Vanessa Nieratschker

Social anxiety disorder (SAD) is a common anxiety disorder (ANX) with moderate heritability that often co-occurs with other mental disorders. Until now, sample sizes in genetic analyses of SAD have been limited, so that the genetic basis of SAD and its subphenotypes is still largely unknown. In a large cohort comprising n = 1,194 SAD patients derived from five German cohorts and n = 3,409 controls from the Heinz Nixdorf Recall Study, we computed polygenic risk scores (PRS) at six p -thresholds using PRSice-2 based on large-scale genome-wide association studies for depression, major depressive disorder (MDD), ANX, schizophrenia (SCZ), bipolar disorder (BD), attention-deficit/hyperactivity disorder (ADHD), anorexia nervosa (AN), autism spectrum disorder (ASD), and alcohol dependence (AD). We used general linear models to examine the association between the PRS and SAD status. In SAD subsamples, we investigated whether the PRS are associated with SAD subphenotypes (i.e., SAD severity, current depressive symptoms, comorbid MDD) using correlation analyses and a general linear model. Results were corrected for multiple testing. The SAD status was significantly associated with PRS for depression, MDD, ANX, SCZ, BD, AN, and ASD ( p _BH -adjusted0.05). Our results support that SAD seems to be genetically highly overlapping with other mental disorders, which might underline a common psychopathological factor. No significant association was found with SAD severity, current depressive symptoms or comorbid MDD. A better understanding of the genetic architecture of SAD may help to develop new diagnostic and treatment approaches.

Adult mental disorders (aMD), including borderline personality disorder (BPD), major depressive disorder (MDD), and social anxiety disorder (SAD), share adverse childhood experiences (ACEs) as an environmental risk factor. Epigenetic mechanisms, including DNA methylation (DNAm), may mediate the biological link between early adversity and psychiatric risk. SIAH3, implicated in stress-related and mitochondrial pathways, has been previously associated with both ACE and aMD. This study examined SIAH3 DNAm in adults with BPD, MDD, or SAD, relative to healthy control participants (HC), testing effects of diagnosis, ACE exposure, and their interaction across the pooled sample and within each diagnostic group. Both aMD diagnosis and high ACE exposure showed trends toward SIAH3 hypomethylation, and a significant diagnosis × ACE interaction emerged, with inconclusive post-hoc tests. Disorder-specific analyses revealed heterogeneous patterns: in BPD, high ACE showed a trend toward hypermethylation in unadjusted models; in MDD, interaction effects were marginal and not robust to covariate adjustment; in SAD, significant main effects and a diagnosis × ACE interaction were observed, with high ACE associated with lower DNAm exclusively in HC. These findings suggest disorder-specific epigenetic responses to ACE, positioning SIAH3 as a potential molecular link between early life stress, mitochondrial function, and aMD.

Recent studies, including our own, have repeatedly identified HECW2 as a gene exhibiting differential DNA methylation (DNAm) in the context of alcohol use disorder (AUD). To investigate the epigenetic regulation of HECW2 in more detail, we conducted a longitudinal, multimodal study investigating HECW2 across several molecular layers—DNAm (in whole blood and saliva), gene expression (in whole blood), and histone modification (H3K4me3 in peripheral blood mononuclear cells)—before and after a standardized three-week inpatient withdrawal treatment. We confirmed HECW2 hypomethylation in both blood and saliva which remained stable through therapy, highlighting saliva as a minimally invasive and previously unstudied tissue for potential biomarker development. Moreover, HECW2 gene expression in whole blood was reduced in AUD patients and showed a reversion toward healthy control levels following therapy. In contrast, H3K4me3 levels at the HECW2 locus remained unaffected by AUD status as well as therapy. None of the investigated molecular signatures demonstrated prognostic value for relapse. Overall, our findings validate HECW2 dysregulation in AUD and extend previous evidence by adding temporal and tissue-specific resolution as well as additional potential molecular regulatory layers, underscoring its relevance as a candidate for further mechanistic and biomarker-focused research.

Alcohol use disorder (AUD) is associated with widespread epigenetic alterations, including changes in DNA methylation (DNAm). This multi-cohort study validated and extended previous findings on DNAm of HECW2 and GDAP1 in AUD, assessed sex differences, and explored DNAm in blood and brain tissue in humans and rats. DNAm was measured via pyrosequencing in human blood (N_Ctrl = 341, N_AUD = 258), postmortem frontal cortex (Brodmann area 9; discovery cohort: N_Ctrl = 10, N_AUD = 13, replication cohort: N_Ctrl = 64, N_AUD = 55) and rat blood and medial prefrontal cortex (N_Ctrl = 16, N_AUD = 15). Gene expression was assessed in human postmortem brain by quantitative real-time PCR. AUD-associated DNAm differences in HECW2 and GDAP1 were replicated in human blood. While decreased GDAP1 DNAm was only observed in men, HECW2 hypomethylation was present in both sexes. In brain tissue, initial DNAm increases in AUD and HECW2 gene expression decreases were not validated in the replication cohort. In rats, HECW2 hypomethylation appeared in the prelimbic cortex but not in blood. Our findings support the involvement of HECW2 and GDAP1 DNAm in AUD, revealing sex-specific and tissue-dependent epigenetic patterns. The opposing DNAm directionality in blood and brain underscores the complexity of alcohol-related epigenetic modifications and suggests the need for multi-tissue, cross-species, and longitudinal studies to clarify causal mechanisms.

Background: Borderline Personality Disorder (BPD) is a complex psychiatric condition with multifactorial origins, with a high proportion of patients reporting early trauma. Stressors such as adverse childhood experiences (ACEs) can shape the epigenetic landscape including DNA methylation (DNAm) and act on gene expression. DNAm is increasingly being investigated as a molecular link between environmental exposures such as ACE and psychiatric outcomes. Differential DNAm of the gene PR domain zinc finger protein 8 (PRDM8), a histone methyltransferase, has recently been reported to be sensitive to early life trauma. Its role in BPD, especially in the context of ACE, remains to be elucidated. Methods: This study investigated DNAm patterns of PRDM8 in peripheral blood and saliva obtained from BPD patients undergoing Dialectic Behavioral Therapy (DBT) compared to healthy control (HC) participants. Associations with ACE and BPD symptom severity were assessed, and therapy-related changes in DNAm were examined. Results: At baseline, BPD patients demonstrated significant hypomethylation of PRDM8 in blood relative to the HC group. Following DBT, a nominally significant increase in DNAm was observed, aligning with inversely correlated symptom severity. No significant differences in saliva were detected. ACE was not associated with PRDM8 DNAm. Conclusions: Our findings suggest that PRDM8 DNAm might be associated with BPD and therapeutic intervention but not with ACE. Together with prior research, the results underscore the importance of future investigation of gene–environment interactions and the functional significance of PRDM8 regulation in the pathophysiology of BPD.

Objective: Volumes of the hippocampus and amygdala, both major hubs for neural stress regulation amongst others, are influenced by social stressors, cortisol awakening response (CAR) and sex, i.e. psychological and physiological stress factors. Importantly, the interplay of these different factors in affecting the morphology of both brain regions remains unclear. This study aimed to elucidate the intricate influence of these factors on grey matter volumes (GMV) of the hippocampus and amygdala. Methods: We analyzed associations between structural brain data, self-reported chronic social stress (including subscales on social tension, social overload, lack of social recognition and social isolation) and CAR of 83 healthy participants (40 females) with multiple regression analyses. Results: In males, but not females, higher social tension predicted lower bilateral hippocampus GMV. In individuals not showing the typical CAR, higher social tension predicted reduced bilateral hippocampus GMV. Amygdala GMV was also related to social stress and CAR, with social overload associated with reduced amygdala GMV in individuals not showing the typical CAR, while the opposite pattern emerged in those with an atypical CAR. Conclusions: Chronic social stress is associated with hippocampus and amygdala volumes, interacting with CAR and sex. The brain morphology in males and in individuals with atypical CAR seems to be more vulnerable to chronic social stress. Our findings enhance our understanding of how brain architecture, social stress, CAR patterns and sex shape individual stress responses.

Social Anxiety Disorder (SAD) involves fear of negative evaluation and social avoidance, impacting quality of life. Early life adversities (ELA) are recognized as risk factors for SAD. Previous research indicated inconsistent alterations in resting state functional connectivity (RSFC) in SAD, particularly in the prefrontal cortex and precuneus. This study investigated the interaction between SAD and ELA at the RSFC level. Functional magnetic resonance imaging (fMRI) was conducted on 120 participants (aged 19–48). Four groups were formed: low/ high ELA controls (n = 49, n = 22) and low/ high ELA SAD participants (n = 30, n = 19). Seed-based correlation analyses (SCA) and multi-voxel pattern analysis (MVPA) were applied. A network in which ELA moderates the neural correlates of SAD during the resting state was identified, involving key nodes like the subgenual anterior cingulate cortex, left middle frontal gyrus, and an area in the calcarine fissure/precuneus. Five distinct interaction patterns of SAD and ELA were observed, showcasing opposite RSFC patterns in individuals with SAD based on ELA experience. Results remained significant when controlled for general anxiety and depression measures. Emotional aspects of ELA played a significant role in these interactions. These findings stress the necessity of considering primarily emotional ELA as covariate in neuroimaging studies investigating SAD and potentially also other psychiatric disorders, addressing inconsistencies in prior research. The left middle frontal gyrus emerges as a link in the SAD-ELA interaction during resting state and anxiety-relevant stimulation. Longitudinal studies, starting from childhood, are needed to understand ELA’s impact on brain function and to identify potential neuromarkers for SAD predisposition post-ELA exposure.

Alcohol use disorder (AUD) contributes significantly to the global burden of disease. The susceptibility for AUD is mediated through an interaction of genetic risk factors and environmental influences. These gene × environment (G × E) interactions manifest as epigenetic regulations of gene expression, among other things. Previous research suggests an association between Ganglioside Induced Differentiation Associated Protein 1 (GDAP1) DNA methylation and AUD. Here, we investigate the epigenetic dysregulation of GDAP1 in AUD through comparing DNA methylation in whole blood and saliva, as well as H3K4-trimethylation (H3K4me3) in PBMC (Peripheral Blood Mononuclear Cell) samples of AUD patients and healthy control individuals. Additionally, the effect of abstinence-based therapy was investigated. AUD patients before treatment exhibit significantly lower promoter DNA methylation levels in whole blood and saliva, as well as lower H3K4me3 near the transcription start site. GDAP1 gene expression was not significantly altered. Following treatment, H3K4me3 was significantly increased in patients and no longer differed from control individuals. There was no significant effect of treatment on DNA methylation. We conclude that GDAP1 is epigenetically dysregulated in AUD patients, and is responsive to abstinence-based therapy at the level of H3K4me3. It should be investigated further to establish its potential as a diagnostic biomarker.

We conducted the largest genome-wide meta-analysis of borderline personality disorder (BPD) to date, with a discovery sample of 12,339 cases and 1,041,717 controls, and a replication study of 685 cases and 107,750 controls (all participants of European ancestry). We identified 11 independent associated genomic loci, and nine risk genes in the gene-based analysis. We observed a single-nucleotide polymorphism (SNP) heritability of 17.3% and derived polygenic scores (PGS) predicted 4.6% of the phenotypic variance in BPD on the liability scale. BPD showed the strongest positive genetic correlations with GWAS of posttraumatic stress disorder, depression, attention deficit hyperactivity disorder, antisocial behavior, and measures of suicide and self-harm. Phenome-wide association analyses using BPD-PGS confirmed these associations and additionally revealed associations with general medical conditions including obstructive pulmonary disease and diabetes. The present analyses highlight BPD as a polygenic disorder, with the genetic risk showing substantial overlap with psychiatric and physical health conditions.

Early-life adversity (ELA) is characterized by exposure to traumatic events during early periods of life, particularly involving emotional, sexual and/or physical adversities during childhood. Mental disorders are strongly influenced by environmental and lifestyle-related risk factors including ELA. However, the molecular link between ELA and the risk of an adult mental disorder is still not fully understood. Evidence is emerging that long-lasting changes in the epigenetic processes regulating gene expression, such as DNA methylation, play an important role in the biological mechanisms linking ELA and mental disorders. Based on a recent study, we analyzed the DNA methylation of a specific CpG site within the gene PXDN—cg10888111—in blood in the context of ELA across a set of psychiatric disorders, namely Borderline Personality Disorder (BPD), Major Depressive Disorder (MDD) and Social Anxiety Disorder (SAD), and its potential contribution to their pathogenesis. We found significant hypermethylation in mentally ill patients with high levels of ELA compared to patients with low levels of ELA, whereas cg10888111 methylation in healthy control individuals was not affected by ELA. Further investigations revealed that this effect was driven by the MDD cohort. Providing a direct comparison of cg10888111 DNA methylation in blood in the context of ELA across three mental disorders, our results indicate the role of PXDN regulation in the response to ELA in the pathogenesis of mental disorders, especially MDD. Further studies will be needed to validate these results and decipher the corresponding biological network that is involved in the transmission of ELA to an adult mental disorder in general.