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

Refining Prevention: Genetic and Epigenetic Contributions

Currently, most prevention efforts are framed as universal interventions. However, despite the demonstrated efficacy of many prevention programs, variability in response is the rule with some participants responding very little and others accounting for the bulk of the positive impact of the program. Better understanding the processes associated with better and worse response to prevention is a critical first step in refining and adapting existing programs, or alternatively designing new prevention programs with enhanced outcomes. Because vulnerabilities to substance use, emotional problems, risky sexual behavior and other behavioral problems are influenced by a combination of environmental, genetic, and epigenetic factors, mediated in part through psychological processes (Kreek et al., 2005; Rutter et al., 2006), the study of genetic and epigenetic vulnerability and susceptibility factors provides an important starting point for efforts to address this critical need. A growing body of research on differential genetic susceptibility indicates that efforts to enhance prevention impact may benefit from consideration of the contribution of individualgenetic differences to treatment response (Brody et al., 2013). In addition, the recent expansion of genetic research to include a focus on epigenetic change provides considerable promise for the development of indicated prevention and individually tailored prevention efforts. However, before this promise can be realized, a number of theoretical and practical challenges remain. Thus, through this special section, we provide a foundation for a new era of prevention research in which the principles of prevention science are combined with genomic science. In the current special section we bring together authors to deal with genetic and epigenetically driven processes relevant to depression, substance abuse, and sexual risk taking. Together they comment on, and provide data relevant to, assessment, research and statistical methods, The papers help to inform the development of a new generation of prevention programs that go beyond universal programs and sensitively target key processes while providing greater precision regarding prediction of population-level impact

Multidimensional assessment of impulsivity in relation to obesity and food addiction

Based on similarities between overconsumption of food and addictive drugs, there is increasing interest in “food addiction,” a compulsive eating pattern defined using symptoms parallel to substance use disorders. Impulsivity, a multidimensional construct robustly linked to drug addiction, has been increasingly examined as an obesity determinant, but with mixed findings. This study sought to clarify relations between three major domains of impulsivity (i.e., impulsive personality traits, discounting of delayed rewards, and behavioral inhibition) in both obesity and food addiction. Based on the association between impulsivity and compulsive drug use, the general hypothesis was that the impulsivity-food addiction relation would be stronger than and responsible for the impulsivity-obesity relation. Using a cross-sectional dimensional design, participants (N ¼ 181; 32% obese) completed a biometric assessment, the Yale Food Addiction Scale (YFAS), the UPPS-P Impulsive Behavior Scales, a Go/NoGo task, and measures of monetary delay discounting. Results revealed significantly higher prevalence of food addiction among obese participants and stronger zero-order associations between impulsivity indices and YFAS compared to obesity. Two aspects of impulsivity were independently significantly associated with food addiction: (a) a composite of Positive and Negative Urgency, reflecting proneness to act impulsively during intense mood states, and (b) steep discounting of delayed rewards. Furthermore, the results supported food addiction as a mediator connecting both urgency and delay discounting with obesity. These findings provide further evidence linking impulsivity to food addiction and obesity, and suggest that food addiction may be a candidate etiological pathway to obesity for individuals exhibiting elevations in these domains

Comparison of Helplessness and Hopelessness as Sources of Cognitive Vulnerability Among Black and White College Students

The Cognitive Style Questionnaire (CSQ), an expansion of the Attributional Style Questionnaire (ASQ), was created as an enhanced measure of cognitive vulnerability to depression using a hopelessness theory framework. However, the CSQ’s development emphasized facets of cognitive vulnerability consistent with a Eurocentric worldview. Consequently, the CSQ may inadvertently degrade rather than enhance assessment of cognitive vulnerability to depression for Black participants whose vulnerability may be shaped by a different sociopolitical context. Participants were 259 White and 180 Black college students. As predicted, cognitive vulnerability to depression assessed via the reformulated learned helplessness (ASQ) but not hopelessness theory (CSQ) was associated with increased symptoms of depression for Black participants. The opposite pattern of results was found for White participants for whom hopelessness (CSQ), but not helplessness (ASQ) was associated with higher levels of depression symptoms. The current findings support the need for more extensive examination of social context and race in assessing cognitive vulnerability to depression

Current and Future Prospects for Epigenetic Biomarkers of Substance Use Disorders

Substance abuse has an enormous impact on economic and quality of life measures throughout the world. In more developed countries, overutilization of the most common forms of substances of abuse, alcohol and tobacco, is addressed primarily through prevention of substance use initiation and secondarily through the treatment of those with substance abuse or dependence. In general, these therapeutic approaches to substance abuse are deemed effective. However, there is a broad consensus that the development of additional tools to aid diagnosis, prioritize treatment selection and monitor treatment response could have substantial impact on the effectiveness of both substance use prevention and treatment. The recent demonstrations by a number of groups that substance use exposure is associated with robust changes in DNA methylation signatures of peripheral blood cells suggests the possibility that methylation assessments of blood or saliva could find broad clinical applications. In this article, we review recent progress in epigenetic approaches to substance use assessment with a particular emphasis on smoking (and alcohol) related applications. In addition, we highlight areas, such as the epigenetics of psychostimulant, opioid and cannabis abuse, which are markedly understudied and could benefit from intensified collaborative efforts to define epigenetic biomarkers of abuse and dependence

Digital methylation assessments of alcohol and cigarette consumption account for common variance in accelerated epigenetic ageing

Smoking and Heavy Alcohol Consumption (HAC) are established risk factors for myriad complex disorders of ageing. Yet many prior studies of Epigenetic Ageing (EA) have shown only modest effects of smoking and drinking on accelerated ageing. One potential reason for this conundrum might be the reliance of some prior EA studies on self-reported substance use, which may be unreliable in many samples. To test whether novel, non-self-reported indices would show a stronger association of smoking and HAC to EA, we used methylation sensitive digital PCR (MSdPCR) and data from 437 African American subjects from Wave 7 of the Family and Community Health Study Offspring Cohort to examine the effects of subjective and objective measures of smoking and HAC on 7 indices of EA. Because of limited overall correlations between the various EA indices, we examined patterns of association separately for each index. Consistent with expectations, MSdPCR assessments of smoking and HAC, but not self-reported alcohol consumption, were strongly correlated with accelerated EA. MSdPCR assessments of smoking and HAC accounted for 57% of GrimAge acceleration and the shared variance in GrimAge and DunedinPOAM accelerated EA. We conclude that MSdPCR assessments of smoking and HAC are valuable tools for understanding EA, represent directly targetable conditions for the prevention of premature ageing, and substantially improve upon self-reported assessment of smoking and HAC

A Direct Comparison of the Relationship of Epigenetic Aging and Epigenetic Substance Consumption Markers to Mortality in the Framingham Heart Study

A number of studies have examined the relationship of indices of epigenetic aging (EA) to key health outcomes. Unfortunately, our understanding of the relationship of EA to mortality and substance use-related health variables is unclear. In order to clarify these interpretations, we analyzed the relationship of the Levine EA index (LEA), as well as established epigenetic indices of cigarette (cg05575921) and alcohol consumption (cg04987734), to all-cause mortality in the Framingham Heart Study Offspring Cohort (n = 2256) Cox proportional hazards regression. We found that cg05575921 and cg04987734 had an independent effect relative to LEA and vice versa, with the model including all the predictors having better performance than models with either LEA or cg05575921 and cg04987734 alone. After correction for multiple comparisons, 195 and 327, respectively, of the 513 markers in the LEA index, as well as the overall index itself, were significantly associated with cg05575921 and cg04987734 methylation status. We conclude that the epigenetic indices of substance use have an independent effect over and above LEA, and are slightly stronger predictors of mortality in head-to-head comparisons. We also conclude that the majority of the strength of association conveyed by the LEA is secondary to smoking and drinking behaviors, and that efforts to promote healthy aging should continue to focus on addressing substance use