Showing papers by "Israel Liberzon published in 2020"

Genomic influences on self-reported childhood maltreatment

Abstract: Childhood maltreatment is highly prevalent and serves as a risk factor for mental and physical disorders. Self-reported childhood maltreatment appears heritable, but the specific genetic influences on this phenotype are largely unknown. The aims of this study were to (1) identify genetic variation associated with self-reported childhood maltreatment, (2) estimate SNP-based heritability (h2snp), (3) assess predictive value of polygenic risk scores (PRS) for childhood maltreatment, and (4) quantify genetic overlap of childhood maltreatment with mental and physical health-related phenotypes, and condition the top hits from our analyses when such overlap is present. Genome-wide association analysis for childhood maltreatment was undertaken, using a discovery sample from the UK Biobank (UKBB) (n = 124,000) and a replication sample from the Psychiatric Genomics Consortium-posttraumatic stress disorder group (PGC-PTSD) (n = 26,290). h2snp for childhood maltreatment and genetic correlations with mental/physical health traits were calculated using linkage disequilibrium score regression. PRS was calculated using PRSice and mtCOJO was used to perform conditional analysis. Two genome-wide significant loci associated with childhood maltreatment (rs142346759, p = 4.35 × 10-8, FOXP1; rs10262462, p = 3.24 × 10-8, FOXP2) were identified in the discovery dataset but were not replicated in PGC-PTSD. h2snp for childhood maltreatment was ~6% and the PRS derived from the UKBB was significantly predictive of childhood maltreatment in PGC-PTSD (r2 = 0.0025; p = 1.8 × 10-15). The most significant genetic correlation of childhood maltreatment was with depressive symptoms (rg = 0.70, p = 4.65 × 10-40), although we show evidence that our top hits may be specific to childhood maltreatment. This is the first large-scale genetic study to identify specific variants associated with self-reported childhood maltreatment. Speculatively, FOXP genes might influence externalizing traits and so be relevant to childhood maltreatment. Alternatively, these variants may be associated with a greater likelihood of reporting maltreatment. A clearer understanding of the genetic relationships of childhood maltreatment, including particular abuse subtypes, with a range of phenotypes, may ultimately be useful in in developing targeted treatment and prevention strategies.

Associations between resting-state functional connectivity and treatment response in a randomized clinical trial for posttraumatic stress disorder.

Abstract: BACKGROUND Alterations in resting-state functional connectivity (rsFC) have been reported in posttraumatic stress disorder (PTSD). Here, we examined pre- and post-treatment rsFC during a randomized clinical trial to characterize alterations and examine predictors of treatment response. METHODS Sixty-four combat veterans with PTSD were randomly assigned to prolonged exposure (PE) plus placebo, sertraline plus enhanced medication management, or PE plus sertraline. Symptom assessment and resting-state functional magnetic resonance imaging (fMRI) scans occurred before and after treatment. Twenty-nine trauma-exposed combat veterans without PTSD served as a control group at intake. Seed-based and region of interest (ROI)-to-ROI connectivities, as well as an exploratory connectome-based approach were used to analyze rsFC patterns. Based on previously reported findings, analyses focused on Salience Network (SN) and Default-Mode Network (DMN). RESULTS At intake, patients with PTSD showed greater DMN-dorsal attention network (DAN) connectivity (between ventromedial prefrontal cortex and superior parietal lobule; family-wise error corrected p = .011), greater SN-DAN connectivity (between insula and middle frontal gyrus; corrected p = .003), and a negative correlation between re-experiencing symptoms and within-DMN connectivity (between posterior cingulate cortex (PCC) and middle temporal gyrus; corrected p < .001). We also found preliminary evidence for associations between rsFC and treatment response. Specifically, high responders (≥50% PTSD symptom improvement), compared with low responders, had greater SN-DMN segregation (i.e., less pre-treatment amygdala-PCC connectivity; p = .011) and lower pre-treatment global centrality (p = .042). CONCLUSIONS Our findings suggest neural abnormalities in PTSD and may inform future research examining neural biomarkers of PTSD treatment response.

DRD4 polymorphisms modulate reward positivity and P3a in a gambling task: Exploring a genetic basis for cultural learning.

Abstract: Prior work shows that people respond more plastically to environmental influences, including cultural influences, if they carry the 7 or 2-repeat (7/2R) allelic variant of the dopamine D4 receptor gene (DRD4) The 7/2R carriers are thus more likely to endorse the norms and values of their culture So far, however, mechanisms underlying this moderation of cultural acquisition by DRD4 are unclear To address this gap in knowledge, we tested the hypothesis that DRD4 modulates the processing of reward cues existing in the environment About 72 young adults, preselected for their DRD4 status, performed a gambling task, while the electroencephalogram was recorded Principal components of event-related potentials aligned to the Reward-Positivity (associated with bottom-up processing of reward prediction errors) and frontal-P3 (associated with top-down attention) were both significantly more positive following gains than following losses As predicted, the gain-loss differences were significantly larger for 7/2R carriers than for noncarriers Also, as predicted, the cultural backgrounds of the participants (East Asian vs European American) did not moderate the effects of DRD4 Our findings suggest that the 7/2R variant of DRD4 enhances (a) the detection of reward prediction errors and (b) controlled attention that updates the context for the reward, thereby suggesting one possible mechanism underlying the DRD4 × Culture interactions