Association of protein phosphatase PPM1G with alcohol use disorder and brain activity during behavioral control in a genome-wide methylation analysis

OBJECTIVE: The genetic component of alcohol use disorder is substantial, but monozygotic twin discordance indicates a role for nonheritable differences that could be mediated by epigenetics. Despite growing evidence associating epigenetics and psychiatric disorders, it is unclear how epigenetics, particularly DNA methylation, relate to brain function and behavior, including drinking behavior. METHOD: The authors carried out a genome-wide analysis of DNA methylation of 18 monozygotic twin pairs discordant for alcohol use disorder and validated differentially methylated regions. After validation, the authors characterized these differentially methylated regions using personality trait assessment and functional MRI in a sample of 499 adolescents. RESULTS: Hypermethylation in the 3'-protein-phosphatase-1G (PPM1G) gene locus was associated with alcohol use disorder. The authors found association of PPM1G hypermethylation with early escalation of alcohol use and increased impulsiveness. They also observed association of PPM1G hypermethylation with increased blood-oxygen-level-dependent response in the right subthalamic nucleus during an impulsiveness task. CONCLUSIONS: Overall, the authors provide first evidence for an epigenetic marker associated with alcohol consumption and its underlying neurobehavioral phenotype

Neuropsychosocial profiles of current and future adolescent alcohol misusers

A comprehensive account of the causes of alcohol misuse must accommodate individual differences in biology, psychology and environment, and must disentangle cause and effect. Animal models1 can demonstrate the effects of neurotoxic substances; however, they provide limited insight into the psycho-social and higher cognitive factors involved in the initiation of substance use and progression to misuse. One can search for pre-existing risk factors by testing for endophenotypic biomarkers2 in non-using relatives; however, these relatives may have personality or neural resilience factors that protect them from developing dependence3. A longitudinal study has potential to identify predictors of adolescent substance misuse, particularly if it can incorporate a wide range of potential causal factors, both proximal and distal, and their influence on numerous social, psychological and biological mechanisms4. Here we apply machine learning to a wide range of data from a large sample of adolescents (n = 692) to generate models of current and future adolescent alcohol misuse that incorporate brain structure and function, individual personality and cognitive differences, environmental factors (including gestational cigarette and alcohol exposure), life experiences, and candidate genes. These models were accurate and generalized to novel data, and point to life experiences, neurobiological differences and personality as important antecedents of binge drinking. By identifying the vulnerability factors underlying individual differences in alcohol misuse, these models shed light on the aetiology of alcohol misuse and suggest targets for prevention

Differential predictors for alcohol use in adolescents as a function of familial risk

Abstract: Traditional models of future alcohol use in adolescents have used variable-centered approaches, predicting alcohol use from a set of variables across entire samples or populations. Following the proposition that predictive factors may vary in adolescents as a function of family history, we used a two-pronged approach by first defining clusters of familial risk, followed by prediction analyses within each cluster. Thus, for the first time in adolescents, we tested whether adolescents with a family history of drug abuse exhibit a set of predictors different from adolescents without a family history. We apply this approach to a genetic risk score and individual differences in personality, cognition, behavior (risk-taking and discounting) substance use behavior at age 14, life events, and functional brain imaging, to predict scores on the alcohol use disorders identification test (AUDIT) at age 14 and 16 in a sample of adolescents (N = 1659 at baseline, N = 1327 at follow-up) from the IMAGEN cohort, a longitudinal community-based cohort of adolescents. In the absence of familial risk (n = 616), individual differences in baseline drinking, personality measures (extraversion, negative thinking), discounting behaviors, life events, and ventral striatal activation during reward anticipation were significantly associated with future AUDIT scores, while the overall model explained 22% of the variance in future AUDIT. In the presence of familial risk (n = 711), drinking behavior at age 14, personality measures (extraversion, impulsivity), behavioral risk-taking, and life events were significantly associated with future AUDIT scores, explaining 20.1% of the overall variance. Results suggest that individual differences in personality, cognition, life events, brain function, and drinking behavior contribute differentially to the prediction of future alcohol misuse. This approach may inform more individualized preventive interventions

Differential predictors for alcohol use in adolescents as a function of familial risk

Abstract: Traditional models of future alcohol use in adolescents have used variable-centered approaches, predicting alcohol use from a set of variables across entire samples or populations. Following the proposition that predictive factors may vary in adolescents as a function of family history, we used a two-pronged approach by first defining clusters of familial risk, followed by prediction analyses within each cluster. Thus, for the first time in adolescents, we tested whether adolescents with a family history of drug abuse exhibit a set of predictors different from adolescents without a family history. We apply this approach to a genetic risk score and individual differences in personality, cognition, behavior (risk-taking and discounting) substance use behavior at age 14, life events, and functional brain imaging, to predict scores on the alcohol use disorders identification test (AUDIT) at age 14 and 16 in a sample of adolescents (N = 1659 at baseline, N = 1327 at follow-up) from the IMAGEN cohort, a longitudinal community-based cohort of adolescents. In the absence of familial risk (n = 616), individual differences in baseline drinking, personality measures (extraversion, negative thinking), discounting behaviors, life events, and ventral striatal activation during reward anticipation were significantly associated with future AUDIT scores, while the overall model explained 22% of the variance in future AUDIT. In the presence of familial risk (n = 711), drinking behavior at age 14, personality measures (extraversion, impulsivity), behavioral risk-taking, and life events were significantly associated with future AUDIT scores, explaining 20.1% of the overall variance. Results suggest that individual differences in personality, cognition, life events, brain function, and drinking behavior contribute differentially to the prediction of future alcohol misuse. This approach may inform more individualized preventive interventions

Genetic and environmental determinants of stress responding

The risk for alcohol dependence throughout development is determined by both genetic and environmental factors. Genetic factors that are thought to modulate this risk act on neurobiological pathways regulating reward, impulsivity, and stress responses. For example, genetic variations in pathways using the brain signaling molecule (i.e., neurotransmitter) dopamine, which likely mediate alcohol’s rewarding effects, and in two hormonal systems involved in the stress response (i.e., the hypothalamic–pituitary–adrenal axis and the corticotropin-releasing factor system) affect alcoholism risk. This liability is modified further by exposure to environmental risk factors, such as environmental stress and alcohol use itself, and the effects of these factors may be enhanced in genetically vulnerable individuals. The transition from alcohol use to dependence is the result of complex interactions of genes, environment, and neurobiology, which fluctuate throughout development. Therefore, the relevant genetic and environmental risk factors may differ during the different stages of alcohol initiation, abuse, and dependence. The complex interaction of these factors is yet to be fully elucidated, and translational studies, ranging from animal studies to research in humans, and well-characterized longitudinal studies are necessary to further understand the development of alcohol dependence

The responsiveness of biological motion processing areas to selective attention towards goals

A growing literature indicates that visual cortex areas viewed as primarily responsive to exogenous stimuli are susceptible to top-down modulation by selective attention. The present study examines whether brain areas involved in biological motion perception are among these areas – particularly with respect to selective attention towards human movement goals. Fifteen participants completed a point-light biological motion study following a two-by-two factorial design, with one factor representing an exogenous manipulation of human movement goals (goal-directed versus random movement), and the other an endogenous manipulation (a goal identification task versus an ancillary color-change task). Both manipulations yielded increased activation in the human homologue of motion-sensitive area MT+ (hMT+) as well as the extrastriate body area (EBA). The endogenous manipulation was associated with increased right posterior superior temporal sulcus (STS) activation, whereas the exogenous manipulation was associated with increased activation in left posterior STS. Selective attention towards goals activated portion of left hMT+/EBA only during the perception of purposeful movement consistent with emerging theories associating this area with the matching of visual motion input to known goal-directed actions. The overall pattern of results indicates that attention towards the goals of human movement activates biological motion areas. Ultimately, selective attention may explain why some studies examining biological motion show activation in hMT+ and EBA, even when using control stimuli with comparable motion properties

The potential of neuroimaging for identifying predictors of adolescent alcohol use initiation and misuse.

BACKGROUND AND AIMS: Dysfunction in brain regions underlying impulse control, reward processing and executive function have been associated previously with adolescent alcohol misuse. However, identifying pre-existing neurobiological risk factors, as distinct from changes arising from early alcohol-use, is difficult. Here, we outline how neuroimaging data can identify the neural predictors of adolescent alcohol-use initiation and misuse by using prospective longitudinal studies to follow initially alcohol-naive individuals over time and by neuroimaging adolescents with inherited risk factors for alcohol misuse. METHOD: A comprehensive narrative of the literature regarding neuroimaging studies published between 2010 and 2016 focusing on predictors of adolescent alcohol use initiation and misuse. FINDINGS: Prospective, longitudinal neuroimaging studies have identified pre-existing differences between adolescents who remained alcohol-naive and those who transitioned subsequently to alcohol use. Both functional and structural grey matter differences were observed in temporal and frontal regions, including reduced brain activity in the superior frontal gyrus and temporal lobe, and thinner temporal cortices of future alcohol users. Interactions between brain function and genetic predispositions have been identified, including significant association found between the Ras protein-specific guanine nucleotide releasing factor 2 (RASGRF2) gene and reward-related striatal functioning. CONCLUSIONS: Neuroimaging predictors of alcohol use have shown modest utility to date. Future research should use out-of-sample performance as a quantitative measure of a predictor's utility. Neuroimaging data should be combined across multiple modalities, including structural information such as volumetrics and cortical thickness, in conjunction with white-matter tractography. A number of relevant neurocognitive systems should be assayed; particularly, inhibitory control, reward processing and executive functioning. Combining a rich magnetic resonance imaging data set could permit the generation of neuroimaging risk scores, which could potentially yield targeted interventions

A translational systems biology approach in both animals and humans identifies a functionally related module of accumbal genes involved in the regulation of reward processing and binge drinking in males

BACKGROUND: The mesolimbic dopamine system, composed primarily of dopaminergic neurons in the ventral tegmental area that project to striatal structures, is considered to be the key mediator of reinforcement-related mechanisms in the brain. Prompted by a genome-wide association meta-analysis implicating the Ras-specific guanine nucleotide-releasing factor 2 (RASGRF2) gene in the regulation of alcohol intake in men, we have recently shown that male Rasgrf2(−/−) mice exhibit reduced ethanol intake and preference accompanied by a perturbed mesolimbic dopamine system. We therefore propose that these mice represent a valid model to further elucidate the precise genes and mechanisms regulating mesolimbic dopamine functioning. METHODS: Transcriptomic data from the nucleus accumbens (NAcc) of male Rasgrf2(−/−) mice and wild-type controls were analyzed by weighted gene coexpression network analysis (WGCNA). We performed follow-up genetic association tests in humans using a sample of male adolescents from the IMAGEN study characterized for binge drinking (n = 905) and ventral striatal activation during an fMRI reward task (n = 608). RESULTS: The WGCNA analyses using accumbal transcriptomic data revealed 37 distinct “modules,” or functionally related groups of genes. Two of these modules were significantly associated with Rasgrf2 knockout status: M5 (p < 0.001) and M6 (p < 0.001). In follow-up translational analyses we found that human orthologues for the M5 module were significantly (p < 0.01) enriched with genetic association signals for binge drinking in male adolescents. Furthermore, the most significant locus, originating from the EH-domain containing 4 (EHD4) gene (p < 0.001), was also significantly associated with altered ventral striatal activity in male adolescents performing an fMRI reward task (p(empirical) < 0.001). LIMITATIONS: It was not possible to determine the extent to which the M5 module was dysregulated in Rasgrf2(−/−) mice by perturbed mesolimbic dopamine signalling or by the loss of Rasgrf2 function in the NAcc. CONCLUSION: Taken together, our findings indicate that the accumbal M5 module, initially identified as being dysregulated in male Rasgrf2(−/−) mice, is also relevant for human alcohol-related phenotypes potentially through the modulation of reinforcement mechanisms in the NAcc. We therefore propose that the genes comprising this module represent important candidates for further elucidation within the context of alcohol-related phenotypes