Exposure to high levels of adversity, such as maltreatment or geopolitical conflict, is a robust risk factor for severe psychiatric illness and is often associated with reduced treatment efficacy. The glucocorticoid receptor co-chaperone FK506 Binding Protein 51 (FKBP51), encoded by FKBP5 (chromosome 6p21.31), is a key regulator of the cortisol-induced stress response and a potential therapeutic target for stress-related psychiatric disorders. FKBP5 induction is moderated by a complex interplay of clinically relevant features including age and genotype, however, little is known about the role of mRNA splicing and the resulting protein isoforms in the human brain. Here, we characterise the expression profiles of three minor FKBP5 transcript variants (variants 2-4) in a large cohort of postmortem human brain samples from the dorsolateral prefrontal cortex of individuals who lived with a major psychiatric disorder (schizophrenia/major depressive disorder/bipolar disorder; n = 329) and controls (n = 231). Overall, expression of variant 3 (encoding full-length FKBP51) and variant 4 (encoding truncated FKBP51) showed the same neurotypical ageing trajectory as variant 1, while the lowly expressed variant 2 (encoding full-length FKBP51) showed no association with ageing past adolescence. In individuals with schizophrenia and major depressive disorder, we found increased expression of the same variants which may be partly moderated by genotype, given rs1360780 risk allele carriers had increased abundance of variants 3 and 4, but not variant 2. These findings suggest that in the human dorsolateral prefrontal cortex, minor FKBP5 mRNA splice variants follow a similar pattern of expression as the predominant variant 1.

Stress exposure early in life is an established risk factor for adult psychiatric illness, yet these disorders-including anxiety disorders and depression-show significant sex differences in prevalence, symptomatology, and treatment response. The biology underlying these differences remains largely unexplored and may contribute to the clinical heterogeneity in anxiety and depression. Here, we characterize the lasting impact of developmental stress on adulthood neurobiology and behavior in mice by combining analyses of multiple levels of brain function, including whole-brain c-Fos mapping, manganese-enhanced MRI, and transcriptomics with advanced behavioral phenotyping. Across levels of investigation, we find distinct and often opposite effects of developmental stress based on sex. These results together showcase the strong influence of sex on how early life adversity affects the onset of stress-related disorders. This work emphasizes the necessity of considering sex when investigating developmental and neurobiological underpinnings of stress-related disorders and displays a vast range of lasting effects of developmental stress on the brain, which provides a valuable resource for future studies aiming to improve psychiatric treatments.

BACKGROUND:Prenatal exposure to parabens, which are environmental endocrine disrupting chemicals and widely used preservatives in cosmetics, may alter DNA methylation (DNAm) in cord blood. Study design In 328 mother-child dyads of the Finnish PREDO Study cohort, we studied with robust linear regression if paraben levels in early pregnancy associated with DNAm levels in cord blood. We measured genome-wide DNAm using Illumina Infinium Human Methylation 450 k or EPIC v1 arrays and concentrations of metabolites of six parabens, namely methyl-, ethyl-, propyl-, isopropyl-, butyl, and isobutylparaben, in early pregnancy urine samples with liquid chromatography - mass spectrometry. All parabens were analyzed as continuous and binary variables (high levels > 66th percentile). As isopropylparaben was present in only 8 % of samples it was analyzed separately as a dichotomic (detected/undetected) variable. Furthermore, we explored the putative functions of associated DNAm markers. RESULTS:Every mother in the cohort had been exposed to parabens during early pregnancy. After correction for multiple testing there were significant associations (p-value ≤ 2.4 × 10 -7) between parabens and hypomethylation of four GpG sites: butylparaben associated with cg19246197 near USP2 (B = -0.009; p = 2.10 × 10-7), high level of isobutylparaben associated with cg27194164 near GLTD25D1 (B = -0.004; p = 1.89 × 10-7), detected isopropylparaben associated with cg00973732 in FAM38A (B = 0.007; p = 1.26 × 10-7), and high levels in the sum of the five most common parabens associated with cg21701043 in chromosome 11 (B = -0.016; p = 1.01 × 10-7). In total, 52 CpG sites associated with at least one of the parabens at a suggestive level (p-value < 1 × 10-5). Moreover, butyl- and isobutylparaben showed associations with differentially methylated regions located within PF4 and ABAT. CONCLUSIONS:Paraben exposure during early pregnancy associates with altered DNAm in cord blood.

Personality stability and change are not only attributable to net contributions of genetic and environmental factors but also to their interplay. Environmental factors can accelerate or decelerate age-related changes in the expressions of genetic factors (i.e., epigenetic aging), which might influence personality change. Conversely, personality differences could drive experiential differences that accelerate or decelerate epigenetic aging. This study explored the associations between epigenetic aging and Big Five personality traits considering (sources of) stable and change differences. We analyzed saliva-based DNA methylation data on chronological and biological clocks and self-reported personality data from 1,088 early adolescent to young adult twins from two timepoints 2.3 years apart. (Biometric) latent change analyses revealed significant mean-level acceleration in epigenetic aging over time and decreases in personality traits except neuroticism, with variance in intraindividual changes mainly driven by environment. Acceleration in epigenetic aging based on chronological clocks was associated with higher baseline agreeableness and conscientiousness and decreases in conscientiousness. Epigenetic aging based on biological clocks and conscientiousness were negatively related at baseline. The links involving stable personality differences were rather genetic and the change correlation primarily environmental. Findings are discussed considering epigenetic aging and personality differences in a system of interacting genetic and environmental factors.

Background Parental genetics matters for children’s behavioural difficulties, but the extent to which this is due to direct genetic transmission versus environmentally mediated indirect genetic effects remains unclear. Methods We studied eight European birth cohorts with over 33,000 family-based trio samples. We analysed polygenic scores (PGSs) for 13 mental health and neurodevelopmental conditions and their composite indices (PC1 and mean) representing general neuropsychiatric liabilities, as well as educational attainment (EA) and alcohol and cigarette use, from children (PGSc), mothers (PGSm), and fathers. Child internalising, externalising, and total difficulties reported by mothers and/or fathers were examined at preschool and school ages. We then conducted multivariate meta-analyses to combine cohort-level results. Findings We observed several direct genetic effects on externalising difficulties, while indirect genetic influences were mainly identified for internalising difficulties. Specifically, child PGSs for attention-deficit/hyperactivity disorder (ADHD) and EA predicted higher and lower levels, respectively, of child externalising and total difficulties (all p FDR<0·001; for school-aged externalising difficulties, PGSc-ADHD: β=0·121 [95% CI 0·091 to 0·151], p FDR<0·0001; PGSc-EA: β=−0·095 [95% CI −0·127 to −0·063], p FDR<0·0001), whereas maternal PGSs for major depressive disorder (MDD) and general neuropsychiatric liabilities were associated with internalising and total difficulties across parental raters and child ages (all p FDR<0·05; for school-aged internalising difficulties, PGSm-MDD: β=0·049 [95% CI 0·017 to 0·081], p FDR=0·016; PGSm-PC1: β=0·056 [95% CI 0·022 to 0·091], p FDR=0·011). No statistically significant effects from paternal PGSs were identified. Interpretation In this multi-cohort study, findings across multiple traits, raters, and ages supported several direct genetic effects of ADHD and EA on child externalising difficulties and indirect genetic effects on internalising difficulties, especially maternal depression and general neuropsychiatric liabilities. These suggest that child internalising difficulties are not solely driven by direct genetic transmission. More comprehensive research is needed to better understand the mechanisms involved, and ultimately how to ameliorate child behavioural difficulties. Funding EU, ERC, RCN, RCF, UKRI, SERI, DFG Evidence before this study Indirect genetic effects (IGEs) refer to the influence of parental genotypes on offspring outcomes beyond direct genetic effects (DGEs), for example via environmental pathways. While IGEs on offspring cognitive traits are well-established for educational attainment, evidence for IGEs of parental liabilities to mental health and neurodevelopmental conditions remains limited. To assess the current state of evidence, we conducted a systematic search of published studies applying trio-based polygenic score (PGS) designs to child and adolescent mental health outcomes. We identified 141 primary studies in MEDLINE, Embase, PsycInfo, and Web of Science, by 6 March 2025, after removing duplicates; following screening, 12 studies met inclusion criteria (see supplement for a full description including results). Ten out of the 12 studies focused on externalising outcomes, with little or inconsistent support for IGEs. When observed, IGEs were mainly driven by maternal liabilities to autism, educational attainment, and cognitive performance on child outcomes. The current evidence was too limited and heterogeneous to synthesize findings quantitatively, therefore a qualitative synthesis was conducted. Many studies were statistically underpowered, and the observed IGEs were in all cases sample-specific. There were no published multi-cohort studies. Added value of this study We integrated information across over 33,000 mother-father-child trios from eight European cohorts, investigating 18 PGSs from parents and children, using maternal and paternal ratings of offspring’s internalising, externalising, and total difficulties as outcomes at both preschool and school age. We mainly observed DGEs on externalising difficulties, consistent with previous studies. Some evidence of IGEs was found for internalising and total difficulties. IGEs were often found to be maternally driven, with the most robust evidence across ages and raters emerging for maternal depression and general neuropsychiatric liabilities. Implications of all the available evidence The current evidence suggests that children’s behavioural difficulties, especially internalising difficulties, may be partly driven by the environment shaped by maternal neuropsychiatric liabilities. Ours and previous findings highlight a pressing need for more comprehensive studies across different cohorts, raters, outcomes, and time points to understand the true extent of IGEs in the intergenerational transmission of mental health. ### Competing Interest Statement O.A.A. is a consultant to CorTechs.ai and Precision Health, and has received speaker's honoraria from BMS, Lundbeck, Lilly, Janssen, Sunovion, and Otsuka, with no conflict of interest relevant to this work. The other authors declare no biomedical financial interests or potentially competing interests. ### Funding Statement This study was funded by the European Union's Horizon Europe Research and Innovation Programme, European Research Council, ERAnet Neuron, Academy of Finland (Council of Finland), Research Council of Norway, South-Eastern Norway Regional Health Authority, Horizon Europe, UK Research and Innovation, Swiss State Secretariat for Education, Research and Innovation, and German Research Foundation ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The PREDO study protocol was approved by the Ethics Committee of Obstetrics and Gynaecology and Women, Children and Psychiatry of the Helsinki and Uusimaa Hospital District and by the participating hospitals. All studies were approved by their institutional ethics review committees and all participants provided written informed consent (see supplement). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Correspondence and requests for materials should be addressed to: jari.lahti{at}helsinki.fi

Antidepressants are widely prescribed for major depressive disorder, yet only one-third of patients achieve remission after initial treatment. Previous genome-wide association studies (GWAS) of clinically assessed antidepressant response combined multiple antidepressant classes, potentially obscuring class-specific effects. This study focused on selective serotonin reuptake inhibitors (SSRIs), often first-line due to better tolerability. Data from 15 cohorts across four ancestries were integrated: European (N = 3887; 11 studies), East Asian (N = 1068; 4), African (N = 277; 1), and Admixed American (N = 250; 1). GWAS of non-remission and percentage improvement were conducted within cohorts, followed by ancestry-specific meta-analyses and trans-ancestry meta-regression. Single nucleotide polymorphism (SNP)-based heritability was estimated in European samples. Polygenic scores were used for leave-one-out prediction and to assess shared genetic architecture with psychiatric traits. Gene-level and gene-set enrichment analyses were also performed. No genome-wide significant variants were identified for either outcome in any ancestry-specific or trans-ancestry analyses. However, trans-ancestry meta-regression yielded eight independent loci with suggestive associations (p < 1 × 10 -5 ) for non-remission and 17 for percentage improvement. Gene-set analyses revealed nominal enrichment of the serotonergic synapse pathway for non-remission. SNP-based heritability estimates were not significantly different from zero for either outcome. Better SSRI response was nominally associated with lower genetic predisposition to major depressive disorder, post-traumatic stress disorder, and schizophrenia. This study represents the largest trans-ancestry GWAS of SSRI response, highlighting emerging biological signals. Limited power emphasises the need for larger and ancestrally diverse cohorts to better characterise the genetic architecture of antidepressant response.

The Developmental Origins of Health and Disease (DOHaD) hypothesis proposes that the perinatal environment shapes susceptibility to complex traits across life [1]. The placenta, a transient organ mediating maternal-fetal exchange, plays a central role in this process and has emerged as a key molecular archive in utero [2-4]. Placental DNA methylation (DNAm) is a unique mediator between prenatal exposures, fetal genetics and later-life outcomes [5-9]. DNAm quantitative trait loci (mQTL) have helped disentangling causal mechanisms underlying GWAS loci for complex diseases [10-15]. Despite growing evidence that placental genomic regulation has broad and profound effects on the developmental programming of early- and later-life health outcomes [17], existing placental studies remain limited in scale and largely focused on growth- and neuro-related traits [12-16]. Here, we construct a high-resolution placental mQTL resource and systematically investigate how placental DNAm relates to early- and later-life traits, and to shared vulnerability and complex interactions among them.

OBJECTIVE:An increasingly compelling body of literature indicates that the glucocorticoid receptor cochaperone FK506-binding protein 51 (FKBP51; encoded by FKBP5) is a promising target for psychiatric therapeutics. Increased mRNA expression of FKBP5 in postmortem brains with psychiatric diagnoses and with aging have been reported previously. The epigenetic mechanisms underlying these effects in the human brain remain largely unknown. METHODS:The authors analyzed previously generated DNA methylation (DNAm) array, single-nucleotide polymorphism genotyping, and bulk RNA-, single-nucleus RNA-, and single-nucleus assay for transposase-accessible chromatin (snATAC)-sequencing data to examine FKBP5 DNAm patterns in postmortem human brain samples from the dorsolateral prefrontal cortex and orbitofrontal cortex of individuals who lived with a major psychiatric disorder (schizophrenia, major depressive disorder, or bipolar disorder) across two independent cohorts (N=378 cases and N=209 controls). RESULTS:Several cytosine-phosphate-guanine dinucleotides (CpGs) were identified across the proximal enhancer of the FKBP5 locus where DNAm was negatively correlated with gene expression, with validation across both cohorts. Data from single-nucleus analyses supported the relevance of these associations across all major cell types. In this functional region, as well as additional sites, associations were observed with age, rs1360780 genotype (CC versus CT/TT), and psychiatric diagnosis. Notably, individuals with schizophrenia exhibited significantly lower DNAm levels in the proximal enhancer region that showed additional converging effects of age and genotype, specifically in glucocorticoid response element-associated CpG sites. CONCLUSIONS:This evidence supports the association of aging and psychiatric diagnosis with changes in FKBP5 DNAm in functionally relevant regulatory elements of the human frontal cortex. This suggests that related changes in FKBP5 mRNA levels may be mediated by these epigenetic mechanisms.

This report provides an overview of the current state of the German twin family panel TwinLife, including information on design and sample characteristics as well as a selection of assessed constructs. TwinLife is a register-based longitudinal panel of four birth cohorts of German-speaking monozygotic and dizygotic same-sex twin pairs, and their core family members, including parents and siblings, but also partners and children of twins, if available. Using address data provided by a representative set of residents' registration offices from across Germany, twin families were identified through a multistage process. The twins were born in 1990-1993, 1997-1998, 2003-2004, and 2009-2010. They were about 5, 11, 17, and 23 years old at the time of the first survey. Designed to investigate the development of social inequalities over the life course, the TwinLife currently covers an observation period from 2014 to 2025. In the first wave, the panel included data on 4096 twin families from all parts of Germany, covering the full range of key socioeconomic indicators. Over the years, the core TwinLife project has been expanded by several satellite projects, such as the molecular genetic TwinSNPs and the TwinLife Epigenetic Change Satellite (TECS) project. TwinLife provides a unique database with a wide-ranging potential for research, since it combines a longitudinal panel with an extended twin family design, adding genetic, epigenetic and additional biological data as well as the possibility to match geographical information.

Stress exposure early in life is an established risk factor for adult psychiatric illness, yet these disorders — including anxiety disorders and depression — show significant sex-dependence in prevalence, symptomatology, and treatment response. The biology underlying these differences remains largely unexplored and may contribute to the clinical heterogeneity in anxiety and depression. Here, we characterize the lasting impact of developmental stress on adulthood neurobiology and behavior in mice by combining analyses of multiple levels of brain function, including whole-brain c-Fos mapping, manganese-enhanced MRI and transcriptomics with advanced behavioral phenotyping. Across levels of investigation, we find distinct and often opposite effects of developmental stress depending on sex. These results together showcase the strong influence of sex on how early life adversity affects the onset of stress-related disorders. This work emphasizes the necessity of considering sex when investigating developmental and neurobiological underpinnings of stress-related disorders and displays a vast range of lasting effects of developmental stress on the brain, which provides a valuable resource for future studies aiming to improve psychiatric treatments. ### Competing Interest Statement The authors have declared no competing interest. Hope for Depression Research Foundation, https://ror.org/01mcwn339 SAME-NeuroID project, 101079181 German Research Foundation (DFG) European Research Council, https://ror.org/0472cxd90, ERC-2021-STG 101042309 Fondazione Cariplo, https://ror.org/01gb56c55, 2020-3632 Airalzh, AGYR2021 Alzheimer's Association, AARG-22-974392 Université Côte d'Azur, https://ror.org/019tgvf94

Environmental exposures influence the risk of psychiatric disorders, yet the biological mechanisms by which such experiences become embedded in brain structure remain poorly understood. The human cerebral cortex is crucial for cognition and emotional regulation, and variation in cortical thickness (CT) and surface area (SA) is linked to various behavioural and psychiatric traits. Here, we present a large-scale epigenome-wide association study that combines peripheral blood DNA methylation (DNAm) with MRI-derived cortical measures in over 7,400 individuals across 20 cohorts within the ENIGMA consortium. We identify mostly non-overlapping DNAm signatures associated with CT and SA, consistent with their distinct developmental and regulatory architectures. CT-associated CpGs are replicated across independent cohorts and are enriched for environmentally responsive regulatory elements and pathways associated with stress, metabolism, and immune signalling. In contrast, SA-associated CpGs cluster within chromatin-regulatory regions involved in early cortical development. Phenome-wide and Mendelian randomisation analyses reveal pleiotropic associations between DNAm, cortical structure, and psychiatric and cognitive traits. These findings suggest that peripheral DNAm captures environmentally sensitive biological processes that link exposure, cortical organisation, and behavioural vulnerability.

The German Twin Family Panel TwinLife is a nationwide longitudinal study of twins and their family members. Primarily focusing on the development of social inequalities over the life course, TwinLife has been collecting data since October 2014 starting with 4,096 twin families ( N total = 16,951 individuals). As Germany’s largest twin study to date, TwinLife has been surveying four birth cohorts of monozygotic and dizygotic same-sex twin pairs (initially ∼5, 11, 17, and 23 years old) and their families for 11 years. Survey data have been collected through five biennial face-to-face interviews with four computer-assisted telephone interviews in the years between. In addition, saliva samples were collected before the COVID-19 pandemic (2018-2020), during the pandemic (2021), and after (2022-2024). In this Cohort Profile, we describe the curation and initial analyses of molecular genetic and epigenetic data from the two TwinLife satellite projects TwinSNPs and TECS. Together, these projects currently comprise 12,108 processed DNA samples from 6,450 participants, extracted from the first two saliva collections before and during the COVID-19 pandemic. We compared the subsamples with the overall TwinLife sample and provide an overview of derived polygenic scores (PGS), epigenetic clocks and other methylation profile scores (MPS). We found that PGS predicted sample attrition in TwinLife, with small but significant associations between higher PGS for educational attainment and continued participation. Epigenetic clocks derived from saliva were highly correlated with chronological age ( r = .71 to r = .94) and were generally more stable over time than other MPS. PGS for epigenetic clocks were associated with the respective clock only during but not before the start of the pandemic. We discuss opportunities of combining prospectively assessed molecular (epi)genetic data in within-family designs such as TwinLife and its implications and avenues for future research.

The major anxiety disorders (ANX; including generalized anxiety disorder, panic disorder and phobias) are highly prevalent, often onset early and cause substantial global disability. Although distinct in their clinical presentations, they probably represent differential expressions of a dysregulated threat-response system. Here, we present a genome-wide association meta-analysis comprising 122,341 European ancestry ANX cases and 729,881 controls. We identified 58 independent genome-wide significant risk variants and 66 genes with robust biological support. In an independent sample of 1,175,012 self-report ANX cases and 1,956,379 controls, 51 out of the 58 associations replicated. As predicted by twin studies, we found substantial genetic correlation between ANX and depression, neuroticism and other internalizing phenotypes. Follow-up analyses demonstrated enrichment in all major brain regions and highlighted GABAergic signaling as one potential mechanism implicated in ANX genetic risk. These results advance our understanding of the genetic architecture of ANX and prioritize genes for functional follow-up studies.

Breastfeeding is associated with short- and long-term beneficial effects on child health, including greater cognitive development, and enhanced immune programming. However, the underlying biological mechanisms are only partially understood, with epigenetics emerging as a potential contributor. In this study, we aimed to investigate whether breastfeeding practices are associated with differential DNA methylation (DNAm) in childhood blood. We conducted meta-analyses of epigenome-wide association studies (meta-EWASs) in 3421 children from eleven international population-based birth cohorts from the Pregnancy And Childhood Epigenetics (PACE) Consortium. Breastfeeding was assessed as “ever” being breastfed vs. “never”, and duration of any and exclusive breastfeeding. DNAm was measured in childhood blood (ages 5–12 years) using the Illumina 450 K or EPIC arrays, with cord blood at birth used as negative outcome control. At False Discovery Rate (FDR) < 5

BACKGROUND:FKBP5 (FK506-binding protein 51, protein), encoded by the FKBP5 (gene, human), is a glucocorticoid receptor-regulating cochaperone. FKBP5 has been suggested as a mediator between stress, vascular morbidity, and neuropsychiatric complications. In this translational proof-of-concept study, we investigated the impact of FKBP5 on stroke outcome in mice and men. METHODS:Fkbp5 (gene, mouse) knockout and wild-type mice were subjected to transient brain ischemia. Lesion volume was assessed at 48 hours after stroke using magnetic resonance imaging. Circulating corticosterone level and adrenal gland weight were determined at 72 hours. Observational data from the Prospective Cohort with Incident Stroke Berlin were used to explore associations between FKBP5 gene variants and functional outcome after 1 year. Poor functional outcome at 1 year was defined as a modified Rankin Scale score of 0 to 1 versus 2 to 6. Risk allele ACT from a predefined FKBP5 haplotype (rs9296158, rs3800373, rs1360780) versus non-ACT was used as the exposure variable. Logistic regression analyses were performed and adjusted for potential confounders. RESULTS:Fkbp5 knockout mice showed reduced corticosterone levels and adrenal weights, together with smaller infarct lesions at 48 hours. Four hundred thirty-three patients with available FKBP5 haplotype were included in the Berlin stroke cohort. FKBP5 risk haplotype ACT, which was present in 204 patients, was associated with poor functional outcome at 1 year (adjusted odds ratio, 1.7 [95% CI, 1.02-2.7]). CONCLUSIONS:Loss of Fkbp5 leads to improved outcome in experimental stroke. In addition, the FKBP5 risk haplotype, indicative of increased FKBP5 expression, was associated with poor functional outcome following stroke.