Effects of Genotype and Child Abuse on DNA Methylation and Gene Expression at the Serotonin Transporter

Altered regulation of the serotonin transporter (SLC6A4) is hypothesized to be a key event in many forms of neuropsychiatric illness, yet our understanding of the molecular mechanisms through which changes in gene function could lead to illness remains incomplete. In prior studies, we and others have demonstrated that methylation of CpG residues in the promoter associated CpG island alters SLC6A4 gene expression, that the extent of that DNA methylation in child abuse is genotype dependent, and that adverse childhood experiences such as child sex abuse are related to methylation. However, we have not examined whether these effects are splice variant specific, whether the association of methylation to gene expression varies as a function of genotype, and whether methylation in other SLC6A4 gene regions are more likely candidates for GxE effects. In the current investigation we measured methylation in lymphoblast DNA from 158 female subjects in the Iowa Adoption Studies at 16 CpG residues spread across the SLC6A4 locus, and analyzed their relationship to gene expression for two SLC6A4 splice variants. Methylation of two CpG residues in the shore of the CpG island (cg22584138 and cg05951817), a location immediately upstream from exon 1A, predicted gene expression for the splice variant containing Exon 1A + 1B. Methylation at two residues in the CpG island itself (cg 25769822 and cg05016953) was associated with total SLC6A4 expression. Examination of these four CpG residues indicated that methylation of cg22584138 was influenced by both genotype and sex abuse, whereas methylation of cg05016953 was influenced only by sex abuse history. Factors influencing methylation at other CpG dinucleotide pairs were not identified. We conclude that methylation effects on transcription may vary as a function of underlying gene motif and splice variant, and that the shore of CpG islands, upstream of TSS, may be of particular interest in examining environmental effects on methylation

Methylation array data can simultaneously identify individuals and convey protected health information: an unrecognized ethical concern

BACKGROUND: Genome-wide methylation arrays are increasingly used tools in studies of complex medical disorders. Because of their expense and potential utility to the scientific community, current federal policy dictates that data from these arrays, like those from genome-wide genotyping arrays, be deposited in publicly available databases. Unlike the genotyping information, access to the expression data is not restricted. An underlying supposition in the current nonrestricted access to methylation data is the belief that protected health and personal identifying information cannot be simultaneously extracted from these arrays. RESULTS: In this communication, we analyze methylation data from the Illumina HumanMethylation450 array and show that genotype at 1,069 highly informative loci, and both alcohol and smoking consumption information, can be derived from the array data. CONCLUSIONS: We conclude that both potentially personally identifying information and substance-use histories can be simultaneously derived from methylation array data. Because access to genetic information about a database subject or one of their relatives is critical to the de-identification process, this risk of de-identification is limited at the current time. We propose that access to genome-wide methylation data be restricted to institutionally approved investigators who accede to data use agreements prohibiting re-identification

The Impact of Recent Alcohol Use on Genome Wide DNA Methylation Signatures

Chronic alcohol intake is associated with a wide variety of adverse health outcomes including depression, diabetes, and heart disease. Unfortunately, the molecular mechanisms through which these effects are conveyed are not clearly understood. To examine the potential role of epigenetic factors in this process, we examined the relationship of recent alcohol intake to genome wide methylation patterns using the Illumina 450 Methylation Bead Chip and lymphoblast DNA derived from 165 female subjects participating in the Iowa Adoption Studies. We found that the pattern of alcohol use over the 6-months immediately prior to phlebotomy was associated with, severity-dependent changes in the degree of genome wide methylation that preferentially hypermethylate the central portion of CpG islands with methylation at cg05600126, a probe in ABR, and the 5′ untranslated region of BLCAP attaining genome wide significance in two point and sliding window analyses of probe methylation data, respectively. We conclude that recent alcohol use is associated with widespread changes in DNA methylation in women and that further study to confirm these findings and determine their relationship to somatic function are in order

Prevention effects on trajectories of African American adolescents\u27 exposure to interparental conflict and depressive symptoms.

The present study investigates the trajectory of children\u27s exposure to interparental conflict during adolescence, its effects on adolescents\u27 psychological adjustment, as well as the ability of a family-centered prevention program to alter this trajectory. A total of 331 African American couples with an adolescent or preadolescent child participated in a randomized control trial of the Promoting Strong African American Families program, a newly developed program targeting couple and cocaregiving processes. Using a multi-informant, latent growth curve approach, child exposure to interparental conflict during adolescence was found to be stable over a period of 2 years among families in the control group, but significantly declined among families in the treatment condition. Rates of change were significantly different between intervention and control groups based on parents\u27 report of youth exposure to interparental conflict, but not for child\u27s report. Structural equation models found trajectory parameters of interparental conflict predicted changes in adolescent depressive symptoms, with increasing rates of changes in conflict associated with increases in adolescent internalizing symptoms over the 2-year duration of the study. Finally, a significant indirect effect was identified linking treatment, changes in parents\u27 reports of child exposure to interparental conflict, and adolescent depressive symptoms. The implications for research and intervention are discussed

Impact of child sex abuse on adult psychopathology: A genetically and epigenetically informed investigation

Genetic, environmental, and epigenetic influences and their transactions were examined in a sample of 155 women from the Iowa adoptee sample who had been removed from their biological parents shortly after birth and assessed when participants were an average of 41.10 years old. We observed an interactive effect of child sex abuse (CSA) and biological parent psychopathology (i.e., genetic load) on substance abuse as well as a main effect of CSA on substance abuse in adulthood. We also observed main effects of CSA and genetic load on depression and on antisocial characteristics. As predicted, CSA, but not genetic load or later substance abuse, was associated with epigenetic change. In addition, the interaction between genetic load and CSA predicted epigenetic change, indicating a potential genetic basis for a differential impact of CSA on epigenetic change. Finally, epigenetic change partially mediated the effect of CSA on antisocial characteristics. The results suggest the relevance of genetic and epigenetic processes for future theorizing regarding marital and family precursors of several forms of adult psychopathology. Implications for preventive intervention are discussed

Mechanisms of Family Impact on African American Adolescents\u27 HIV-Related Behavior

A longitudinal model that tested mediating pathways between protective family processes and HIV-related behavior was evaluated with 195 African American youth. Three waves of data were collected when the youth were 13, 15, and 19 years old. Evidence of mediation and temporal priority were assessed for 3 constructs: academic engagement, evaluations of prototypical risk-taking peers, and affiliations with risk-promoting peers. Structural equation modeling indicated that protective family processes assessed during early adolescence were associated with HIV-related behavior during emerging adulthood and that academic engagement, evaluations of prototypical risk-taking peers, and affiliations with risk-promoting peers accounted for this association. Evidence of a specific pathway emerged: protective family processes→academic engagement→negative evaluations of prototypical risk-taking peers→affiliations with risk-promoting peers→HIV-related behavior. Academic engagement also was a direct predictor of HIV-related risk behavior

Why now? Examining antecedents for substance use initiation among African American adolescents

Current adolescent substance use risk models have inadequately predicted use for African Americans, with limited knowledge on differential predictability as a function of developmental period. Among a sample of 500 African American youth (ages 11–21), four risk indices (i.e., social, attitudinal, intrapersonal, and racial discrimination) were examined in the prediction of alcohol, marijuana, and cigarette initiation during early (ages 11–13), mid (ages 16–18) and late (ages 19–21) adolescence. Results showed that when developmental periods were combined, racial discrimination was the only index that predicted initiation for all three substances. However, when risk models were stratified based on developmental period, variation was found within and across substance types. Results highlight the importance of racial discrimination in understanding substance use initiation among African American youth and the need for tailored interventions based on developmental stage

Methylation Array Data Can Simultaneously Identify Individual and Convey Protected Health Information: an Unrecognized Ethical Concern

Background: Genome-wide methylation arrays are increasingly used tools in studies of complex medical disorders. Because of their expense and potential utility to the scientific community, current federal policy dictates that data from these arrays, like those from genome-wide genotyping arrays, be deposited in publicly available databases. Unlike the genotyping information, access to the expression data is not restricted. An underlying supposition in the current nonrestricted access to methylation data is the belief that protected health and personal identifying information cannot be simultaneously extracted from these arrays. Results: In this communication, we analyze methylation data from the Illumina HumanMethylation450 array and show that genotype at 1,069 highly informative loci, and both alcohol and smoking consumption information, can be derived from the array data. Conclusions: We conclude that both potentially personally identifying information and substance-use histories can be simultaneously derived from methylation array data. Because access to genetic information about a database subject or one of their relatives is critical to the de-identification process, this risk of de-identification is limited at the current time. We propose that access to genome-wide methylation data be restricted to institutionally approved investigators who accede to data use agreements prohibiting re-identification