Although suicide claims more lives than war and homicide, we still have no sufficient and effective methods either for its prediction or for its prevention. Our screening methods are laborous and subjective both on the side of the patient and on the side of the clinician. Understanding the genetic background of suicidal behaviour would help identify biomarkers for screening as well as pathways as potential targets for novel intervention and prevention approaches. However, in spite of a number of GWAS studies, results are few and rarely replicate, and generally accurate phenotyping and sufficient consideration of environmental stressors is also missing.

In our present study we performed a genome-wide analysis study for suicidal ideation in interaction with early childhood traumas in a deep-phenotyped general population sample.

Our analysis used data from 1800 volunteers in the NewMood project. As outcome phenotype the suicidal ideation item of the Brief Symptom Inventory was used. A modified version of the Childhood Trauma Questionnaire was used to assess early adverse experiences. A genome-wide association analysis was performed with Plink 1.9, including a total of 3,474,641 variants after quality control steps, followed by genome-wide by environment interaction analyses. Our models included control variables for sex, age, and the top 10 genomic principal components. Functional annotation of SNPs was carried out using FUMA v1.5.6, gene-based tests were performed using MAGMA v1.08.

7 SNPs met suggestive significance in main effect analyses, of which 2 reached genome-wide significance including rs79912020 (p=3.21E-10, β=0.746) and rs10236520 (p=1.71E-08, β=0.484), with no significant findings in gene-based tests. Interaction analyses with childhood adversities yielded 31 SNPs that met genome-wide significance, including rs7983955 (p=2.28E-11, β=0.182), rs141039461 (p=3.90E-11, β=0.0541), rs12692827 (p=3.69E-10, β=0.0612) as the top SNPs. In interaction with childhood adversities, 31 genes showed a significant association in gene-based tests, including RBFOX1 (p=1.09E-10), GRM7 (p=1.20E-10), MTCH1 (p=5.59E-09), and CDH13 (p=6.60E-09) as the most significant findings.

Our results indicate several important novel SNPs associated with suicidal ideation when considered in interaction with the effect of childhood adversities. Furthermore, gene-based analyses replicate several genes playing a key role in central nervous system function such as GRM7 (encoding metabotropic glutamate receptor 7) or previously implicated in association with suicide (CDH13) or suicide-related factors such as aggression (RBFOX1).

Funding: NAP2022-I-4/2022, K143391, 2019-2.1.7-ERA-NET-2020-00005, TKP2021-EGA-25

None Declared

Depression is a highly prevalent, multifactorial, complex disorder, its etiology is assumed to involve both genetic and environmental factors. Genetic factors, including biological clock genes such as CLOCK and SIRT1, have been linked to depression, particularly its symptom related sleep disturbances. Environmental factors also play a crucial role in the background of depression, particularly in interaction with genetic factors. Known environmental stress factors include stress caused negative life events or childhood adversities.

This study aims to delve into the chronotype-specific impacts of genes previously correlated with circadian functionality on the pathomechanism of depression in interaction with environmental stress factors.

A genome-wide association study on the ‘morning chronotype’ phenotype was conducted with Plink2, utilizing data from the UK Biobank discovery sample (N = 139135). Using LDPred2we derived a polygenic risk score (PRS) for the NewMood Hungarian dataset (N = 1820). We performed pathway-specific analyses including genes implicated within the genetic pathway, drawing on prior research findings. Specifically, we selected the top genes (with a false discovery rate-corrected p-value < 0.05) from the “responders vs. non-responders” analysis conducted by Jerome C. Foo et al.Transl Psychiatry 2019; 9 343). We performed a main effect analysis investigating the pathway specific PRS’s effect on BSI depression scores and interaction analyses using life course (number of negative life events in the past life) and recent (number of negative life events in the past year) stress scores to investigate how the interaction term predicts depression in our target sample.

Our primary analysis revealed a nominally significant protective effect (beta = -20.90938, p = 0.070218). Subsequently, in the context of our interaction analysis, we identified significant risk associations, both with lifetime stress (beta = 13.7416, p = 0.0171) and recent stress (beta = 24.6034, p = 0.0038)

Our study unveiled a protective role in our primary analysis, juxtaposed with risk associations in our interaction analyses. This intriguing dichotomy underscores that this genetic pathway, associated with circadian dysregulation, exerts a protective influence in association with the morning chronotype. However, it transitions into a predisposing factor for depression when influenced by environmental stress factors.

Considering these findings, our study substantiates the hypothesis that both circadian genes and chronotype contribute to the pathogenesis and clinical manifestation of depression. Additionally, it underscores the pivotal role of stress as a contributing factor in the intricate pathogenesis of depression.

None Declared

The premenstrual dysphoric disorder (PMDD) is a new distinct diagnostic entity in the Fifth Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). However, the severe premenstrual (PM) symptoms associated with PMDD result in functional impairment, globally, it remains highly underdiagnosed, underscoring the need for enhanced clinical recognition.

This ongoing study aims to assess the prevalence and symptom profile of PMDD in a sample of Hungarian women. It is part of a comprehensive research process aiming to validate a prospective PMDD diagnostic questionnaire (Daily Record of Severity of Problems, DRSP) in order to facilitate the diagnosis of the disorder.

The study was performed in three steps. Firstly, retrospective data were collected from 112 women. Probable PMDD was assessed using the DSM-5 Based Screening Tool, while anxio-depressive symptoms and well-being were evaluated using the Beck Depression Inventory, the state subscale of the State-Trait Anxiety Inventory, and the WHO Well-Being Scale. Subsequently, prospective data were obtained from 9 women who completed the DRSP along with the aforementioned mood questionnaires during both their PM and follicular phases.

In the first research phase, the sample was divided into women with probable PMDD diagnosis (PMDD group, n=68) and women without probable PMDD diagnosis (nonPMDD group, n=45) based on the DSM-5-Based Screening Tool. The PMDD group reported significantly more severe depressive (F(1; 56.2) = 19.394, p≤0.001) and anxiety (F(1; 35.6)=17.714, p≤0.001) symptoms and lower well-being (F(1; 44.3)=4.288, p=0.04) compared to the non-PMDD group, irrespective of the menstrual phase they experienced.

In the second and third research phases based on the DRSP, the sample was divided into women with probable PMDD diagnosis (PMDD group, n= 3) and those without probable PMDD diagnosis (nonPMDD group, n=6). A statistically significant association was observed between the classifications according to the DSM-5 Based Screening Tool and the DRSP (p=0.048; Cramer’s V=0.79). The PMDD group showed a tendency of lower well-being and more severe anxio-depressive symptoms than the nonPMDD group (Well-being: between phases p=0.93, between groups p=0.06; BDI-II: between phases p=0.79, between groups p=0.07; STAI-S: between phases p=0.87, between groups p=0.17).

The prevalence of PMDD was high in our sample. Women with probable PMDD retrospectively reported substantial affective difficulties and a decline in subjective well-being, regardless of their menstrual cycle. Prospective preliminary findings suggest a trend toward differentiation associated with probable PMDD. These results highlight the need for prospective clinical studies addressing the psychological symptoms of women with PM issues and the importance of appropriate treatment of the clinical appearance of PMDD.

None Declared

Depressive disorders are known heterogeneous both in their clinical manifestations and etiopathophysiology. Affective temperaments have a strong biological background and heritability, manifest at early age and remain stable throughout the life span, and have a pathoplastic effect in depression. Thus, they have been suggested as intermediate phenotypes for depression.

Our aim was to investigate if polygenic risk scores (PRS) calculated for the five affective temperaments predict depression and to examine their interaction effects of early and recent stressors.

1820 nonrelated participants from a general population were genotyped and provided data on current depression (Brief Symptom Inventory-BSI), early (Childhood Trauma Questionnaire, CHA) and recent stressors (List of Threatening Life Events, RLE), and affective temperaments (Temperament Evaluation of Memphis, Pisa, Paris and San Diego, TEMPS-A). Our previously performed TEMPS-A GWAS analysis was used as discovery sample and the NewMood database as target sample for analysing the effects of affective temperament PRS on depression. Linear regression models were used to calculate the interaction effect of early and recent stressors.

PRSs derived from anxious, cyclothymic, depressive, and irritable temperaments had a significant effect on current depression, explaining 2.6-7.1% of variance. PRSs calculated from the anxious, depressive and hyperthymic temperaments significantly predicted current depression in interaction with CHA, explaining 10% of variance. In case of interaction models including both early and recent stressors, a significant effect of depressive PRS was found. Detailed results are shown in Table 1.

Our results confirm the genetic association between affective temperaments and depressive symptoms, which highlight their role as possible clinically relevant intermediate phenotypes for depression.

None Declared

Depression shows a moderate heritability of 37-42%, which can be up to 75% in severely depressed samples 75%. At the same time SNP-based heritability of depression in GWAS-s is around 8-9%. Heterogeneity of the depressive phenotype may contribute not only to the lack of understanding its genetic background but may also hinder the identification of novel targets. Thus clinically relevant intermediate endophenotypes are needed for. The affective temperaments in the Akiskal model may be considered high-risk states or subclinical manifestations of mood disorders. Considering their strong genetic and biological background, high heritability in family studies, and their temporal stability, they may prove to be relevant endophenotypes for depression.

The aim of the current study was to investigate the genetic determinants and heritability of affective temperaments based on a GWAS approach.

775 subjects aged between 18-60 years recruited in Budapest, Hungary provided genetic samples and completed questionnaires including the TEMPS-A (Temperament Evaluation of Memphis, Pisa, Paris and San Diego) scale. A genome-wide association analysis was performed with the five affective temperaments as outcome variables. Age, gender, the top 10 principal components of the genome, and the other 4 phenotype were added in the model as covariates. Summary statistics derived from the GWAS analyses were used to estimate the heritability, i.e. the genetic variance explained by the different affective temperaments. LD score regression using LDPred2 [4] was performed to estimate heritability from the beta values and effect size in case of all 5 affective temperament phenotypes.

rs3798978 showed a genome-wide significance (p=4.44x10-8) for anxious temperament, and several other variants showed suggestive significances for all five temperaments. The highest estimated heritability (h2 = 0.5224) was observed for the depressive temperament, and similarly high heritability was observed for the hyperthymic temperament (h2 = 0.4956). Anxious and cyclothymic temperaments showed almost the same heritability (cyclothymic h2 = 0.1651, anxious h2 = 0.1663), whereas for the irritable temperament, we got negative heritability estimation (h2 = -0.0567), which means that all of the phenotypic variance is explained by environmental factors.

Our analyses yielded remarkably high heritability values for depressive and hyperthymic temperaments explaining 52% and 50% of phenotypic variances. In contrast to the 8-9% SNP-based heritability in depression studies our findings suggest that these temperaments may be relevant endophenotypes for mood disorders.

None Declared