Leveraging genome-wide data to investigate differences between opioid use vs. opioid dependence in 41,176 individuals from the Psychiatric Genomics Consortium.

To provide insights into the biology of opioid dependence (OD) and opioid use (i.e., exposure, OE), we completed a genome-wide analysis comparing 4503 OD cases, 4173 opioid-exposed controls, and 32,500 opioid-unexposed controls, including participants of European and African descent (EUR and AFR, respectively). Among the variants identified, rs9291211 was associated with OE (exposed vs. unexposed controls; EUR z = -5.39, p = 7.2 × 10-8). This variant regulates the transcriptomic profiles of SLC30A9 and BEND4 in multiple brain tissues and was previously associated with depression, alcohol consumption, and neuroticism. A phenome-wide scan of rs9291211 in the UK Biobank (N > 360,000) found association of this variant with propensity to use dietary supplements (p = 1.68 × 10-8). With respect to the same OE phenotype in the gene-based analysis, we identified SDCCAG8 (EUR + AFR z = 4.69, p = 10-6), which was previously associated with educational attainment, risk-taking behaviors, and schizophrenia. In addition, rs201123820 showed a genome-wide significant difference between OD cases and unexposed controls (AFR z = 5.55, p = 2.9 × 10-8) and a significant association with musculoskeletal disorders in the UK Biobank (p = 4.88 × 10-7). A polygenic risk score (PRS) based on a GWAS of risk-tolerance (n = 466,571) was positively associated with OD (OD vs. unexposed controls, p = 8.1 × 10-5; OD cases vs. exposed controls, p = 0.054) and OE (exposed vs. unexposed controls, p = 3.6 × 10-5). A PRS based on a GWAS of neuroticism (n = 390,278) was positively associated with OD (OD vs. unexposed controls, p = 3.2 × 10-5; OD vs. exposed controls, p = 0.002) but not with OE (p = 0.67). Our analyses highlight the difference between dependence and exposure and the importance of considering the definition of controls in studies of addiction.

Psychosocial moderation of polygenic risk for cannabis involvement: the role of trauma exposure and frequency of religious service attendance.

Cannabis use and disorders (CUD) are influenced by multiple genetic variants of small effect and by the psychosocial environment. However, this information has not been effectively incorporated into studies of gene-environment interaction (GxE). Polygenic risk scores (PRS) that aggregate the effects of genetic variants can aid in identifying the links between genetic risk and psychosocial factors. Using data from the Pasman et al. GWAS of cannabis use (meta-analysis of data from the International Cannabis Consortium and UK Biobank), we constructed PRS in the Collaborative Study on the Genetics of Alcoholism (COGA) participants of European (N: 7591) and African (N: 3359) ancestry. The primary analyses included only individuals of European ancestry, reflecting the ancestral composition of the discovery GWAS from which the PRS was derived. Secondary analyses included the African ancestry sample. Associations of PRS with cannabis use and DSM-5 CUD symptom count (CUDsx) and interactions with trauma exposure and frequency of religious service attendance were examined. Models were adjusted for sex, birth cohort, genotype array, and ancestry. Robustness models were adjusted for cross-term interactions. Higher PRS were associated with a greater likelihood of cannabis use and with CUDsx among participants of European ancestry (p < 0.05 and p < 0.1 thresholds, respectively). PRS only influenced cannabis use among those exposed to trauma (R2: 0.011 among the trauma exposed vs. R2: 0.002 in unexposed). PRS less consistently influenced cannabis use among those who attend religious services less frequently; PRS × religious service attendance effects were attenuated when cross-term interactions with ancestry and sex were included in the model. Polygenic liability to cannabis use was related to cannabis use and, less robustly, progression to symptoms of CUD. This study provides the first evidence of PRS × trauma for cannabis use and demonstrates that ignoring important aspects of the psychosocial environment may mask genetic influences on polygenic traits.

Genetic correlates of the development of theta event related oscillations in adolescents and young adults.

The developmental trajectories of theta band (4-7Hz) event-related oscillations (EROs), a key neurophysiological constituent of the P3 response, were assessed in 2170 adolescents and young adults ages 12 to 25. The theta EROs occurring in the P3 response, important indicators of neurocognitive function, were elicited during the evaluation of task-relevant target stimuli in visual and auditory oddball tasks. Associations between the theta EROs and genotypic variants of 4 KCNJ6 single nucleotide polymorphisms (SNPs) were found to vary with age, sex, scalp location, and task modality. Three of the four KCNJ6 SNPs studied here were found to be significantly associated with the same theta EROs in adults in a previous family genome wide association study. Since measures of the P3 response have been found to be a useful endophenotypes for the study of a number of clinical and behavioral disorders, studies of genetic effects on its development in adolescents and young adults may illuminate neurophysiological factors contributing to the onset of these conditions.

Gender modulates the development of theta event related oscillations in adolescents and young adults.

The developmental trajectories of theta band (4-7 Hz) event-related oscillations (EROs), a key neurophysiological constituent of the P3 response, were assessed in 2170 adolescents and young adults ages 12 to 25. The theta EROs occurring in the P3 response, important indicators of neurocognitive function, were elicited during the evaluation of task-relevant target stimuli in visual and auditory oddball tasks. These tasks call upon attentional and working memory resources. Large differences in developmental rates between males and females were found; scalp location and task modality (visual or auditory) differences within males and females were small compared to gender differences. Trajectories of interregional and intermodal correlations between ERO power values exhibited increases with age in both genders, but showed a divergence in development between auditory and visual systems during ages 16 to 21. These results are consistent with previous electrophysiological and imaging studies and provide additional temporal detail about the development of neurophysiological indices of cognitive activity. Since measures of the P3 response has been found to be a useful endophenotypes for the study of a number of clinical and behavioral disorders, studies of its development in adolescents and young adults may illuminate neurophysiological factors contributing to the onset of these conditions.

EEG coherence: topography and frequency structure.

Topographical patterns of bipolar EEG coherence are frequency specific, indicating the presence of diverse neuroanatomical and neurophysiological factors in EEG production. Bipolar EEG coherence values were calculated at 50 frequency bins ranging from 3 to 28 Hz for 39 coherence pairs. Data were derived from 4.25 min of resting EEG obtained from 106 healthy adult male subjects and analyzed in 0.5 Hz bins by Fourier transform methods. Frequency bands were clearly separated at 8.5 and 13 Hz, with a less distinct separations at 6 and 20 Hz. Within pair (non-topographic) and across pair (topographic), measures gave similar patterns of separation. Significant pathways were primarily anterior-posterior interhemispheric or perpendicular to the anterior-posterior axis. There was little difference between left and right for comparable pairs. Theta band coherent activity involves distinct midline and temporal sources, with temporal sources showing anterior/posterior differentiation. In contrast, alpha activity has a distinct posterior focus, while beta activity shows no clear global structure. A spatially homogeneous model based on characteristics of thalamocortical connectivity accounts for much of the data, but departures from the model indicate the contribution of other neural factors to coherence.

Evoked gamma band response in male adolescent subjects at high risk for alcoholism during a visual oddball task.

This study investigates early evoked gamma band activity in male adolescent subjects at high risk for alcoholism (HR; n=68) and normal controls (LR; n=27) during a visual oddball task. A time-frequency representation method was applied to EEG data in order to obtain stimulus related early evoked (phase-locked) gamma band activity (29-45 Hz) and was analyzed within a 0-150 ms time window range. Significant reduction of the early evoked gamma band response in the frontal and parietal regions during target stimulus processing was observed in HR subjects compared to LR subjects. Additionally, the HR group showed less differentiation between target and non-target stimuli in both frontal and parietal regions compared to the LR group, indicating difficulty in early stimulus processing, probably due to a dysfunctional frontoparietal attentional network. The results indicate that the deficient early evoked gamma band response may precede the development of alcoholism and could be a potential endophenotypic marker of alcoholism risk.

Alcohol-related ERP changes recorded from different modalities: a topographic analysis.

BACKGROUND: There is controversy in the literature regarding the relationship between event-related-potential (ERP) abnormalities in abstinent alcoholics and stimulus-processing modality (i.e., visual versus auditory). The first purpose of this study was to address questions about whether ERP abnormalities observed in alcoholics are modality specific. The second purpose was to employ current source density (CSD) analyses to investigate topographic differences between alcoholics and controls within each modality. METHODS: Data were collected from 30 sober male alcoholics and 39 normal males in a typical auditory oddball task and in a visual oddball paradigm with novel stimuli, with an extensive set of 61 scalp electrodes. Visual and quantitative assessment of CSD maps as well as analyses of variances on both raw and normalized ERP data were performed. RESULTS: Positive findings were limited to the N1 and P3 components. The visual N1 amplitude was significantly smaller in alcoholics than in controls at the parietal region; no significant group differences in N1 were found in the auditory modality. Alcoholics had widespread reductions in P3 amplitudes in both modalities compared with controls, although in the frontal region this effect was partially due to the influence of age. These P3 reductions in alcoholics were statistically more pronounced in the posterior compared with the anterior regions regardless of modality. Topographically, sources in CSD maps were weaker in alcoholics than in controls; in the frontal and central regions, the weakness was more pronounced in the auditory modality but, in parietal and occipital regions, it was more pronounced in the visual modality. CONCLUSIONS: The results suggest that, in abstinent alcoholics, abnormalities in auditory ERPs may be localized to more anterior sources, while abnormalities in visual ERPs may be localized to more posterior sources. ERP topographic features are more sensitive than amplitude measurements in assessing alcoholic-related modality effects.