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An Epigenome-Wide Association Study of Early-Onset Major Depression in Monozygotic Twins Roxann Roberson-Nay 1,2,Danam.Lapato2,3,Aaronr.Wolen4, Eva E

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An Epigenome-Wide Association Study of Early-Onset Major Depression in Monozygotic Twins Roxann Roberson-Nay 1,2,Danam.Lapato2,3,Aaronr.Wolen4, Eva E Roberson-Nay et al. Translational Psychiatry (2020) 10:301 https://doi.org/10.1038/s41398-020-00984-2 Translational Psychiatry ARTICLE Open Access An epigenome-wide association study of early-onset major depression in monozygotic twins Roxann Roberson-Nay 1,2,DanaM.Lapato2,3,AaronR.Wolen4, Eva E. Lancaster2,3, Bradley T. Webb 1,2,3, Bradley Verhulst1,2,5, John M. Hettema1,2 and Timothy P. York 2,3 Abstract Major depression (MD) is a debilitating mental health condition with peak prevalence occurring early in life. Genome- wide examination of DNA methylation (DNAm) offers an attractive complement to studies of allelic risk given it can reflect the combined influence of genes and environment. The current study used monozygotic twins to identify differentially and variably methylated regions of the genome that distinguish twins with and without a lifetime history of early-onset MD. The sample included 150 Caucasian monozygotic twins between the ages of 15 and 20 (73% female; Mage = 17.52 SD = 1.28) who were assessed during a developmental stage characterized by relatively distinct neurophysiological changes. All twins were generally healthy and currently free of medications with psychotropic effects. DNAm was measured in peripheral blood cells using the Infinium Human BeadChip 450 K Array. MD associations with early-onset MD were detected at 760 differentially and variably methylated probes/regions that mapped to 428 genes. Genes and genomic regions involved neural circuitry formation, projection, functioning, and plasticity. Gene enrichment analyses implicated genes related to neuron structures and neurodevelopmental processes including cell–cell adhesion genes (e.g., PCDHA genes). Genes previously implicated in mood and psychiatric disorders as well as chronic stress (e.g., NRG3) also were identified. DNAm regions associated with early-onset MD were found to overlap genetic loci identified in the latest Psychiatric Genomics Consortium meta-analysis of depression. 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Understanding the time course of epigenetic influences during emerging adulthood may clarify developmental phases where changes in the DNA methylome may modulate individual differences in MD risk. Introduction negative socioemotional outcomes including recurrent Major depression (MD) is highly prevalent, ranking MDEs3,4. Adolescence/young adulthood is characterized second in the global burden of disease, with the overall by neurophysiological changes (e.g., synaptic pruning, lifetime risk estimated to be 16.2% in the general popu- myelination) that significantly influence brain function lation1. MD is associated with increased mortality, parti- and behavior, which may increase risk for MD and other cularly suicide1. Among adolescents, MD is associated psychiatric conditions5. Thus, understanding the genetic with the greatest level of impairment of all psychiatric contributions to MD during this dynamic neurophysio- – conditions, with 16% of females and 12% of males logical period where peak incidence is observed2,6 8 is endorsing at least one major depressive episode (MDE) by critical to elucidating developmentally informed pathways age 182. An early age of onset confers increased risk for to mood disorders. Twin and family studies robustly demonstrate that genetic factors play a role in risk for MD, with heritability Correspondence: Roxann Roberson-Nay ([email protected]) estimates of roughly 35% for MD and 45% for early-onset 1Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, MD9; these heritability estimates indicate that MD is USA suitable for epigenetic study using twins10. Moreover, a 2Virginia Commonwealth University, Virginia Institute for Psychiatric and Behavioral Genetics, Richmond, VA, USA large number of genetic loci have been identified for MD, Full list of author information is available at the end of the article © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Roberson-Nay et al. Translational Psychiatry (2020) 10:301 Page 2 of 12 supporting the role of genetic factors in the etiology of comorbidities and medication usage as well as long-term MD11,12. Twin study variance component analyses also nicotine use. Moreover, it eliminates the well-known – indicate a considerable contribution of unique environ- epigenetic changes associated with aging36 38. The mental risk factors to MD9. Due to the substantial link developmental window of young adulthood also is asso- between environmental hardship and onset of an ciated with moderate conservation of DNAm that is MDE13,14, epigenetic mechanisms may, in part, mediate nonetheless responsive to environmental signals39, mak- the influence of environmental stress and combine with ing it an ideal sensitive period for the study of MD. – genetic liability to increase MD risk over the lifespan15 17. Epigenetic mechanisms refer to DNA, chromatin, and Methods RNA modifications that can influence the expression of Participants genes but do not alter the underlying genetic sequence. One hundred sixty-six MZ twins (83 pairs) were drawn Animal studies have been critical to establishing a causal from a larger sample of twins (N = 430 pairs) enrolled in a association between early life environments, epigenetic parent study (R01MH101518)40, which was designed to alterations, and phenotypic outcomes. For example, the estimate genetic and environmental contributions to seminal work of Michael Meaney and his research team RDoC Negative Valence Systems constructs using classi- reveals the importance of maternal care in altering the cal twin modeling (i.e., disaggregating variance into expression of genes that regulate behavioral and neu- additive genetic, common shared, and unique non-shared – roendocrine responses to stress as well as synaptic environmental variation)41 51. Blood samples were col- – development in the rat hippocampus18 23. Indeed, a lected as part of the parent R01 for future use. Twins were number of animal and human studies demonstrate lasting primarily recruited through the Mid-Atlantic Twin Reg- epigenetic alterations occurring in the genomes of cells istry (MATR), a population-based registry40,41. All parti- including changes to postmitotic neurons that integrate cipants (parents/minor children, adults) provided written experience-dependent changes24. Thus, the timing of informed consent/assent. environmental stress plays an important role in sub- Of the 83 twin pairs initially identified as MZ via the sequent epigenetic consequences, with early life stress zygosity questionnaire, five pairs (6.3%) were determined paradigms in mice and humans demonstrating enduring to be DZ pairs using DNA-based markers and were – changes in epigenetic profiles18,21,25 29. removed (for zygosity determination, see Supplementary). A number of studies have utilized genome-wide plat- One or both twins from three additional pairs failed forms to determine DNA methylation (DNAm) differ- DNA-based quality control checks, reducing the final ences between MD cases and controls. However, as much analyzed sample to 75 MZ twin pairs (150 twins; see Table as 37% of DNAm variance can be accounted for by genetic 1 for details). Of the 150 twins, 39 twins endorsed a his- factors30 with recent studies indicating that common tory of at least one MD episode, resulting in 27 dis- genetic variation (i.e., methylation quantitative trait loci cordant, 42 concordant negative (i.e., both twins MD – [mQTLs]) influence DNAm levels31 35. Most MD case- unaffected), and 6 concordant positive (i.e., both twins control studies of DNAm do not account for allelic var- MD affected) pairs. All twins were raised together in the iation, which means genetic and environmental influences same home and were required to be free of psychotropic on DNAm cannot be disaggreagated. In contrast, the medications/medications with psychotropic effects at the quasi-experimental design afforded by monozygotic (MZ) time of study entry, although ~4.0% (n = 6) endorsed a twins greatly improves on the unmatched case-control history of psychotropic medication use, slightly lower design (see Supplementary Table 1). The use of MZ twins, than the national average42. See full study exclusionary both discordant and concordant pairs for outcome, criteria in Supplementary material. adjusts for much of the impact of unmeasured confounds such as genetic variation, uterine environment, age, sex, Measures race, cohort effects, and exposure to many shared envir- Major depression onmental events. All twin pairs completed a psychiatric history based on The current study utilized the robust MZ twin design an expanded version of the Composite International coupled with an analytically powerful approach
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