Epigenetic signatures relating to disease-associated genotypic burden in familial risk of bipolar disorder
Abstract Environmental factors contribute to risk of bipolar disorder (BD), but how environmental factors impact the development of psychopathology within the context of elevated genetic risk is unknown. We herein sought to identify epigenetic signatures operating in the context of polygenic risk fo...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-08-01
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| Series: | Translational Psychiatry |
| Online Access: | https://doi.org/10.1038/s41398-022-02079-6 |
| _version_ | 1818504955243266048 |
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| author | Sonia Hesam-Shariati Bronwyn J. Overs Gloria Roberts Claudio Toma Oliver J. Watkeys Melissa J. Green Kerrie D. Pierce Howard J. Edenberg Holly C. Wilcox Emma K. Stapp Melvin G. McInnis Leslie A. Hulvershorn John I. Nurnberger Peter R. Schofield Philip B. Mitchell Janice M. Fullerton |
| author_facet | Sonia Hesam-Shariati Bronwyn J. Overs Gloria Roberts Claudio Toma Oliver J. Watkeys Melissa J. Green Kerrie D. Pierce Howard J. Edenberg Holly C. Wilcox Emma K. Stapp Melvin G. McInnis Leslie A. Hulvershorn John I. Nurnberger Peter R. Schofield Philip B. Mitchell Janice M. Fullerton |
| author_sort | Sonia Hesam-Shariati |
| collection | DOAJ |
| description | Abstract Environmental factors contribute to risk of bipolar disorder (BD), but how environmental factors impact the development of psychopathology within the context of elevated genetic risk is unknown. We herein sought to identify epigenetic signatures operating in the context of polygenic risk for BD in young people at high familial risk (HR) of BD. Peripheral blood-derived DNA was assayed using Illumina PsychArray, and Methylation-450K or -EPIC BeadChips. Polygenic risk scores (PRS) were calculated using summary statistics from recent genome-wide association studies for BD, major depressive disorder (MDD) and cross-disorder (meta-analysis of eight psychiatric disorders). Unrelated HR participants of European ancestry (n = 103) were stratified based on their BD-PRS score within the HR-population distribution, and the top two quintiles (High-BD-PRS; n = 41) compared against the bottom two quintiles (Low-BD-PRS; n = 41). The High-BD-PRS stratum also had higher mean cross-disorder-PRS and MDD-PRS (ANCOVA p = 0.035 and p = 0.024, respectively). We evaluated DNA methylation differences between High-BD-PRS and Low-BD-PRS strata using linear models. One differentially methylated probe (DMP) (cg00933603; p = 3.54 × 10−7) in VARS2, a mitochondrial aminoacyl-tRNA synthetase, remained significantly hypomethylated after multiple-testing correction. Overall, BD-PRS appeared to broadly impact epigenetic processes, with 1,183 genes mapped to nominal DMPs (p < 0.05); these displayed convergence with genes previously associated with BD, schizophrenia, chronotype, and risk taking. We tested poly-methylomic epigenetic profiles derived from nominal DMPs in two independent samples (n = 54 and n = 82, respectively), and conducted an exploratory evaluation of the effects of family environment, indexing cohesion and flexibility. This study highlights an important interplay between heritable risk and epigenetic factors, which warrant further exploration. |
| first_indexed | 2024-12-10T21:44:12Z |
| format | Article |
| id | doaj.art-ff11262f15f149c59e842d964d12f209 |
| institution | Directory Open Access Journal |
| issn | 2158-3188 |
| language | English |
| last_indexed | 2024-12-10T21:44:12Z |
| publishDate | 2022-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Translational Psychiatry |
| spelling | doaj.art-ff11262f15f149c59e842d964d12f2092022-12-22T01:32:24ZengNature Publishing GroupTranslational Psychiatry2158-31882022-08-0112111310.1038/s41398-022-02079-6Epigenetic signatures relating to disease-associated genotypic burden in familial risk of bipolar disorderSonia Hesam-Shariati0Bronwyn J. Overs1Gloria Roberts2Claudio Toma3Oliver J. Watkeys4Melissa J. Green5Kerrie D. Pierce6Howard J. Edenberg7Holly C. Wilcox8Emma K. Stapp9Melvin G. McInnis10Leslie A. Hulvershorn11John I. Nurnberger12Peter R. Schofield13Philip B. Mitchell14Janice M. Fullerton15Neuroscience Research AustraliaNeuroscience Research AustraliaSchool of Psychiatry, Faculty of Medicine, University of New South WalesNeuroscience Research AustraliaNeuroscience Research AustraliaNeuroscience Research AustraliaNeuroscience Research AustraliaDepartment of Medical and Molecular Genetics, Indiana UniversityChild Psychiatry & Public Health, Johns Hopkins UniversityJohns Hopkins Bloomberg School of Public HealthDepartment of Psychiatry, University of MichiganDepartment of Psychiatry, Stark Neurosciences Research Institute, Indiana University School of MedicineDepartment of Medical and Molecular Genetics, Indiana UniversityNeuroscience Research AustraliaSchool of Psychiatry, Faculty of Medicine, University of New South WalesNeuroscience Research AustraliaAbstract Environmental factors contribute to risk of bipolar disorder (BD), but how environmental factors impact the development of psychopathology within the context of elevated genetic risk is unknown. We herein sought to identify epigenetic signatures operating in the context of polygenic risk for BD in young people at high familial risk (HR) of BD. Peripheral blood-derived DNA was assayed using Illumina PsychArray, and Methylation-450K or -EPIC BeadChips. Polygenic risk scores (PRS) were calculated using summary statistics from recent genome-wide association studies for BD, major depressive disorder (MDD) and cross-disorder (meta-analysis of eight psychiatric disorders). Unrelated HR participants of European ancestry (n = 103) were stratified based on their BD-PRS score within the HR-population distribution, and the top two quintiles (High-BD-PRS; n = 41) compared against the bottom two quintiles (Low-BD-PRS; n = 41). The High-BD-PRS stratum also had higher mean cross-disorder-PRS and MDD-PRS (ANCOVA p = 0.035 and p = 0.024, respectively). We evaluated DNA methylation differences between High-BD-PRS and Low-BD-PRS strata using linear models. One differentially methylated probe (DMP) (cg00933603; p = 3.54 × 10−7) in VARS2, a mitochondrial aminoacyl-tRNA synthetase, remained significantly hypomethylated after multiple-testing correction. Overall, BD-PRS appeared to broadly impact epigenetic processes, with 1,183 genes mapped to nominal DMPs (p < 0.05); these displayed convergence with genes previously associated with BD, schizophrenia, chronotype, and risk taking. We tested poly-methylomic epigenetic profiles derived from nominal DMPs in two independent samples (n = 54 and n = 82, respectively), and conducted an exploratory evaluation of the effects of family environment, indexing cohesion and flexibility. This study highlights an important interplay between heritable risk and epigenetic factors, which warrant further exploration.https://doi.org/10.1038/s41398-022-02079-6 |
| spellingShingle | Sonia Hesam-Shariati Bronwyn J. Overs Gloria Roberts Claudio Toma Oliver J. Watkeys Melissa J. Green Kerrie D. Pierce Howard J. Edenberg Holly C. Wilcox Emma K. Stapp Melvin G. McInnis Leslie A. Hulvershorn John I. Nurnberger Peter R. Schofield Philip B. Mitchell Janice M. Fullerton Epigenetic signatures relating to disease-associated genotypic burden in familial risk of bipolar disorder Translational Psychiatry |
| title | Epigenetic signatures relating to disease-associated genotypic burden in familial risk of bipolar disorder |
| title_full | Epigenetic signatures relating to disease-associated genotypic burden in familial risk of bipolar disorder |
| title_fullStr | Epigenetic signatures relating to disease-associated genotypic burden in familial risk of bipolar disorder |
| title_full_unstemmed | Epigenetic signatures relating to disease-associated genotypic burden in familial risk of bipolar disorder |
| title_short | Epigenetic signatures relating to disease-associated genotypic burden in familial risk of bipolar disorder |
| title_sort | epigenetic signatures relating to disease associated genotypic burden in familial risk of bipolar disorder |
| url | https://doi.org/10.1038/s41398-022-02079-6 |
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