Early-life adversity severity, timing, and context type are associated with SLC6A4 methylation in emerging adults: Results from a prospective cohort study
Epigenetic modifications, including DNA methylation (DNAm), can play a role in the biological embedding of early-life adversity (ELA) through serotonergic mechanisms. The current study examines methylation of the CpG island in the promoter region of the stress-responsive serotonin transporter gene (...
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| creator | Koning, Stephanie M. Kessler, Courtenay L. Canli, Turhan Duman, Elif A. Adam, Emma K. Zinbarg, Richard Craske, Michelle G. Stephens, Jacquelyn E. Vrshek-Schallhorn, Suzanne |
| description | Epigenetic modifications, including DNA methylation (DNAm), can play a role in the biological embedding of early-life adversity (ELA) through serotonergic mechanisms. The current study examines methylation of the CpG island in the promoter region of the stress-responsive serotonin transporter gene (SLC6A4) and is the first to jointly assess how it is influenced by ELA severity, timing, and type—specifically, deprivation and threat.
We use data from 627 Youth Emotion Project study participants, recruited from two US high schools. Using adjusted linear regressions, we analyze DNA collected in early adulthood from 410 participants and ELA based on interviewer-rated responses from concurrent Childhood Trauma Interviews, adjusting for survey-measured covariates.
ELA robustly predicted mean CpG island SLC6A4 DNAm percent across 71 CpG sites. Each additional major-severity ELA event was associated with a 0.121-percentage-point increase (p |
| doi_str_mv | 10.1016/j.psyneuen.2024.107181 |
| format | Article |
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We use data from 627 Youth Emotion Project study participants, recruited from two US high schools. Using adjusted linear regressions, we analyze DNA collected in early adulthood from 410 participants and ELA based on interviewer-rated responses from concurrent Childhood Trauma Interviews, adjusting for survey-measured covariates.
ELA robustly predicted mean CpG island SLC6A4 DNAm percent across 71 CpG sites. Each additional major-severity ELA event was associated with a 0.121-percentage-point increase (p<0.001), equating to a 0.177 standard deviation (sd) higher DNAm level (95 % CI: 0.080, 0.274) with each 1-sd higher adversity score. When modeled separately, both childhood and adolescent ELA predicted SLC6A4 DNAm. When modeled jointly, adolescent ELA was most strongly predictive, and child adversity remained significantly associated with DNAm through indirect associations via adolescent adversity. Additionally, the ELA-SLC6A4 DNAm association may vary by adversity type. Across separate models for childhood and adolescent exposures, deprivation coefficients are positive and statistically significant. Meanwhile, threat coefficients are positive and not significantly significant but do not statistically differ from deprivation coefficients. In models including all ELA dimensions, one major adolescent deprivation event is associated with a 0.222-percentage-point increased SLC6A4 DNAm (p<0.05), or a 1-sd higher deprivation score with a 0.157-sd increased DNAm.
Results further implicate epigenetic modification on serotonergic neurotransmission via DNAm in the downstream sequelae of ELA—particularly adolescent deprivation—and support preventive interventions in adolescence to mitigate biological embedding.
•How adversity is associated with hypermethylation varies by severity, timing, and type.•Childhood and adolescent adversity each predicted SLC6A4 methylation.•When modeled jointly, adolescent adversity was a more direct predictor of hypermethylation.•When modeled jointly, adolescent deprivation was a particularly strong hypermethylation predictor.</description><identifier>ISSN: 0306-4530</identifier><identifier>ISSN: 1873-3360</identifier><identifier>EISSN: 1873-3360</identifier><identifier>DOI: 10.1016/j.psyneuen.2024.107181</identifier><identifier>PMID: 39298801</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Adolescent ; Adult ; Adverse Childhood Experiences ; Child ; CpG Islands - genetics ; Deprivation ; DNA methylation ; DNA Methylation - genetics ; Early life adversity ; Epigenesis, Genetic - genetics ; Epigenetics ; Female ; Humans ; Male ; Promoter Regions, Genetic - genetics ; Prospective Studies ; Serotonin Plasma Membrane Transport Proteins - genetics ; Stress, Psychological - genetics ; Stress, Psychological - metabolism ; Threat ; Young Adult ; Youths</subject><ispartof>Psychoneuroendocrinology, 2024-12, Vol.170, p.107181, Article 107181</ispartof><rights>2024</rights><rights>Copyright © 2024. Published by Elsevier Ltd.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c245t-9032468ef0c76577d3e68edbad44790bc51eee10060b6f3560eccd5342b9de353</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0306453024002269$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39298801$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Koning, Stephanie M.</creatorcontrib><creatorcontrib>Kessler, Courtenay L.</creatorcontrib><creatorcontrib>Canli, Turhan</creatorcontrib><creatorcontrib>Duman, Elif A.</creatorcontrib><creatorcontrib>Adam, Emma K.</creatorcontrib><creatorcontrib>Zinbarg, Richard</creatorcontrib><creatorcontrib>Craske, Michelle G.</creatorcontrib><creatorcontrib>Stephens, Jacquelyn E.</creatorcontrib><creatorcontrib>Vrshek-Schallhorn, Suzanne</creatorcontrib><title>Early-life adversity severity, timing, and context type are associated with SLC6A4 methylation in emerging adults: Results from a prospective cohort study</title><title>Psychoneuroendocrinology</title><addtitle>Psychoneuroendocrinology</addtitle><description>Epigenetic modifications, including DNA methylation (DNAm), can play a role in the biological embedding of early-life adversity (ELA) through serotonergic mechanisms. The current study examines methylation of the CpG island in the promoter region of the stress-responsive serotonin transporter gene (SLC6A4) and is the first to jointly assess how it is influenced by ELA severity, timing, and type—specifically, deprivation and threat.
We use data from 627 Youth Emotion Project study participants, recruited from two US high schools. Using adjusted linear regressions, we analyze DNA collected in early adulthood from 410 participants and ELA based on interviewer-rated responses from concurrent Childhood Trauma Interviews, adjusting for survey-measured covariates.
ELA robustly predicted mean CpG island SLC6A4 DNAm percent across 71 CpG sites. Each additional major-severity ELA event was associated with a 0.121-percentage-point increase (p<0.001), equating to a 0.177 standard deviation (sd) higher DNAm level (95 % CI: 0.080, 0.274) with each 1-sd higher adversity score. When modeled separately, both childhood and adolescent ELA predicted SLC6A4 DNAm. When modeled jointly, adolescent ELA was most strongly predictive, and child adversity remained significantly associated with DNAm through indirect associations via adolescent adversity. Additionally, the ELA-SLC6A4 DNAm association may vary by adversity type. Across separate models for childhood and adolescent exposures, deprivation coefficients are positive and statistically significant. Meanwhile, threat coefficients are positive and not significantly significant but do not statistically differ from deprivation coefficients. In models including all ELA dimensions, one major adolescent deprivation event is associated with a 0.222-percentage-point increased SLC6A4 DNAm (p<0.05), or a 1-sd higher deprivation score with a 0.157-sd increased DNAm.
Results further implicate epigenetic modification on serotonergic neurotransmission via DNAm in the downstream sequelae of ELA—particularly adolescent deprivation—and support preventive interventions in adolescence to mitigate biological embedding.
•How adversity is associated with hypermethylation varies by severity, timing, and type.•Childhood and adolescent adversity each predicted SLC6A4 methylation.•When modeled jointly, adolescent adversity was a more direct predictor of hypermethylation.•When modeled jointly, adolescent deprivation was a particularly strong hypermethylation predictor.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Adverse Childhood Experiences</subject><subject>Child</subject><subject>CpG Islands - genetics</subject><subject>Deprivation</subject><subject>DNA methylation</subject><subject>DNA Methylation - genetics</subject><subject>Early life adversity</subject><subject>Epigenesis, Genetic - genetics</subject><subject>Epigenetics</subject><subject>Female</subject><subject>Humans</subject><subject>Male</subject><subject>Promoter Regions, Genetic - genetics</subject><subject>Prospective Studies</subject><subject>Serotonin Plasma Membrane Transport Proteins - genetics</subject><subject>Stress, Psychological - genetics</subject><subject>Stress, Psychological - metabolism</subject><subject>Threat</subject><subject>Young Adult</subject><subject>Youths</subject><issn>0306-4530</issn><issn>1873-3360</issn><issn>1873-3360</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFUV1P5CAUJcaNjq5_wfDogx2hUNr6pJm4ajLJJvvxTCjcOkxaWoGO27-yv1Ymo_u6D4QDOfece-9B6JKSJSVU3GyXY5gdTOCWOcl5-ixpRY_QglYlyxgT5BgtCCMi4wUjp-gshC0hRFQiP0GnrM7rqiJ0gf4-KN_NWWdbwMrswAcbZxwgoQSucbS9dS_XWDmD9eAi_Ik4zmMi-3RCGLRVEQx-s3GDf65X4p7jHuJm7lS0g8PWYejBvySRpD91MdziHxD2ALd-6LHCox_CCDraHSSLzeAjDnEy81f0pVVdgIuP-xz9_vbwa_WUrb8_Pq_u15nOeRGzmrCciwpaoktRlKVhkF6mUYbzsiaNLigA0DQ7aUTLCkFAa1Mwnje1AVawc3R10E2NvE4Qouxt0NB1ysEwBcn2uy0qxnmiigNVp56Dh1aO3vbKz5ISuc9FbuVnLnKfizzkkgovPzympgfzr-wziES4OxAgTbqz4GXQFpwGY33ajTSD_Z_HO1-opV4</recordid><startdate>202412</startdate><enddate>202412</enddate><creator>Koning, Stephanie M.</creator><creator>Kessler, Courtenay L.</creator><creator>Canli, Turhan</creator><creator>Duman, Elif A.</creator><creator>Adam, Emma K.</creator><creator>Zinbarg, Richard</creator><creator>Craske, Michelle G.</creator><creator>Stephens, Jacquelyn E.</creator><creator>Vrshek-Schallhorn, Suzanne</creator><general>Elsevier Ltd</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>202412</creationdate><title>Early-life adversity severity, timing, and context type are associated with SLC6A4 methylation in emerging adults: Results from a prospective cohort study</title><author>Koning, Stephanie M. ; Kessler, Courtenay L. ; Canli, Turhan ; Duman, Elif A. ; Adam, Emma K. ; Zinbarg, Richard ; Craske, Michelle G. ; Stephens, Jacquelyn E. ; Vrshek-Schallhorn, Suzanne</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c245t-9032468ef0c76577d3e68edbad44790bc51eee10060b6f3560eccd5342b9de353</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Adverse Childhood Experiences</topic><topic>Child</topic><topic>CpG Islands - genetics</topic><topic>Deprivation</topic><topic>DNA methylation</topic><topic>DNA Methylation - genetics</topic><topic>Early life adversity</topic><topic>Epigenesis, Genetic - genetics</topic><topic>Epigenetics</topic><topic>Female</topic><topic>Humans</topic><topic>Male</topic><topic>Promoter Regions, Genetic - genetics</topic><topic>Prospective Studies</topic><topic>Serotonin Plasma Membrane Transport Proteins - genetics</topic><topic>Stress, Psychological - genetics</topic><topic>Stress, Psychological - metabolism</topic><topic>Threat</topic><topic>Young Adult</topic><topic>Youths</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Koning, Stephanie M.</creatorcontrib><creatorcontrib>Kessler, Courtenay L.</creatorcontrib><creatorcontrib>Canli, Turhan</creatorcontrib><creatorcontrib>Duman, Elif A.</creatorcontrib><creatorcontrib>Adam, Emma K.</creatorcontrib><creatorcontrib>Zinbarg, Richard</creatorcontrib><creatorcontrib>Craske, Michelle G.</creatorcontrib><creatorcontrib>Stephens, Jacquelyn E.</creatorcontrib><creatorcontrib>Vrshek-Schallhorn, Suzanne</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Psychoneuroendocrinology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Koning, Stephanie M.</au><au>Kessler, Courtenay L.</au><au>Canli, Turhan</au><au>Duman, Elif A.</au><au>Adam, Emma K.</au><au>Zinbarg, Richard</au><au>Craske, Michelle G.</au><au>Stephens, Jacquelyn E.</au><au>Vrshek-Schallhorn, Suzanne</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Early-life adversity severity, timing, and context type are associated with SLC6A4 methylation in emerging adults: Results from a prospective cohort study</atitle><jtitle>Psychoneuroendocrinology</jtitle><addtitle>Psychoneuroendocrinology</addtitle><date>2024-12</date><risdate>2024</risdate><volume>170</volume><spage>107181</spage><pages>107181-</pages><artnum>107181</artnum><issn>0306-4530</issn><issn>1873-3360</issn><eissn>1873-3360</eissn><abstract>Epigenetic modifications, including DNA methylation (DNAm), can play a role in the biological embedding of early-life adversity (ELA) through serotonergic mechanisms. The current study examines methylation of the CpG island in the promoter region of the stress-responsive serotonin transporter gene (SLC6A4) and is the first to jointly assess how it is influenced by ELA severity, timing, and type—specifically, deprivation and threat.
We use data from 627 Youth Emotion Project study participants, recruited from two US high schools. Using adjusted linear regressions, we analyze DNA collected in early adulthood from 410 participants and ELA based on interviewer-rated responses from concurrent Childhood Trauma Interviews, adjusting for survey-measured covariates.
ELA robustly predicted mean CpG island SLC6A4 DNAm percent across 71 CpG sites. Each additional major-severity ELA event was associated with a 0.121-percentage-point increase (p<0.001), equating to a 0.177 standard deviation (sd) higher DNAm level (95 % CI: 0.080, 0.274) with each 1-sd higher adversity score. When modeled separately, both childhood and adolescent ELA predicted SLC6A4 DNAm. When modeled jointly, adolescent ELA was most strongly predictive, and child adversity remained significantly associated with DNAm through indirect associations via adolescent adversity. Additionally, the ELA-SLC6A4 DNAm association may vary by adversity type. Across separate models for childhood and adolescent exposures, deprivation coefficients are positive and statistically significant. Meanwhile, threat coefficients are positive and not significantly significant but do not statistically differ from deprivation coefficients. In models including all ELA dimensions, one major adolescent deprivation event is associated with a 0.222-percentage-point increased SLC6A4 DNAm (p<0.05), or a 1-sd higher deprivation score with a 0.157-sd increased DNAm.
Results further implicate epigenetic modification on serotonergic neurotransmission via DNAm in the downstream sequelae of ELA—particularly adolescent deprivation—and support preventive interventions in adolescence to mitigate biological embedding.
•How adversity is associated with hypermethylation varies by severity, timing, and type.•Childhood and adolescent adversity each predicted SLC6A4 methylation.•When modeled jointly, adolescent adversity was a more direct predictor of hypermethylation.•When modeled jointly, adolescent deprivation was a particularly strong hypermethylation predictor.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>39298801</pmid><doi>10.1016/j.psyneuen.2024.107181</doi></addata></record> |
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| subjects | Adolescent Adult Adverse Childhood Experiences Child CpG Islands - genetics Deprivation DNA methylation DNA Methylation - genetics Early life adversity Epigenesis, Genetic - genetics Epigenetics Female Humans Male Promoter Regions, Genetic - genetics Prospective Studies Serotonin Plasma Membrane Transport Proteins - genetics Stress, Psychological - genetics Stress, Psychological - metabolism Threat Young Adult Youths |
| title | Early-life adversity severity, timing, and context type are associated with SLC6A4 methylation in emerging adults: Results from a prospective cohort study |
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