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. 2022 Jan;14(1):11-25.
doi: 10.2217/epi-2021-0310. Epub 2021 Dec 8.

Leukocyte methylomic imprints of exposure to the genocide against the Tutsi in Rwanda: a pilot epigenome-wide analysis

Clarisse Musanabaganwa  1   2   3   4 , Agaz H Wani  3 , Janelle Donglasan  3 , Segun Fatumo  5   6 , Stefan Jansen  7 , Jean Mutabaruka  2 , Eugene Rutembesa  2 , Annette Uwineza  1 , Erno J Hermans  4 , Benno Roozendaal  4 , Derek E Wildman  3 , Leon Mutesa  1 , Monica Uddin  3
Affiliations

Leukocyte methylomic imprints of exposure to the genocide against the Tutsi in Rwanda: a pilot epigenome-wide analysis

Clarisse Musanabaganwa et al. Epigenomics. 2022 Jan.

Abstract

Aim & methods: We conducted a pilot epigenome-wide association study of women from Tutsi ethnicity exposed to the genocide while pregnant and their resulting offspring, and a comparison group of women who were pregnant at the time of the genocide but living outside of Rwanda.Results: Fifty-nine leukocyte-derived DNA samples survived quality control: 33 mothers (20 exposed, 13 unexposed) and 26 offspring (16 exposed, 10 unexposed). Twenty-four significant differentially methylated regions (DMRs) were identified in mothers and 16 in children. Conclusions:In utero genocide exposure was associated with CpGs in three of the 24 DMRs: BCOR, PRDM8 and VWDE, with higher DNA methylation in exposed versus unexposed offspring. Of note, BCOR and VWDE show significant correlation between brain and blood DNA methylation within individuals, suggesting these peripherally derived signals of genocide exposure may have relevance to the brain.

Keywords: PTSD; differentially methylated region; epigenetics; epigenomic; genocide; intergenerational transmission; maternal stress; methylation; offspring; trauma.

Plain language summary

Lay abstract The 1994 Rwandan genocide against ethnic Tutsi has been associated with adverse mental health outcomes in survivors decades later, but the molecular mechanisms that contribute to this association remain poorly characterized. Epigenetic mechanisms such as DNA methylation regulate gene function and change in response to life experiences. We identified differentially methylated regions (DMRs) in genocide-exposed versus unexposed mothers and children. In utero genocide exposure was linked with methylation differences in three maternal DMRs, with higher methylation in exposed offspring. Two of three DMRs show correlation between brain and blood methylation within individuals, suggesting that peripherally derived signals of genocide exposure may be relevant to the brain.

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Conflict of interest statement

Financial & competing interests disclosure

This work was funded by the NIH (grant no. U01MH115485). M Uddin was a paid consultant for System Analytic in 2020. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Figures

Figure 1.
Figure 1.. Selection probabilities of child sex, in utero genocide exposure, maternal age and maternal DNA methylation for the top three highly enriched differentially methylated region-related CpGs highly associated with in utero genocide exposure.
The colors represent the strength of the selection probability.
Figure 2.
Figure 2.. Post hoc comparison of averaged estimated marginal means of DNA methylation in children for the top three enriched CpG sites of differentially methylated regions associated with in utero genocide exposure by case and control groups.
The post hoc pairwise comparison plot shows that mean child methylation estimates are higher in in utero genocide exposure cases. The standard errors calculated here are for visualization purposes and are only based on an assessment of the variance of the estimates. *Top three highly enriched CpGs of each DMR: BCOR = cg15627188, cg02931660, cg02932805; PRDM8 = cg18073471, cg05059566, cg06307913; VWDE = cg03579179, cg06484146, cg20607287. DMR: Differentially methylated region.
Figure 3.
Figure 3.. t-test comparison of methylation (%) means between genocide-exposed versus unexposed children and mothers, respectively.
Blue represents lower mean methylation in unexposed individuals, and red represents higher mean methylation in exposed individuals. Each dot represents an individual sample. Methylation (%) of significant (p < 0.05) CpGs in the top two genes (BCOR, PRDM8) that are consistently significant in the differentially methylated regions and intergenerational analysis is shown. There is a significant difference in methylation levels between exposed versus unexposed subjects in both children and mothers (p < 0.05). Both CpGs (cg15627188, cg05059566) showed higher methylation levels in those exposed to genocide.
Figure 4.
Figure 4.. t-test comparison of methylation (%) means between genocide-exposed versus unexposed children and mothers, respectively.
Blue represents lower mean methylation in unexposed individuals, and red represents higher mean methylation in exposed individuals. Each dot represents an individual sample. Methylation (%) of significant CpGs in VWDE is shown. All three-top enriched CpGs (cg03579179, cg06484146, cg20607287) showed higher methylation levels in those exposed to genocide at p < 0.05.
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