbances in exposed neonates, though the underlying molecular mechanisms remain poorly understood. In utero exposure to SSRIs may have an effect on DNA methylation (DNAme) in the human placenta, which is an epigenetic mark that is established during development and is associated with gene expression. Methods Chorionic villus samples from 64 human placentas
... re profiled with the Illumina MethylationEPIC BeadChip and clinical assessments of maternal mood were collected at multiple time points during pregnancy. Case distribution was 20 SSRI-exposed cases and 44 SSRI non-exposed cases. Maternal depression using a mean maternal Hamilton Depression score >8 to indicate symptomatic depressed mood (maternally-depressed) further classified cases into SSRI-exposed, maternally-depressed (n=14); SSRI-exposed, not maternally-depressed (n=6); SSRI non-exposed, maternally-depressed (n=20); and SSRI non-exposed, not maternally- depressed (n=24). To provide a replication cohort, Illumina 450K DNAme profiles were obtained from 34 additional cases from an independent cohort (n=17 SSRI-exposed, n=17 SSRI non-exposed). Results No CpGs were differentially methylated at FDR < 0.05 comparing SSRI-exposed to non-exposed placentas, while adjusting for mean maternal Hamilton Depression score, nor comparing SSRI- exposed maternally-depressed to SSRI-non-exposed maternally-depressed cases. At a relaxed threshold of FDR < 0.25, five CpGs were differentially methylated (|Δβ| > 0.03) by SSRI exposure status. Four of these CpGs were covered by the 450K array and were examined in the replication cohort, but none replicated. Amongst SSRI non-exposed cases, no CpGs were differentially methylated (FDR < 0.25) comparing maternally depressed to not depressed cases. In sex-stratified analyses for SSRI-exposed versus non-exposed cases (females n=31; males n=33), three additional CpGs in females, but none in males, were differentially methylated at the relaxed FDR < 0.25 cut-off. Conclusions We did not observe large-scale alterations of DNAme in placentas exposed to maternal SSRI treatment compared to placentas with no SSRI exposure. We also found no evidence for altered DNAme in maternal depression-exposed versus depression non-exposed placentas. This novel work in a prospectively recruited cohort with clinician-ascertained SSRI exposure and mood assessments would benefit from future replication.