Tracy D. Gunter

Methylation at SLC6A4 is linked to family history of child abuse: An examination of the Iowa Adoptee sample

In this letter we describe novel, preliminary work, examining a possible mechanism of the Gene-environment interactions thought to moderate the response of individuals to stressful life events. The molecular mechanisms through which this moderation may be accomplished are currently unknown but some have suggested DNA methylation (Lui and others, 1997; McGowan and others 2009). In order to test this hypothesis, we analyzed the relationship of child abuse to methylation of cytosine residues in the promoter region of the serotonin transporter gene in DNA from 96 male and 96 female subjects from the Iowa Adoptee Studies using a principal components analysis. The results from this preliminary work suggest a lasting effect of child abuse on overall methylation levels in both males and females.

Methylation at 5HTT Mediates the Impact of Child Sex Abuse on Women's Antisocial Behavior: An Examination of the Iowa Adoptee Sample

Objective: To examine epigenetic processes linking childhood sex abuse to symptoms of antisocial personality disorder (ASPD) in adulthood and to investigate the possibility that the link between childhood sex abuse and deoxyribonucleic acid methylation at the 5HTT promoter might represent a pathway of long-term impact on symptoms of ASPD. Method: Deoxyribonucleic acid was prepared from lymphoblast cell lines derived from 155 female participants in the latest wave of the Iowa Adoptee Study. Methylation at 71 CpG residues was determined by quantitative mass spectroscopy, and the resulting values were averaged to produce an average CpG ratio for each participant. Simple associations and path analyses within an Mplus framework were examined to characterize the relationships among childhood sex abuse, overall level of methylation among women, and subsequent antisocial behavior in adulthood. Direct effects of biological parent psychopathology and 5HTT genotype were controlled. Results: Replicating prior work, we found that a significant effect of childhood sex abuse on methylation of the 5HTT promoter region emerged for women. In addition, a significant effect of methylation at 5HTT on symptoms of ASPD emerged. Conclusions: Child sex abuse may create long-lasting changes in methylation of the promoter region of 5HTT in women. Furthermore, hypermethylation may be one mechanism linking childhood sex abuse to changes in risk for adult antisocial behavior in women. Better understanding of the methylome may prove critical in understanding the role of childhood environments on long-term psychiatric sequelae. 5HTT = serotonin transporter gene; CpG = a site at which cytosine (C) lies next to guanine (G) in the deoxyribonucleic acid sequence; ASPD = antisocial personality disorder.

Child maltreatment moderates the association of MAOA with symptoms of depression and antisocial personality disorder.

There is a growing body of data indicating that Gene x Child Maltreatment interactions at monoamine oxidase A (MAOA) play a role in vulnerability to symptoms of antisocial personality disorder (ASPD) but not major depression (MD). Using a sample of 538 participants from the Iowa Adoption Studies, we introduce a conceptual model that highlights two distinct pathways from child maltreatment to symptoms of MD, suggesting that maltreatment has different effects depending on genotype and highlighting the importance of including the indirect pathway through ASPD. As predicted by the model, high activity alleles predispose to symptoms of MD in the context of child maltreatment whereas low activity alleles predispose to symptoms of ASPD. We conclude that the Gene x Environment interplay at this locus (MAOA) contributes to both symptoms of ASPD and MD and that careful specification of child maltreatment may be essential if genetic association research is to produce replicable results.

A pilot examination of the genome-wide DNA methylation signatures of subjects entering and exiting short-term alcohol dependence treatment programs

Alcoholism has a profound impact on millions of people throughout the world. However, the ability to determine if a patient needs treatment is hindered by reliance on self-reporting and the clinician’s capability to monitor the patient’s response to treatment is challenged by the lack of reliable biomarkers. Using a genome-wide approach, we have previously shown that chronic alcohol use is associated with methylation changes in DNA from human cell lines. In this pilot study, we now examine DNA methylation in peripheral mononuclear cell DNA gathered from subjects as they enter and leave short-term alcohol treatment. When compared with abstinent controls, subjects with heavy alcohol use show widespread changes in DNA methylation that have a tendency to reverse with abstinence. Pathway analysis demonstrates that these changes map to gene networks involved in apoptosis. There is no significant overlap of the alcohol signature with the methylation signature previously derived for smoking. We conclude that DNA methylation may have future clinical utility in assessing acute alcohol use status and monitoring treatment response.

Role of GABRA2 on risk for alcohol, nicotine, and cannabis dependence in the Iowa Adoption Studies.

Aim A number of studies have shown that genetic variation at GABRA2 alters vulnerability to alcohol dependence. The exact identity of the causal variant(s), and the relationship of these variants to other forms of substance use and behavioral illness is, however, uncertain. Objective Therefore, we genotyped 516 individuals from the Iowa Adoption Studies, a large longitudinal case and control adoption study of substance use, at 39 single nucleotide polymorphisms encompassing the GABRA2 locus and analyzed them with respect to their lifetime history of three common forms of substance use dependence [alcohol dependence (AD), nicotine dependence (ND), and cannabis dependence (CD)] in the Iowa Adoption Studies and relevant exposure variables. Result Using regression analysis, we found substantial evidence that both GABRA2 genotype and haplotype are significantly related to vulnerability to AD, ND, and CD, with the strongest relationships noted with respect to ND. Consistent with earlier studies suggesting exposure is an important step in the development of substance use, we found the inclusion of substance exposure data in our analytic models markedly increased the strength of the genetic associations of GABRA2 haplotype with substance use. Finally, we report that the genetic effects were markedly more pronounced in females than in males. Conclusion We conclude that genetic variation at or near the GABRA2 locus significantly affects vulnerability not only to AD, but to other forms of substance use including ND and CD, and that the effects may be sex dependent.

The Relationship of Deiodinase 1 Genotype and Thyroid Function to Lifetime History of Major Depression in Three Independent Populations

Major depression (MD) is often associated with disturbances of the hypothalamic/pituitary/thyroid (HPT) axis. Unfortunately, whether this association is secondary to common underlying genetic variation or whether the MD‐associated disturbances in HPT function are chronic or state‐dependent is unknown. To examine these questions, we genotyped 12 single nucleotide polymorphisms identified in previous genome wide association analyses of thyroid function in DNA contributed by 1,555 subjects from three longitudinal ethnically diverse studies that are well‐characterized for lifetime MD and thyroid function. We then examined associations between genetic variants and key outcomes of thyroid stimulating hormone, free thyroxine (FT4) and depression. We confirmed prior findings that two variants in deiodinase 1 (DIO1), including a variant in the 3′UTR of DIO1 (rs11206244), were associated with altered FT4 levels in both White and African American subjects. We also found that rs11206244 genotype was associated with lifetime MD in White female subjects, in particular those from high‐risk cohorts. However, we found no association of current FT4 levels with lifetime MD in either ethnic group. We conclude that genetic variation influencing thyroid function is a risk factor for MD. Given the evidence from prior studies, further investigations of role of HPT variation in etiology and treatment of MD are indicated.

Relative Contributions of Gender and Traumatic Life Experience to the Prediction of Mental Disorders in a Sample of Incarcerated Offenders

The objective of this study was to quantify the relative contributions of gender and traumatic life experience to psychiatric disorders in a sample of 320 offenders entering a state prison. Women were more likely than men to report traumatic events and personal and family mental health treatment histories; and were more likely to meet criteria for posttraumatic stress, borderline personality, and eating disorders. People reporting traumatic life experiences were more likely than those not so reporting to have family mental histories and to meet criteria for mood, anxiety, psychotic, antisocial personality, and borderline personality disorders, as well as elevated suicide risk. With both gender and trauma included in the logistic regression models, only trauma was a significant predictor of mood, anxiety, psychotic, attention deficit hyperactivity, and antisocial personality disorders, as well as suicide risk. Trauma-informed programming, regardless of gender, is important for incarcerated offenders. To the extent that trauma is also criminogenic, these data suggest that women and men share the risk.

Drug and Alcohol Treatment Services Effective for Methamphetamine Abuse

BACKGROUND Methamphetamine abuse has become a major public health problem as demonstrated by increases in the number of emergency room visits, substance abuse treatment episodes, and arrests attributable to methamphetamine manufacture and abuse. We examine the effectiveness of conventional substance abuse treatment in the recovery of individuals seeking voluntary treatment for methamphetamine abuse. METHODS At the request of the Iowa Department of Public Health, the Iowa Consortium for Substance Abuse Research and Evaluation contacted clients who had been admitted to voluntary treatment for methamphetamine abuse. Staff from the Consortium asked subjects to volunteer for follow-up interviews at designated intervals following admission. Agency staff conducted interviews based on the Mini International Neuropsychiatric Interview (MINI) at admission and at designated intervals and reported results to the Consortium for analysis. RESULTS Subjects were predominantly Caucasian and over one half were female with an average age of 30 years. The criminal justice system was a primary referral source. Reported psychiatric symptoms dropped substantially in the first 60 days following admission and appeared to remain low at 6 and 12 months. Most clients reported abstinence and employment and denied arrests at the 6-month interview. Outcomes were not correlated with psychiatric symptoms. CONCLUSIONS Psychiatric symptoms improved over time with usual substance abuse treatment. There was no evidence that referral by the court system or symptoms of antisocial personality disorder affected outcome. Conventional treatment resulted in sobriety, employment, and fewer arrests at 6 and 12 months following treatment.

Examination of the Nicotine Dependence (NICSNP) Consortium findings in the Iowa adoption studies population

INTRODUCTION Nicotine dependence results from a complex interplay of genetic and environmental factors. Over the past several years, a large number of studies have been performed to identify distinct gene loci containing genetic vulnerability to nicotine dependence. Two of the most prominent studies were conducted by the Collaborative Study of the Genetics of Nicotine Dependence (NICSNP) Consortium using both candidate gene and high-density association approaches. METHODS We attempted to confirm and extend the most significant findings from the high-density association study and the candidate gene study using the behavioral and genetic resources of the Iowa Adoption Studies, the largest case-control adoption study of substance use in the United States. RESULTS We found evidence that genetic variation at CHRNA1, CHRNA2, CHRNA7, and CHRNB1 alters susceptibility to nicotine dependence, but we did not replicate any of the most significant single nucleotide polymorphism associations from the NICSNP high-density association study. DISCUSSION Further examination of the NICSNP findings in other population samples is indicated.

Characteristics of Admissions for Primary Stimulant Dependence During 2001

The production and consumption of synthetic stimulants has been increasing in recent years accompanied by an increase in the number of individuals seeking treatment for synthetic stimulant “abuse.” The misuse of stimulants is occurring at younger ages and primarily in the context of polysubstance use. This article examines the characteristics of admissions entering treatment centers that received some form of public funding in 2001 as compiled in the Treatment Episodes Data Set produced by the Substance Abuse Mental Health Services Administration, Office of Applied Studies. It compares those admissions indicating stimulants as a primary substance of use with those admissions not listing stimulants. Findings indicated that stimulant primary admissions were younger, more frequently Caucasian, and more frequently female than nonstimulant admissions. Additionally, stimulant primary admissions had fewer prior treatment episodes and substance use referrals than the nonstimulant admissions but were more commonly referred by the criminal justice system, raising the concern that adequate screening for stimulant misuse is not occurring in health care settings.