Risk factors for parental psychopathology: a study in families with children or adolescents with psychopathology.

The parents of children with psychopathology are at increased risk for psychiatric symptoms. To investigate which parents are mostly at risk, we assessed in a clinical sample of families with children with psychopathology, whether parental symptom scores can be predicted by offspring psychiatric diagnoses and other child, parent and family characteristics. Parental depressive, anxiety, avoidant personality, attention-deficit/hyperactivity (ADHD), and antisocial personality symptoms were measured with the Adult Self Report in 1805 mothers and 1361 fathers of 1866 children with a psychiatric diagnosis as assessed in a child and adolescent psychiatric outpatient clinic. In a multivariate model, including all parental symptom scores as outcome variables, all offspring psychiatric diagnoses, offspring comorbidity and age, parental age, parental educational attainment, employment, and relationship status were simultaneously tested as predictors. Both 35.7% of mothers and 32.8% of fathers scored (sub)clinical for at least one symptom domain, mainly depressive symptoms, ADHD symptoms or, only in fathers, avoidant personality symptoms. Parental psychiatric symptoms were predicted by unemployment. Parental depressive and ADHD symptoms were further predicted by offspring depression and offspring ADHD, respectively, as well as by not living together with the other parent. Finally, parental avoidant personality symptoms were also predicted by offspring autism spectrum disorders. In families with children referred to child and adolescent psychiatric outpatient clinics, parental symptom scores are associated with adverse circumstances and with similar psychopathology in their offspring. This signifies, without implying causality, that some families are particularly vulnerable, with multiple family members affected and living in adverse circumstances.

Childhood intelligence is heritable, highly polygenic and associated with FNBP1L.

Intelligence in childhood, as measured by psychometric cognitive tests, is a strong predictor of many important life outcomes, including educational attainment, income, health and lifespan. Results from twin, family and adoption studies are consistent with general intelligence being highly heritable and genetically stable throughout the life course. No robustly associated genetic loci or variants for childhood intelligence have been reported. Here, we report the first genome-wide association study (GWAS) on childhood intelligence (age range 6-18 years) from 17,989 individuals in six discovery and three replication samples. Although no individual single-nucleotide polymorphisms (SNPs) were detected with genome-wide significance, we show that the aggregate effects of common SNPs explain 22-46% of phenotypic variation in childhood intelligence in the three largest cohorts (P=3.9 × 10(-15), 0.014 and 0.028). FNBP1L, previously reported to be the most significantly associated gene for adult intelligence, was also significantly associated with childhood intelligence (P=0.003). Polygenic prediction analyses resulted in a significant correlation between predictor and outcome in all replication cohorts. The proportion of childhood intelligence explained by the predictor reached 1.2% (P=6 × 10(-5)), 3.5% (P=10(-3)) and 0.5% (P=6 × 10(-5)) in three independent validation cohorts. Given the sample sizes, these genetic prediction results are consistent with expectations if the genetic architecture of childhood intelligence is like that of body mass index or height. Our study provides molecular support for the heritability and polygenic nature of childhood intelligence. Larger sample sizes will be required to detect individual variants with genome-wide significance.

Trajectories of maternal depressive symptoms predict child problem behaviour: the Generation R study.

BACKGROUND: It is unclear how the course of maternal depressive symptoms affects child development. We modelled trajectories of maternal depressive symptoms from mid-pregnancy to 3 years after childbirth to better determine their associations with child problem behaviour. METHOD: Mother-child dyads (n = 4167) participated in a population-based prospective cohort in The Netherlands. Depressive symptoms were assessed with the Brief Symptom Inventory during pregnancy and at 2, 6 and 36 months postnatally. When children were 3 years old, problem behaviour was assessed with the Child Behaviour Checklist completed by each parent. A group-based modelling technique was used to model trajectories of maternal depressive symptoms and to examine their association with child problem behaviour. The added value of trajectory modelling was determined with successive linear regressions. RESULTS: We identified four trajectories of maternal depressive symptoms; 'no' (34%), 'low' (54%), 'moderate' (11%) and 'high' (1.5%). Child problem behaviour varied as a function of maternal trajectory membership. Whether rated by mother or father, children of mothers assigned to higher trajectories had significantly more problem behaviours than children of mothers assigned to lower trajectories. The model including trajectories had additive predictive value over a model relying only on a summed repeated measure of severity and a predefined chronicity variable. CONCLUSIONS: Depending on their course, maternal depressive symptoms have different effects on child problem behaviour. More information is gained by studying trajectories of symptoms, than only predefined measures of severity and chronicity. Moreover, trajectories can help identifying clinically depressed mothers who are possible candidates for early interventions.

Identification and functional characterization of three novel alleles for the serotonin transporter-linked polymorphic region.

A promoter polymorphism in the serotonin transporter gene (5-HTTLPR) has been reported to confer relative risk for phenotypes (depression/anxiety) and endophenotypes (amygdala reactivity). In this report, we identify and characterize three rare 5-HTTLPR alleles not previously described in the human literature. The three novel alleles were identified while genotyping 5-HTTLPR in a family-based attention deficit hyperactivity disorder clinical population. Two of the novel alleles are longer than the common 16-repeat long (L) allele (17 and 18 repeats) and the third is significantly smaller than the 14-repeat short (S) allele (11 repeats). The sequence and genetic architecture of each novel allele is described in detail. We report a significant decrease in the expression between the XL17 (17r) allele and the L(A) (16r) allele. The XS11 (11r) allele showed similar expression with the S (14r) allele. A 1.8-fold increase in expression was observed with the L(A)(16r) allele compared with the L(G) (16r) allele, which replicates results from earlier 5-HTTLPR expression experiments. In addition, transcription factor binding site (TFBS) analysis was performed using MatInspector (Genomatix) that showed the presence or absence of different putative TFBSs between the novel alleles and the common L (16r) and S (14r) alleles. The identification of rare variants and elucidation of their functional impact could potentially lead to understanding the contribution that the rare variant may have on the inheritance/susceptibility of multifactorial common diseases.

Berberine and evodiamine influence serotonin transporter (5-HTT) expression via the 5-HTT-linked polymorphic region.

The aim of this study was to investigate the effect of berberine and evodiamine on serotonin transporter (5-HTT) expression and then test how allelic variations previously identified in the promoter region could modulate that effect in the serotonergic neuronal cell line RN46A. Both berberine and evodiamine, alone and in combination, increased 5-HTT mRNA and protein expression significantly across the various alleles. When tested against the S, XS(11), L(G), L(A), XL(17), and XL(18) alleles, respectively, 100 µM berberine increased 5-HTT promoter activities by 67%, 128.7%, 106.9%, 100.4%, 26.2% and 82%, 2 µM evodiamine increased 5-HTT promoter activities by 216.7%, 81.6%, 305.6%, 181.5%, 175.3% and 102.2%. Berberine and evodiamine increased 5-HTT promoter activity differently depending on the genetic variation of the 5-HTTLPR polymorphism. This study has provided a convincing example of how herbal compounds influence the expression of one of the most intensively studied psychiatric candidate genes, the serotonin transporter.

Spousal resemblance in psychopathology: A comparison of parents of children with and without psychopathology.

BACKGROUND: Spouses resemble each other for psychopathology, but data regarding spousal resemblance in externalizing psychopathology, and data regarding spousal resemblance across different syndromes (e.g. anxiety in wives and attention deficit/hyperactivity disorder [ADHD] in husbands) are limited. Moreover, knowledge is lacking regarding spousal resemblance in parents of children with psychiatric disorders. We investigated and compared spousal resemblance within and across internalizing and externalizing symptom domains in parents of children with and without psychopathology. METHODS: Symptoms of depression, anxiety, avoidant personality, ADHD, and antisocial personality were assessed with the Adult Self Report in 728 mothers and 544 fathers of 778 children seen in child and adolescent psychiatric outpatient clinics and in 2075 mothers and 1623 fathers of 2784 children from a population-based sample. Differences in symptom scores and spousal correlations between the samples were tested. RESULTS: Parents in the clinical sample had higher symptom scores than in the population-based sample. In both samples, correlations within and across internalizing and externalizing domains of psychopathology were significant. Importantly, correlations were significantly higher in the clinical sample (P=0.03). Correlations, within and across symptoms, ranged from 0.14 to 0.30 in the clinical sample and from 0.05 to 0.23 in the population-based sample. CONCLUSIONS: This large study shows that spousal resemblance is not only present within but also across symptom domains. Especially in the clinical sample, ADHD symptoms in fathers and antisocial personality symptoms in mothers were correlated with a range of psychiatric symptoms in their spouses. Clinicians need to be alert of these multiple affected families.

How to early recognize mood disorders in primary care: A nationwide, population-based, cohort study.

BACKGROUND: Mood disorders are managed predominantly in primary care. However, general practitioners' (GPs) ability to detect and diagnose patients with mood disorders is still considered unsatisfactory. The aim of the present study was to identify predictors for the early recognition of depressive disorder (DD) and bipolar disorder (BD) in general practice. METHODS: A cohort of 1,144,622 patients (605,285 women, 539,337 men) was investigated, using the Health Search IMS Health Longitudinal Patient Database. Predictors of DD or BD were identified at baseline encompassing somatization-related features, lifestyle variables, medical and psychiatric comorbidities. Patients were followed up as long as the following events occurred: diagnoses of DD or BD, death, end of the registration with the GP, end of the study period. RESULTS: We found an incidence rate of DD or BD of 53.61 and 1.5 per 10,000 person-years, respectively. For both the conditions, the incidence rate grew with age. Most of the lifestyle variables and medical comorbidities increased the risk of mood disorders. The strongest effect was found for migraine/headache (HR [95% CI]=1.32 [1.26-1.38]), fatigue (1.32 [1.25-1.39]) irritable bowel syndrome (1.15 [1.08-1.23]), and pelvic inflammation disease (1.28 [1.18-1.38]). CONCLUSIONS: Several predictors, in particular somatic symptoms, could be interpreted as an early sign of a mood disorder, and represent a valid indication for the GPs diagnostic process of mental disorders.

Genetic and environmental influences on Anxious/Depression during childhood: a study from the Netherlands Twin Register.

For a large sample of twin pairs from the Netherlands Twins Register who were recruited at birth and followed through childhood, we obtained parental ratings of Anxious/Depression (A/D). Maternal ratings were obtained at ages 3 years (for 9025 twin pairs), 5 years (9222 pairs), 7 years (7331 pairs), 10 years (4430 pairs) and 12 years (2363 pairs). For 60-90% of the pairs, father ratings were also available. Multivariate genetic models were used to test for rater-independent and rater-specific assessments of A/D and to determine the genetic and environmental influences on individual differences in A/D at different ages. At all ages, monozygotic twins resembled each other more closely for A/D than dizygotic twins, implying genetic influences on variation in A/D. Opposite sex twin pairs resembled each other to same extent as same-sex dizygotic twins, suggesting that the same genes are expressed in boys and girls. Heritability estimates for rater-independent A/D were high in 3-year olds (76%) and decreased in size as children grew up [60% at age 5, 67% at age 7, 53% at age 10 (60% in boys) and 48% at age 12 years]. The decrease in genetic influences was accompanied by an increase in the influence of the shared family environment [absent at ages 3 and 7, 16% at age 5, 20% at age 10 (5% in boys) and 18% at age 12 years]. The agreement between parental A/D ratings was between 0.5 and 0.7, with somewhat higher correlations for the youngest group. Disagreement in ratings between the parents was not merely the result of unreliability or rater bias. Both the parents provided unique information from their own perspective on the behavior of their children. Significant influences of genetic and shared environmental factors were found for the unique parental views. At all ages, the contribution of shared environmental factors to variation in rater-specific views was higher for father ratings. Also, at all ages except age 12, the heritability estimates for the rater-specific phenotype were higher for mother ratings (59% at age 3 and decreasing to 27% at age 12 years) than for father ratings (between 14 and 29%). Differences between children, even as young as 3 years, in A/D are to a large extent due to genetic differences. As children grow up, the variation in A/D is due in equal parts to genetic and environmental influences. Anxious/Depression, unlike many other common childhood psychopathologies, is influenced by the shared family environment. These findings may provide support for why certain family therapeutic approaches are effective in the A/D spectrum of illnesses.

Regular exercise behaviour in youth is not related to current body mass index or body mass index at 7-year follow-up.

OBJECTIVE: This population-based study aimed (1) to test the presence of an association between regular voluntary exercise behaviour (EB) that is performed in leisure time and body mass index (BMI) in youth and (2) to investigate the causal nature of this association using a longitudinal design in genetically informative subjects. DESIGN AND METHODS: Both EB and BMI were assessed repeatedly over time in 21 458 twin individuals from the Netherlands Twin Register (47.5% male) - first by parental report (ages 7, 10 and 12) and subsequently through self-report surveys (ages 14, 16 and 18). EB was quantified as weekly metabolic equivalent of task hours. RESULTS: Correlations over time were higher for BMI than for EB (r ≈ 0.70 vs. r ≈ 0.35) across 12 different follow-up periods. Cross-sectionally, regular involvement in EB was not associated with lower BMI in childhood and in genetically identical twin pairs discordant for EB; the exercising twin did not have a lower BMI than the non-exercising twin. Longitudinally, linear and quadratic relationships between EB and BMI were non-significant. Changes in EB over time did not induce opposite changes in BMI. CONCLUSIONS: No consistent association between regular EB and BMI was observed from ages 7 to 18 years.

Clinical study of the relation of borderline personality disorder to Briquet's syndrome (hysteria), somatization disorder, antisocial personality disorder, and substance abuse disorders.

OBJECTIVE: The criteria for borderline personality disorder seem to select patients with very high rates of Briquet's syndrome (hysteria), somatization disorder, antisocial personality disorder, and substance abuse disorders. This study was undertaken to determine whether systematic assessment of patients with borderline personality disorder would reveal characteristic features of that condition which would distinguish it from these other disorders. METHOD: Eighty-seven white female patients (75 in St. Louis and 12 in Milan, Italy) who had borderline personality disorder according to both the DSM-III-R criteria and the Revised Diagnostic Interview for Borderlines were further examined with the DSM-III-R Checklist and the Perley-Guze Hysteria Checklist to determine their patterns of psychiatric comorbidity. RESULTS: Every patient had at least one additional DSM diagnosis. Patients in St. Louis and Milan averaged five and four additional diagnoses, respectively. Eighty-four percent of the patients in St. Louis met criteria for either somatization disorder, Briquet's syndrome, antisocial personality disorder, or substance abuse disorders. Patterns of comorbidity for panic (51%), generalized anxiety disorder (55%), and major depression (87%) in St. Louis were consistent with those in other studies. CONCLUSIONS: The data indicate that the boundaries for the borderline condition are not specific and identify a high percentage of patients with these other disorders. Furthermore, the comorbidity profiles closely resemble the psychiatric profiles of patients with these disorders. If the borderline syndrome is meant to include all of these disorders, its usefulness as a diagnosis is limited. Until the fundamental features of borderline personality disorder that distinguish it from the others are identified, it is recommended that clinicians carefully assess patients for these other diagnoses. Efforts should be made to change the borderline personality disorder criteria by shifting away from overlap with the criteria for the other disorders.

Familiality and heritability of subtypes of attention deficit hyperactivity disorder in a population sample of adolescent female twins.

OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is a highly heritable but clinically heterogeneous syndrome. The study examined the familiality and heritability of ADHD subtypes as defined by DSM-IV and by latent-class analysis in a population sample of adolescent female twins. METHOD: To determine which elements of ADHD cluster together, latent-class analysis was applied to data obtained from parents on the 18 DSM-IV ADHD symptoms in 4,036 female twins age 13-23 years in a population sample identified from the registry of all births in Missouri for the years 1968-1996. Relative risk and odds ratios were used to assess within-subtype and between-subtype familiality and heritability of both DSM-IV and latent-class ADHD subtypes. RESULTS: Latent-class analysis was most compatible with the existence of three mild and three severe classes of ADHD symptoms in the general population. The three severe classes showed moderate overlap with DSM-IV ADHD subtypes. The primarily inattentive and combined subtypes of DSM-IV ADHD co-clustered within families. The primarily hyperactive/impulsive DSM-IV subtype and the individual latent-class analysis subtypes did not co-cluster. Subtypes defined by both approaches were highly heritable. CONCLUSIONS: Unlike DSM-IV subtypes of ADHD, latent-class ADHD subtypes appear to be independently transmitted in families. These classes may be more appropriate targets for molecular genetic studies of ADHD.

A twin study of inattentive, aggressive, and anxious/depressed behaviors.

OBJECTIVE: To estimate genetic, environmental, and rater contrast influences on parental report of Attention Problems (AP), Aggressive (Agg), and Anxious/Depressed (AxD) behaviors of 492 twin pairs assessed with the Child Behavior Checklist. METHOD: A parent (92% mothers) of twins aged 8 to 12 years completed the Child Behavior Checklist. Genetic, shared and unique environmental, and rater bias effects were estimated for the AP, Agg, and AxD syndromes. Data on boys and girls were analyzed separately. Results were compared to prior research on related DSM disorders. RESULTS: Estimates of genetic influences on AP (60%-68%), Agg (70%-77%), and AxD (61%-65%) were high for both sexes, but lower for AP than prior findings using DSM attention-deficit hyperactivity disorder (ADHD). However, unlike equivalent analyses of DSM ADHD based on parental report, there was no evidence of rater bias. CONCLUSIONS: Estimates of genetic influence on these common child psychopathological domains were high. There was no evidence of rater contrast effects. These findings have implications for diagnosis, particularly when assessing families with multiple children.

Latent class analysis of Child Behavior Checklist attention problems.

OBJECTIVE: To test whether attention problems in children are continuously distributed or categorically discrete, the authors performed latent class analyses (LCA) of items from the Attention Problems scale of the Child Behavior Checklist (CBCL) using data from the clinical and nonclinical samples used in the derivation of the CBCL syndromes. METHOD: A CBCL was completed by a parent or guardian of each of 2,100 nonreferred children selected to be representative of U.S. nonreferred children and a demographically matched sample of 2,100 clinically referred children. Attention problems symptoms were subjected to LCA. RESULTS: LCAs were consistent with the presence of 3 levels of symptom presentation in both samples. Children in the nonclinical sample were classified as having no symptoms, mild symptoms, or moderate symptoms. Children in the clinical group had mild, moderate, or severe symptoms. CONCLUSIONS: These results suggest that child and adolescent psychiatric symptoms such as attention problems can be thought of as continuously distributed phenomena rather than discrete disease entities, lending support for an empirical approach to both clinical work and research. In addition, high prevalence rates of attention problems in both clinical and nonclinical samples suggest the need for careful screening of attention problems in clinic and academic settings.

Latent class analysis of child behavior checklist anxiety/depression in children and adolescents.

OBJECTIVE: Comorbidity of psychiatric problems such as anxiety and depression poses challenges to treatment and research. This study tested whether problem items from the Anxious/Depressed scale of the Child Behavior Checklist (CBCL) can be separated into distinct anxiety and depression classes or are continuously distributed throughout a population. METHOD: A CBCL was completed by a parent or guardian of each of 1,987 children and adolescents selected to represent nonreferred children in the United States, as well as by a parent or guardian of each of a demographically matched sample of 1,987 clinically referred children and adolescents. Problem items from the Anxious/Depressed scale of the CBCL were subjected to latent class analysis. RESULTS: Analyses revealed three levels of problem presentation in both samples. Children in the nonreferred sample were classified as having no problems, mild problems, or moderate anxiety/depression problems. Children and adolescents in the referred group were classified as having mild, moderate, or severe levels of problems. No pure anxiety or depression classes were found, only classes containing a mixture of both anxiety and depressive problems. Age, gender, and sample differences were found in class groupings, with nonreferred adolescent girls showing elevated levels of problems. CONCLUSIONS: Results suggest that the comorbid conditions of anxiety and depression, as assessed by the CBCL anxiety/depression problem items, can be thought of as part of the same continuum of problems. Implications for assessment and treatment utilization are discussed.

Latent class and factor analysis of DSM-IV ADHD: a twin study of female adolescents.

OBJECTIVE: In an attempt to validate the current DSM-IV criteria for attention-deficit/hyperactivity disorder (ADHD) in females and to determine whether symptoms are continuously distributed or categorically discrete, the authors performed factor and latent class analysis on ADHD symptom data from a large general population of adolescent female twins (1,629 pairs). METHOD: A structured diagnostic assessment of DSM-IV ADHD was completed with at least one parent of 1,629 pairs by telephone. ADHD symptoms from 1,549 pairs were subjected to latent class and factor analysis. RESULTS: Latent class and factor analyses were consistent with the presence of separate continuous domains of inattention (ATT), hyperactivity-impulsivity (H-I), and combined ATT with H-I problems. Severe latent classes corresponding to the predominantly inattentive, predominantly hyperactive-impulsive, and combined types were identified with lifetime prevalence estimates of 4.0%, 2.2%, and 3.7%, respectively. Membership in the severe ATT class predicted academic problems, family problems, and referral to health care providers. Membership in the H-I and combined classes also predicted impaired social relationships. CONCLUSIONS: These results suggest that DSM-IV ADHD subtypes can be thought of as existing on separate continua of inattention, hyperactivity-impulsivity, and combined type problems. Membership in any of there severe ADHD latent classes did not preclude academic excellence, but it was associated with different types of impairment and health care-seeking behavior. These data have implications in the areas of diagnosis, classification, treatment, and research.

Evaluation of ADHD typology in three contrasting samples: a latent class approach.

OBJECTIVE: To identify subtypes of attention-deficit/hyperactivity disorder (ADHD) and characterize them as either categorical or continuous; to investigate familial resemblance for ADHD among sibling pairs; and to test the robustness of all results by using contrasting data sets. METHOD: Latent class analysis was applied to the ADHD symptom profiles obtained from parents or best informant about their offspring in 3 samples: a population-based set of female adolescent twins (724 monozygotic pairs, 594 dizygotic pairs) and male (N = 425) and female (N = 430) child and adolescent offspring ascertained from high-risk alcoholic families. RESULTS: Latent class analysis revealed 2 categories of clinically significant ADHD which were replicated in all 3 study groups: a subtype with high endorsements of ADHD inattention symptoms and a second combined type with high endorsements of both inattention and hyperactivity-impulsivity items. Both appeared to be continuous across all 3 data groups. The high-risk families contained a class in which members heavily endorsed the ADHD "fidget" item but not other ADHD items. A large proportion of the monozygotic sibs (80%) versus a smaller proportion of dizygotic sibs (52%) were assigned to the same latent class. Among the high-risk children and adolescents, 51% of the female and 41% of the male siblings were concordant for class membership. CONCLUSIONS: The pattern of latent classes suggested that ADHD consists of an inattentive and a combined subtype, within each of which lies a dimensional domain. These analyses further support that genetic factors are significant determinants of latent class membership.

Genetic and environmental mechanisms underlying stability and change in problem behaviors at ages 3, 7, 10, and 12.

Maternal ratings on internalizing (INT) and externalizing (EXT) behaviors were collected in a large, population-based longitudinal sample. The numbers of participating twin pairs at ages 3, 7, 10, and 12 were 5,602, 5,115, 2,956, and 1,481, respectively. Stability in both behaviors was accounted for by genetic and shared environmental influences. The genetic contribution to stability (INT: 43%; EXT: 60%) resulted from the fact that a subset of genes expressed at an earlier age was still active at the next time point. A common set of shared environmental factors operated at all ages (INT: 47%; EXT: 34%). The modest contribution of nonshared environmental factors (INT: 10%; EXT: 6%) could not be captured by a simple model. Significant age-specific influences were found for all components, indicating that genetic and environmental factors also contributed to changes in problem behavior.

The role of phenotypes (diagnoses) in genetic studies of attention-deficit/hyperactivity disorder and related child psychopathology.

The new medical genetics and its molecular, population, and statistical techniques offer a cadre of tools that will improve the child psychiatrist's ability to diagnose and treat children who exhibit emotional and behavioral disorders. To take advantage of these remarkable advances, child psychiatry must enhance the likelihood that scientific expeditions into gene discovery are informed by a taxonomy that meets the criteria of a genetic nosology. As the taxonomic approach is refined, there may be more success in identifying genetic and environmental risks for attention-deficit/hyperactivity disorder (ADHD).

Glucocorticoid receptor gene (NR3C1) methylation following stressful events between birth and adolescence. The TRAILS study.

Stress early in life is a known risk factor for the development of affective disorders later in life. Epigenetic mechanisms, such as DNA methylation, may have an important role in mediating that risk. Recent epigenetic research reported on the long-term relationship between traumatic stress in childhood and DNA methylation in adulthood. In this study, we examined the impact of various types of stress (perinatal stress, stressful life events (SLEs) and traumatic youth experiences) on methylation of the glucocorticoid receptor gene (NR3C1) in the blood of a population sample of 468 adolescents (50.4% female, mean age 16.1 years). Second, we determined whether stress at different ages was associated with higher NR3C1 methylation. NR3C1 methylation rates were higher after exposure to SLEs and after exposure to traumatic youth experiences. NR3C1 methylation in adolescence was not higher after exposure to perinatal stress. Experience of SLEs in adolescence was associated with a higher NR3C1 methylation, independently of childhood SLEs. We demonstrate that not only traumatic youth experiences but also (more common) SLEs are associated with higher NR3C1 methylation. In addition, our findings underline the relevance of adolescent stress for epigenetic changes in the NR3C1 gene.