Jonathan R. I. Coleman

Binge-eating behavior and anorexia nervosa have shared and distinct genetic components

Identifying differential interactions of potentially traumatic experiences with genetic risk for posttraumatic stress disorder

ABSTRACT Background: Posttraumatic stress disorder (PTSD) occurs following potentially traumatic experiences, but not everyone who experiences trauma develops PTSD. Genetic factors play an important role in shaping how individuals respond to trauma, reflecting gene-environment interaction. An open and important question in PTSD genetics research is the extent to which gene-environment interactions vary across specific traumas. Objective: We aimed to compare gene-environment interaction effects across a broad range of self-reported potentially traumatic experiences across the lifespan. Method: We analysed existing data from two large UK cohorts: the UK Biobank and GLAD-EDGI-COPING (N = 144,702). PTSD symptoms were assessed using the six-item abbreviated PTSD Checklist. We examined eleven self-reported trauma exposures, including five childhood traumas and six adulthood traumas. We conducted gene-environment interaction analyses for each trauma at three levels of genetic specificity: polygenic risk scores, specific genes, and specific genetic variants. Results: Childhood traumas showed stronger associations with PTSD symptoms and greater gene-environment interactions than adulthood traumas on average. Childhood emotional and physical neglect also demonstrated greater gene-environment interactions than childhood abuse. Interaction patterns varied across genes and variants, with several leading PTSD-associated genes (e.g. ANAPC, FAM120A, SGCD) having particularly strong interactions with certain traumas. Several genes (DTX4, PSMD12, TYW3, ZNF660) demonstrated consistently stronger interactions across all childhood or all adulthood traumas. Differences in gene-environment interactions across traumas were not explained by variation in exposure rates, associations with PTSD symptoms, or gene-environment correlations. Conclusions: Our findings are consistent with differential gene-environment interactions on PTSD across potentially traumatic experiences, with those in childhood exhibiting the strongest interactions. To account for the moderating role of trauma type on genetic associations, genetic research on PTSD should incorporate detailed trauma exposure information, which may improve PTSD risk prediction and support more personalised prevention approaches.

Genomic dimensions deconstruct the clinical heterogeneity of bipolar disorder

Bipolar disorder’s (BD) clinical heterogeneity has an unresolved genetic basis. We meta-analyzed genome-wide association studies (GWAS) of 16 BD subphenotypes in 226,032 individuals from 57 cohorts (38,022 cases); 10 advanced to multivariate and multi-trait analyses. Four factors (compulsive, psychotic, dysregulated, internalizing) explained 82.8% of shared genetic variance. BD1 and BD2 loaded on distinct factors despite a high genetic correlation; 87.0% of common-factor loci were significant in neither subtype. Unipolar mania aligned with psychosis over internalizing, and was distinguishable from BD1, and rapid cycling showed heritable cross-domain liability. We identified 356 risk loci, 158 novel, including the first univariate-GWAS associations for psychosis, unipolar mania, rapid cycling and schizoaffective disorder—and 249 credible genes (89 high-confidence), 12 with approved-drug or clinical-phase annotations. Cell-type association showed a midbrain dopaminergic–GABAergic gradient along the psychotic factor. BD’s genetic architecture appears hierarchical—a general liability resolving into dimensions of course and comorbidity, beyond subtypes.