Embers of the Past: Early Childhood Traumas Interact with Variation in P2RX7 Gene Implicated in Neuroinflammation on Markers of Current Suicide Risk.

Both early childhood traumatic experiences and current stress increase the risk of suicidal behaviour, in which immune activation might play a role. Previous research suggests an association between mood disorders and P2RX7 gene encoding P2X7 receptors, which stimulate neuroinflammation. We investigated the effect of P2RX7 variation in interaction with early childhood adversities and traumas and recent stressors on lifetime suicide attempts and current suicide risk markers. Overall, 1644 participants completed questionnaires assessing childhood adversities, recent negative life events, and provided information about previous suicide attempts and current suicide risk-related markers, including thoughts of ending their life, death, and hopelessness. Subjects were genotyped for 681 SNPs in the P2RX7 gene, 335 of which passed quality control and were entered into logistic and linear regression models, followed by a clumping procedure to identify clumps of SNPs with a significant main and interaction effect. We identified two significant clumps with a main effect on current suicidal ideation with top SNPs rs641940 and rs1653613. In interaction with childhood trauma, we identified a clump with top SNP psy_rs11615992 and another clump on hopelessness containing rs78473339 as index SNP. Our results suggest that P2RX7 variation may mediate the effect of early childhood adversities and traumas on later emergence of suicide risk.

Variation along P2RX7 interacts with early traumas on severity of anxiety suggesting a role for neuroinflammation.

Emotional stress is a leading risk factor in the development of neuropsychiatric disorders possibly via immune activation. P2X7 receptors promote neuroinflammation, and research suggests a relationship between chromosome region 12q2431, in which the P2X7R gene is located, and development of mood disorders, however, few studies concentrate on its association with anxiety. Our aim was to investigate the effects of P2RX7 variation in interaction with early childhood traumas and recent stressors on anxiety. 1752 participants completed questionnaires assessing childhood adversities and recent negative life events, provided data on anxiety using the Brief Symptom Inventory, and were genotyped for 681 SNPs in the P2RX7 gene, 335 of which passed quality control and were entered into linear regression models followed by a linkage disequilibrium-based clumping procedure to identify clumps of SNPs with a significant main or interaction effect. We identified a significant clump with top SNP rs67881993 and containing a set of 29SNPs that are in high LD, which significantly interacted with early childhood traumas but not with recent stress conveying a protective effect against increased anxiety in those exposed to early adversities. Our study demonstrated that P2RX7 variants interact with distal and more etiological stressors in influencing the severity of anxiety symptoms, supporting previous scarce results and demonstrating its role in moderating the effects of stress.

Association between change in suicidal ideation, and distinct symptoms of depression and sleep changes during COVID-19.

COVID-19 has created a situation that has never been experienced before, challenging the mobilization of adaptive coping strategies. There has been a marked increase in suicides and suicidal ideation following the onset of COVID-19 likely reflecting the toll of the pandemic on mental health. The aim of our study to investigate the associations between depressive symptoms and distinct symptom clusters and lifestyle changes related to sleep, eating and physical activity and change in suicidal thoughts and thinking about death during the pandemic. Analyses involved data from the Hungarian part of the COMET-G (COVID-19 Mental health in Ternational for the General population) study, including 763 Hungarian adults, who completed a detailed questionnaire focusing on changes in behavior, lifestyle, activity and mental health during the pandemic. The dataset was analyzed using ordinal regression models adjusted for age and sex. Depression, as well as its symptom clusters, including anhedonia and depressed mood and somatic complaints had a significant, but small effect increasing suicidal ideation, while the effect of irritability and social relationship problems was more marked. In case of lifestyle factors no associations was found between change in eating habits or physical activity and change in suicidal ideations, however, sleeprelated changes were associated with a significant increase in suicidal thoughts during the pandemic. Our findings show that not all symptoms related to mood disturbance have an equally marked effect on suicidal ideating and thus suicide risk, emphasizing the role of detailed screening and evaluation even in subclinical populations in times of such crises, and also highlight the importance of considering sleep problems when evaluating suicide risk. Thus, our findings help identify relevant targets for screening and intervention in decreasing suicide risk during crises. (Neuropsychopharmacol Hung 2022; 24(3): 134-143).

Visual imagery vividness declines across the lifespan.

The capacity to elicit vivid visual mental images varies within an extensive range across individuals between hyper- and aphantasia. It is not clear, however, whether imagery vividness is constant across the lifespan or changes during development and later in life. Without enforcing the constraints of strict experimental procedures and representativity across the entire population, our purpose was to explore the self-reported level of imagery vividness and determine the relative proportions of aphantasic/hyperphantasic participants in different age groups. Relying on the frequently used Vividness of Visual Imagery Questionnaire, we collected data on a random sample of 2252 participants between the ages of 12-60 years. We found a novel developmental pattern that describes a declining ability to elicit vivid visual mental images in the group averages of different age groups from adolescence to middle age. This effect involves both a decreasing proportion of individuals with vivid visual imagery vividness and an increasing proportion of individuals with low imagery vividness as maturation (based on bone age assessments in adolescents) and ageing progress. These findings may shed some light on the developmental mechanisms of our internal, stimulus-independent processes, and might also help to determine genetic, maturational, and age-dependent factors in the cases of hyper- and aphantasia.

Inflamed Mind: Multiple Genetic Variants of IL6 Influence Suicide Risk Phenotypes in Interaction With Early and Recent Adversities in a Linkage Disequilibrium-Based Clumping Analysis.

Background: Understanding and predicting suicide remains a challenge, and a recent paradigm shift regarding the complex relationship between the immune system and the brain brought attention to the involvement of inflammation in neuropsychiatric conditions including suicide. Among cytokines, IL-6 has been most frequently implicated in suicide, yet only a few candidate gene studies and without considering the effect of stress investigated the role of IL6 in suicidal behaviour. Our study aimed to investigate the association of IL6 variation with a linkage disequilibrium-based clumping method in interaction with childhood adversities and recent stress on manifestations along the suicide spectrum. Methods: One thousand seven hundred and sixty-two participants provided information on previous suicide attempts, current suicidal ideation, thoughts of death, and hopelessness, and were genotyped for 186 variants in IL6. Early childhood adversities were recorded with an instrument adapted from the Childhood Trauma Questionnaire, recent life events were registered using the List of Threatening Life Events. Following a 3-step quality control, logistic and linear regression models were run to explore the effect of genotype and gene-environment interactions on suicide phenotypes. All regression models were followed by a clumping process based on empirical estimates of linkage disequilibrium between clumps of intercorrelated SNPs. Interaction effects of distinct types of recent life events were also analysed. Results: No clumps with significant main effects emerged, but we identified several clumps significantly interacting with childhood adversities on lifetime suicide attempts, current suicidal ideation, and current thoughts of death. We also identified clumps significantly interacting with recent negative life events on current suicidal ideation. We reported no clumps with significant effect on hopelessness either as a main effect or in interaction with childhood adversities or recent stress. Conclusion: We identified variant clumps in IL6 influencing suicidal behaviour, but only in interaction with childhood or recent adversities. Our results may bring us a step further in understanding the role of neuroinflammation and specifically of IL-6 in suicide, towards identifying novel biological markers of suicidal behaviour especially in those exposed to stressful experiences, and to fostering the adaptation of a new paradigm and identifying novel approaches and targets in the treatment of suicidal behaviour.

Every Night and Every Morn: Effect of Variation in CLOCK Gene on Depression Depends on Exposure to Early and Recent Stress.

The role of circadian dysregulation is increasingly acknowledged in the background of depressive symptoms, and is also a promising treatment target. Similarly, stress shows a complex relationship with the circadian system. The CLOCK gene, encoding a key element in circadian regulation has been implicated in previous candidate variant studies in depression with contradictory findings, and only a few such studies considered the interacting effects of stress. We investigated the effect of CLOCK variation with a linkage-disequilibrium-based clumping method, in interaction with childhood adversities and recent negative life events, on two phenotypes of depression, lifetime depression and current depressive symptoms in a general population sample. Methods: Participants in NewMood study completed questionnaires assessing childhood adversities and recent negative life events, the Brief Symptom Inventory to assess current depressive symptoms, provided data on lifetime depression, and were genotyped for 1054 SNPs in the CLOCK gene, 370 of which survived quality control and were entered into linear and logistic regression models with current depressive symptoms and lifetime depression as the outcome variable, and childhood adversities or recent life events as interaction variables followed by a linkage disequilibrium-based clumping process to identify clumps of SNPs with a significant main or interaction effect. Results: No significant clumps with a main effect were found. In interaction with recent life events a significant clump containing 94 SNPs with top SNP rs6825994 for dominant and rs6850524 for additive models on current depression was identified, while in interaction with childhood adversities on current depressive symptoms, two clumps, both containing 9 SNPs were found with top SNPs rs6828454 and rs711533. Conclusion: Our findings suggest that CLOCK contributes to depressive symptoms, but via mediating the effects of early adversities and recent stressors. Given the increasing burden on circadian rhythmicity in the modern lifestyle and our expanding insight into the contribution of circadian disruption in depression especially as a possible mediator of stress, our results may pave the way for identifying those who would be at an increased risk for depressogenic effects of circadian dysregulation in association with stress as well as new molecular targets for intervention in stress-related psychopathologies in mood disorders.

P2RX7 gene variation mediates the effect of childhood adversity and recent stress on the severity of depressive symptoms.

The P2X purinoceptor 7 (P2RX7) mediates inflammatory microglial responses and is implicated in neuroimmune mechanisms of depression and neurodegenerative disorders. A number of studies suggest that psychosocial stress may precipitate depression through immune activation. Genetic association studies of P2RX7 variants with depression have been inconclusive. However, nearly all studies have focused on only one single-nucleotide polymorphism (SNP) and have not considered interaction with psychosocial stress. We investigated the effect of several variations in P2RX7 gene using a clumping method in interaction with early adversities and recent stress on depression severity. 1752 subjects provided information on childhood adversities, recent life events, and current depression severity. Participants were genotyped for 681 SNPs in the P2RX7 gene, 335 of them passed quality control and were entered into linear regression models followed by a clumping procedure for main effect and interactions. No significant main effect was observed. Rs74892325 emerged as a top SNP for interaction with childhood adversities and rs61953400 for interaction with recent life events. Our study is the first to investigate several variants in the P2RX7 gene and in interaction with two types of stress, extending our understanding of neuroinflammation in depression, and supporting that the majority of genes influence depression by enhancing sensitivity to stressors.

"Out, out, brief candle! Life's but a walking shadow": 5-HTTLPR Is Associated With Current Suicidal Ideation but Not With Previous Suicide Attempts and Interacts With Recent Relationship Problems.

BACKGROUND: Suicide is an unresolved psychiatric and public health emergency, claiming 800,000 lives each year, however, its neurobiological etiology is still not understood. In spite of original reports concerning the involvement of 5-HTTLPR in interaction with recent stress in the appearance of suicidal ideation and attempts, replication studies have yielded contradictory results. In our study, we analyzed the association between 5-HTTLPR and lifetime suicide attempts, current suicidal ideation, hopelessness and thoughts of death as main effects, and in interaction with childhood adversities, recent stress, and different types of recent life events in a general population sample. METHODS: Two thousand and three hundred fifty-eight unrelated European volunteers were genotyped for 5-HTTLPR, provided phenotypic data on previous suicide attempts, and current suicidal ideation, hopelessness and thoughts about death, and information on childhood adversities and recent life events. Logistic and linear regression models were run with age, gender, and population as covariates to test for the effect of 5-HTTLPR as a main effect and in interaction with childhood adversities and recent life events on previous suicide attempts and current suicidal ideation. Benjamini-Hochberg FDR Q values were calculated to correct for multiple testing. RESULTS: 5-HTTLPR had no significant effect on lifetime suicide attempts either as a main effect on in interaction with childhood adversities. 5-HTTLPR had a significant main effect on current suicidal ideation in the dominant model (Q=0.0344). 5-HTTLPR did not interact with childhood adversities or total number of recent life events on any phenotypes related to current suicidal risk, however, a significant interaction effect between 5-HTTLPR and current relationship problems emerged in the case of current suicidal ideation in the dominant model (Q=0.0218) and in the case of thoughts about death and dying in the dominant (Q=0.0094) and additive models (Q=0.0281). CONCLUSION: While 5-HTTLPR did not influence previous suicide attempts or interacted with childhood adversities, it did influence current suicidal ideation with, in addition, an interaction with recent relationship problems supporting the involvement of 5-HTTLPR in suicide. Our findings that 5-HTTLPR impacts only certain types of suicide risk-related behaviors and that it interacts with only distinct types of recent stressors provides a possible explanation for previous conflicting findings.

Nature and Nurture: Effects of Affective Temperaments on Depressive Symptoms Are Markedly Modified by Stress Exposure.

BACKGROUND: Lack of proper consideration of the interaction between biological and environmental factors limits our understanding of the development of depression. Our cross-sectional study investigated whether recent stress influences the effect of affective temperaments on depressive symptoms. METHODS: 1015 general population participants completed the Brief Symptom Inventory to capture depressive symptoms, the List of Threatening Experiences Questionnaire to assess recent stressors, and the Temperament Evaluation of Memphis Pisa, Paris, and San Diego Autoquestionnaire to evaluate affective temperaments (TEMPS-A). Linear regression models were built to investigate the effect of temperament and stress on depression, temperament on stress, and the effect of temperament on depressive symptoms in different stress exposure groups. RESULTS: Recent life events and anxious, depressive, cyclothymic, and hyperthymic temperaments significantly predicted depressive symptoms, and cyclothymic, and hyperthymic temperaments significantly predicted recent life event exposure. While in case of mild stress all affective temperaments except irritable predicted depression, in case of moderate exposure only the effect of depressive, cyclothymic, and hyperthymic temperament, while in the high exposure group only the effect of anxious temperament was significant. LIMITATIONS: All measures were based on self-report, and subjective impact of life events was not considered. This was a cross-sectional study with a correlational nature which does not allow for causative conclusions. CONCLUSIONS: The contribution of affective temperaments to depression is much higher compared to stress, and severity of exposure to life events influences the impact of affective temperaments on depressive symptoms, pointing to divergent pathways of emotional reactivity mediating the effects of stress on depression which can be exploited for prevention and treatment.

Effects of Different Stressors Are Modulated by Different Neurobiological Systems: The Role of GABA-A Versus CB1 Receptor Gene Variants in Anxiety and Depression.

Environmental stress and its interaction with genetic variation are key contributors in the development of depression and anxiety, yet there is a failure to identify replicable genetic variants and gene-interaction effects in the background of these psychiatric symptoms. Recently it has been reported that 5-HTTLPR and NOSI interact with financial but not other types of recent stressors in the development of depression. In the present study we investigated the interaction of GABRA6 rs3219151 and CNR1 rs7766029 in interaction with different types of recent life events on the presence of depression and anxiety in a large general population sample. 2191 participants completed the List of Threatening Experiences questionnaire which covers four categories of stressful life events (financial problems, illness/personal problems, intimate relationships, and social network) experienced over the previous year and the Brief Symptom Inventory for depression and anxiety symptoms. Participants were genotyped for rs3219151 and rs7766029. Data were analyzed with linear regression models with age and gender as covariates. Results indicated that CNR1 rs7766029 interacted significantly with financial but not other types of life events both in case of depression and anxiety symptoms. In contrast, GABRA6 rs3219151 showed a significant interaction with social network related life events in case of anxiety and with illness/personal problem-related life events in case of depression. Our results suggest that the psychological impact of different types of recent stress may be differentially modulated by distinct molecular genetic pathways. Furthermore, in case of certain genetic variants, the occurring psychiatric symptom may depend on the type of stress experienced.