Oklahoma Family Health Patterns Project Research Articles

Early-Life Adversity Interacts with FKBP5 Genotypes: Altered Working Memory and Cardiac Stress Reactivity in the Oklahoma Family Health Patterns Project

Exposure to stress during critical periods of development can have adverse effects on adult health behaviors, and genetic vulnerabilities may enhance these stress effects. We carried out an exploratory examination of psychological, physiological, and behavioral characteristics of 252 healthy young adults for the impact of early-life adversity (ELA) in relation to the G-to-A single nucleotide polymorphism (SNP), rs9296158, of the FKBP5 gene. FKBP5 is a molecular cochaperone that contributes to the functional status of the glucocorticoid receptor (GR) and to the quality of corticosteroid signaling. FKBP5 expression is upregulated by cortisol exposure during stressful episodes, with greater upregulation seen in A-allele carriers. As such, FKBP5 expression and GR function may be environmentally sensitive in A-allele carriers and therefore suitable for the study of gene-by-environment (G × E) interactions. Compared with FKBP5, GG homozygotes (N=118), A-allele carriers (N = 132) without psychiatric morbidity had progressively worse performance on the Stroop color-word task with increasing levels of ELA exposure (Genotype × ELA, F=5.14, P=0.007), indicating a G × E interaction on working memory in early adulthood. In addition, heart rate response to mental stress was diminished overall in AA/AG-allele carriers (F=5.15, P=0.024). Diminished working memory and attenuated autonomic responses to stress are both associated with risk for alcoholism and other substance use disorders. The present data suggest that FKBP5 in the GR pathway may be a point of vulnerability to ELA, as seen in this group of non-traumatized young adults. FKBP5 is accordingly a potential target for more extensive studies of the impact of ELA on health and health behaviors in adulthood.

Risk factors for alcoholism in the Oklahoma Family Health Patterns project: Impact of early life adversity and family history on affect regulation and personality

AimThis study examined the impact of early lifetime adversity (ELA) on affect regulation and personality in persons with family history (FH+) and without (FH−) a family history of alcoholism. We examined the impact of early life adversity in healthy young adults, 18–30 years of age enrolled in a long-term study on risk for alcohol and other substance abuse. MethodsELA was assessed by a composite score of low socioeconomic status and personal experience of physical or sexual abuse and/or separation from parents before age 16, resulting in a score of 0, 1–2, or >3 adverse events. Unstable affect regulation and personality variables were obtained via self-report measures. ResultsHigher ELA scores were seen in FH+ (χ2=109.2, p<0.0001) and in women (χ2=17.82, p=0.0019). Although higher ELA predicted less emotional stability and more behavioral undercontrol, further analysis including both FH and ELA showed that FH+ persons are prone to poor affect regulation, negative moods, and have risky drinking and drug abuse tendencies independent of ELA level. ELA predicts reduced stress reactivity and poorer cognitive control over impulsive behaviors as shown elsewhere. ConclusionsThe present work shows that FH+ have poor mood regulation and antisocial characteristics. The greater prevalence of ELA in FH+ persons indicates that life experience and FH+ work in tandem to result in risky patterns of alcohol and drug experimentation to elevate risk for alcoholism. Further studies of genetic and environmental contributions to alcoholism are called for.

Anomalous temporoparietal activity in individuals with a family history of alcoholism: studies from the Oklahoma Family Health Patterns Project.

Individuals with a family history of alcoholism (FH+) are at enhanced risk of developing alcohol or other substance use disorders relative to those with no family history (FH-). Alcoholics and FH+ subjects have greater interference scores on the Stroop color-word task, suggesting these impairments may be a component of the cognitive phenotype of at-risk individuals. In this study, we examined whole-brain activations in 24 FH+ and 28 FH- young adults performing the counting Stroop task, a variant of the Stroop task adapted for neuroimaging studies. Across all subjects, incongruent versus congruent comparisons showed activations in regions including parietal lobe areas, frontal eye fields, premotor areas, the anterior cingulate cortex, dorsolateral prefrontal cortex, and bilateral insula, indicating typical regions of activation involved in conflict resolution tasks. Compared with FH- participants, FH+ participants had greater activations in the left superior parietal lobule and precuneus (BA 7 and 19), inferior parietal lobule (BA 40), and middle temporal gyrus (BA 39 and 19), indicating a predominance of greater left hemisphere activity among FH+ in temporoparietal regions. There were no regions showing greater activations in the FH- group compared with the FH+ group. These results are consistent with less efficient cognitive functioning potentially due to poorer communication over long pathways connecting temporoparietal regions to prefrontal brain regions that participate in a distributed network involved in cognitive processing and working memory necessary for conflict resolution.

Differential impact of serotonin transporter activity on temperament and behavior in persons with a family history of alcoholism in the Oklahoma Family Health Patterns Project.

Central serotonergic (5-HT) function is implicated in pathways to alcohol dependence, including dysphoria manifested by symptoms of anxiety and depression. However, little is known about genetic variation in central 5-HT function and its potential impact on temperament and behavior in persons with a family history of alcoholism (FH+). We tested 314 healthy young adults (23.5 years of age, 57% female; 193 FH- and 121 FH+) enrolled in the Oklahoma Family Health Patterns project, a study of alcoholism risk in relation to temperament and behavioral dyscontrol. Dysphoria was assessed using the Eysenck neuroticism and Beck depression scales, and Cloninger's Tridimensional Personality Questionnaire. Risk taking was assessed with the Iowa Gambling Task (IGT) and Balloon Analogue Response Task (BART). All subjects were genotyped for a functional polymorphism (5-HTTLPR) in the promoter region of the serotonin transporter gene (SLC6A4). FH+ subjects with the gain-of-function 5-HTTLPR genotype scored higher in neuroticism, harm avoidance, and symptoms of depression (p-values ≤ 0.03). No effect of 5-HTTLPR genotype was seen in FH-. FH+ carriers of the gain-of-function 5-HTTLPR genotype played to minimize their frequency of losses in the IGT, whereas FH- carriers played a balanced strategy (p < 0.003). No 5-HTTLPR effects were seen in the BART. Results were unaffected by sex, education, drug use, and antisocial characteristics. The functional 5-HTTLPR polymorphism predicted significant variation in negative moods and poorer affect regulation in FH+ persons, with possible consequences for behavior, as seen in a simulated gambling task. This pattern may contribute to a drinking pattern that is compensatory for such affective tendencies.

Early Life Adversity Contributes to Impaired Cognition and Impulsive Behavior: Studies from the Oklahoma Family Health Patterns Project

Stressful early life experience may have adverse consequences in adulthood and may contribute to behavioral characteristics that increase vulnerability to alcoholism. We examined early life adverse experience in relation to cognitive deficits and impulsive behaviors with a reference to risk factors for alcoholism. We tested 386 healthy young adults (18 to 30years of age; 224 women; 171 family history positive for alcoholism) using a composite measure of adverse life experience (low socioeconomic status plus personally experienced adverse events including physical and sexual abuse and separation from parents) as a predictor of performance on the Shipley Institute of Living scale, the Stroop color-word task, and a delay discounting task assessing preference for smaller immediate rewards in favor of larger delayed rewards. Body mass index (BMI) was examined as an early indicator of altered health behavior. Greater levels of adversity predicted higher Stroop interference scores (F=3.07, p=0.048), faster discounting of delayed rewards (F=3.79, p=0.024), lower Shipley mental age scores (F=4.01, p=0.019), and higher BMIs in those with a family history of alcoholism (F=3.40, p=0.035). These effects were not explained by age, sex, race, education, or depression. The results indicate a long-term impact of stressful life experience on cognitive function, impulsive behaviors, and early health indicators that may contribute to risk in persons with a family history of alcoholism.

Naltrexone effects on cortisol secretion in women and men in relation to a family history of alcoholism: Studies from the Oklahoma Family Health Patterns Project

Naltrexone evokes a cortisol response through its blockade of central opioid receptors on the hypothalamic-pituitary-adrenocortical axis (HPA). The magnitude of this cortisol response may be useful as a probe for central opioid activity in different groups of subjects. Accordingly, the present study examined the effect of opioid blockade on the HPA in 70 women and 58 men with (N=41) and without (N=87) a family history of alcoholism, using a randomized, placebo-controlled, double blind administration of oral naltrexone (50mg). Saliva cortisol was sampled at baseline prior to placebo or naltrexone and again every 30 min over the next 180 min. Women had significantly larger cortisol responses to naltrexone than did the men, F=6.88, p<0.0001. There were no significant differences in cortisol response between groups differing in family history of alcoholism, F=0.65, p>0.69. The present results confirm that women have much greater central opioid restraint on the HPA than men do and that this endogenous restraint is unmasked by opioid blockade. However the results provide no evidence of a differential central opioid tonus in persons with a family history of alcoholism at this dose of naltrexone. The cortisol response to naltrexone may be a useful probe for central opioid activity in women and to a lesser degree in men.

Lifetime Adversity Leads to Blunted Stress Axis Reactivity: Studies from the Oklahoma Family Health Patterns Project

Can stressful events in early life alter the response characteristics of the human stress axis? Individual differences in stress reactivity are considered potentially important in long-term health and disease; however, little is known about the sources of these individual differences. We present evidence that adverse experience in childhood and adolescence can alter core components of the stress axis, including cortisol and heart rate reactivity. We exposed 354 healthy young adults (196 women) to public speaking and mental arithmetic stressors in the laboratory. Stress responses were indexed by self-report, heart rate, and cortisol levels relative to measures on a nonstress control day. Subjects were grouped into those who had experienced 0, 1, or 2 or more significant adverse life events, including Physical or Sexual Adversity (mugged, threatened with a weapon, experienced a break-in or robbery or raped or sexually assaulted by a relative or nonrelative) or Emotional Adversity (separation from biological mother or father for at least 6 months before age 15). Experience of adversity predicted smaller heart rate and cortisol responses to the stressors in a dose-dependent fashion (0 > 1 > 2 or more events) (F values = 5.79 and 8.11, p values < .004) for both men and women. This was not explained by differences in socioeconomic status, the underlying cortisol diurnal cycle, or subjective experience during the stress procedure. The results indicate a long-term impact of stressful life experience on the reactivity of the human stress axis.

Greater Discounting of Delayed Rewards in Young Adults with Family Histories of Alcohol and Drug Use Disorders: Studies from the Oklahoma Family Health Patterns Project

Increased discounting of delayed rewards may be a premorbid characteristic and possible risk factor for alcohol and other drug use disorders; however, previous studies have found no or minimal differences in delay discounting in individuals at risk for substance use disorders based on family history. It is possible that increased delay discounting may be more closely associated with antisocial traits, evident in a subset of individuals with positive family histories of alcohol and drug use disorders, and that previous studies were underpowered for detecting subtle to modest overall group differences. In this study, we compared 143 young adults with family histories of alcohol and other drug use disorders (FH+) and 155 young adults with no such histories (FH-) on delay discounting and subsequently examined how delay discounting was related to antisocial traits and other selected psychological and demographic variables. The FH+ group discounted delayed rewards more than the FH- group. Subsequent analyses revealed that increased delay discounting was correlated with having more parents and grandparents with alcohol and drug use disorders, more antisocial traits, more depressive tendencies and lower IQs, and lower income. After controlling for all these relationships, more antisocial traits and lower IQ still predicted greater delay discounting, and subsequent analysis revealed that the greater delay discounting in the FH+ group was mediated by this group's greater number of individuals with antisocial traits. FH+ individuals who discount delayed rewards more may be at increased risk for developing alcohol and other drug use disorders; however, additional descriptive studies and longitudinal studies are needed.

Differential activation of the anterior cingulate cortex and caudate nucleus during a gambling simulation in persons with a family history of alcoholism: Studies from the Oklahoma Family Health Patterns Project

Individuals with a family history of alcoholism (FH+) are at enhanced risk of developing an alcohol or other substance use disorder relative to those without this history (FH−). Recent studies comparing FH+ and FH− individuals have revealed differences in cognition, emotion processing, sociability, and decision-making. These differences suggest possible altered brain functioning in FH+ individuals that may play a crucial role in vulnerability to substance use disorders. In the present study, 15 FH+ and 19 FH− individuals performed the Iowa Gambling Task (IGT), a simulated card game requiring integration of payoff-to-penalty ratios, while undergoing functional magnetic resonance imaging. All participants performed the task more conservatively as the session progressed, and the FH groups achieved similar payoffs by the end of the game. Imaging revealed a distributed network of brain regions that was engaged when subjects performed this task, including the right inferior frontal and postcentral gyri, left parahippocampal gyrus, insula and precuneous cortices, left inferior and superior parietal lobules, left lentiform nucleus and bilateral culmen, claustrum, lingual gyri and cerebellar tonsils. Despite a lack of behavioral differences between groups, the FH+ participants showed significantly more activation in the left dorsal anterior cingulate cortex and left caudate nucleus. These findings correspond to models of risk in FH+ persons that postulate biases in brain decision-making systems as underlying elevated risk for alcoholism.

Reduced Amygdala Activation in Young Adults at High Risk of Alcoholism: Studies from the Oklahoma Family Health Patterns Project

Risk of alcoholism is higher in those with a positive family history (FH+) and in those showing behavioral disinhibition, possibly reflecting altered limbic system function. We performed functional magnetic resonance imaging (fMRI) in 17 nonabusing young adults, 9 with FH+ and high in disinhibition versus 8 with a negative family history (FH-) and low in disinhibition. We probed limbic system reactivity with a recognition task using faces expressing fear versus geometric objects. Subjects with FH- had robust activation to the faces in the region of the right and left amygdalar complexes (p's < .05), while subjects with FH+ had no such activation (p's > .46). The blood oxygenation level-dependent (BOLD) signal in the region of the amygdala was correlated with scores on the self-report measure of temperament in the combined groups (r = .51, p < .04). Behaviorally disinhibited temperament, found in many with FH+, may be associated with amygdalar hyporesponsiveness and a failure to avoid risky decisions, increasing the person's liability for alcohol abuse.

Working Memory and Decision‐Making Biases in Young Adults With a Family History of Alcoholism: Studies from the Oklahoma Family Health Patterns Project

Alcohol misuse is more common in persons with a family history of alcoholism (FH+) than in those with no such history (FH-). Among FH+, behavioral disinhibition and male sex seem to signal the presence of an increased risk. This study examined cognitive and behavioral characteristics of 175 nonabusing 18- to 30-year-olds, 87 FH+ and 88 FH-, who were further characterized by their degree of behavioral disinhibition using the Sociability scale of the California Personality Inventory. Working memory and decision making were tested using the Stroop Color-Word Test and the Iowa Gambling Task, a simulated card game. Persons with a family history of alcoholism who were behaviorally disinhibited displayed significantly greater interference on the Stroop task than the other subgroups. On the Iowa Gambling Task, FH+ males, but not the females, were significantly more attentive to financial gains than other subgroups, and they had greater consistency in their choice behaviors. Persons with a family history of alcoholism, in combination with behavioral disinhibition, appears to signal working memory deficits and in combination with male sex indicates an attraction to the rewarding aspects of a risk-taking challenge. These findings are not secondary to heavy exposure to alcohol or other drugs, but instead reflect intrinsic risk-related familial and personal characteristics of the subjects.