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Previous studies have suggested that processing of visual contrast information could be altered in major depressive disorder. To clarify the changes at different levels of the visual hierarchy, we behaviourally measured contrast perception in 2 centre-surround conditions, assessing retinal and cortical processing. As part of a prospective cohort study, our sample consisted of controls (n = 29; 21 female) and patients with unipolar depression, bipolar disorder and borderline personality disorder who had baseline major depressive episodes (n = 111; 74 female). In a brightness induction test that assessed retinal processing, participants compared the perceived luminance of uniform patches (presented on a computer screen) as the luminance of the backgrounds was varied. In a contrast suppression test that assessed cortical processing, participants compared the perceived contrast of gratings, which were presented with collinearly or orthogonally oriented backgrounds. Brightness induction was similar for patients with major depressive episodes and controls (p = 0.60, d = 0.115, Bayes factor = 3.9), but contrast suppression was significantly lower for patients than for controls (p < 0.006, d = 0.663, Bayes factor = 35.2). We observed no statistically significant associations between contrast suppression and age, sex, or medication or diagnostic subgroup. At follow-up (n = 74), we observed some normalization of contrast perception. We assessed contrast perception using behavioural tests instead of electrophysiology. The reduced contrast suppression we observed may have been caused by decreased retinal feedforward or cortical feedback signals. Because we observed intact brightness induction, our results suggest normal retinal but altered cortical processing of visual contrast during a major depressive episode. This alteration is likely to be present in multiple types of depression and to partially normalize upon remission.

Early life stress (ELS) may increase the risk of anxiety throughout the life course. Whether this effect extends to late adulthood is poorly known. In our study comprising 1872 participants from the Helsinki Birth Cohort Study born in 1934–1944, we investigated the association of various forms of ELS and their accumulation with self-reported anxiety symptoms at the age of 65–77 years. Data on childhood socioeconomic status and separation from parents were based on national registers for all participants. Information on self-reported emotional and physical trauma, parental divorce, and death of a family member in childhood was obtained from 1277 participants. We found that experiencing emotional trauma, physical trauma, and low socioeconomic status in childhood were associated with increased anxiety symptoms in late adulthood [B = 0.44 (95% CI = 0.31–0.58); B = 0.33 (95% CI = 0.20–0.46); B = 0.10 (95% CI = 0.01–0.19), respectively]. These associations remained significant even after controlling for other forms of ELS. Accumulation of early life stress also increased the levels of late-adulthood anxiety symptoms and the risk of anxiety regarded as clinically significant. Screening for potentially stressful childhood experiences in elderly populations may help identifying individuals with increased anxiety symptoms and planning preventive and therapeutic interventions for those exposed to ELS.

Maternal depressive symptoms during pregnancy have been associated with child behavioural symptoms of attention-deficit/hyperactivity disorder (ADHD) in early childhood. However, it remains unclear if depressive symptoms throughout pregnancy are more harmful to the child than depressive symptoms only during certain times, and if maternal depressive symptoms after pregnancy add to or mediate any prenatal effects. 1,779 mother-child dyads participated in the Prediction and Prevention of Pre-eclampsia and Intrauterine Growth Restriction (PREDO) study. Mothers filled in the Center of Epidemiological Studies Depression Scale biweekly from 12+0-13+6 to 38+0-39+6 weeks+days of gestation or delivery, and the Beck Depression Inventory-II and the Conners' Hyperactivity Index at the child's age of 3 to 6 years (mean 3.8 years, standard deviation [SD] 0.5). Maternal depressive symptoms were highly stable throughout pregnancy, and children of mothers with consistently high depressive symptoms showed higher average levels (mean difference = 0.46 SD units, 95% Confidence Interval [CI] 0.36, 0.56, p < 0.001 compared to the low group), and proportion (32.1% vs. 14.7%) and odds (odds ratio = 2.80, 95% CI 2.20, 3.57, p < 0.001) of clinically significant ADHD symptoms. These associations were not explained by the effects of maternal depressive symptoms after pregnancy, which both added to and partially mediated the prenatal effects. Maternal depressive symptoms throughout pregnancy are associated with increased ADHD symptomatology in young children. Maternal depressive symptoms after pregnancy add to, but only partially mediate, the prenatal effects. Preventive interventions suited for the pregnancy period may benefit both maternal and offspring mental health.

BackgroundSocial isolation and loneliness have been associated with increased risk of dementia, but it is not known whether this risk is modified or confounded by genetic risk of dementia.MethodsWe used the prospective UK Biobank study with 155 070 participants (mean age 64.1 years), including self-reported social isolation and loneliness. Genetic risk was indicated using the polygenic risk score for Alzheimer’s disease and the incident dementia ascertained using electronic health records.ResultsOverall, 8.6% of participants reported that they were socially isolated and 5.5% were lonely. During a mean follow-up of 8.8 years (1.36 million person years), 1444 (0.9% of the total sample) were diagnosed with dementia. Social isolation, but not loneliness, was associated with increased risk of dementia (HR 1.62, 95% CI 1.38 to 1.90). There were no interaction effects between genetic risk and social isolation or between genetic risk and loneliness predicting incident dementia. Of the participants who were socially isolated and had high genetic risk, 4.4% (95% CI 3.4% to 5.5%) were estimated to developed dementia compared with 2.9% (95% CI 2.6% to 3.2%) of those who were not socially isolated but had high genetic risk. Comparable differences were also in those with intermediate and low genetic risk levels.ConclusionsSocially isolated individuals are at increased risk of dementia at all levels of genetic risk.

Background Gestational age is often used as a proxy for developmental maturity by clinicians and researchers alike. DNA methylation has previously been shown to be associated with age and has been used to accurately estimate chronological age in children and adults. In the current study, we examine whether DNA methylation in cord blood can be used to estimate gestational age at birth. Results We find that gestational age can be accurately estimated from DNA methylation of neonatal cord blood and blood spot samples. We calculate a DNA methylation gestational age using 148 CpG sites selected through elastic net regression in six training datasets. We evaluate predictive accuracy in nine testing datasets and find that the accuracy of the DNA methylation gestational age is consistent with that of gestational age estimates based on established methods, such as ultrasound. We also find that an increased DNA methylation gestational age relative to clinical gestational age is associated with birthweight independent of gestational age, sex, and ancestry. Conclusions DNA methylation can be used to accurately estimate gestational age at or near birth and may provide additional information relevant to developmental stage. Further studies of this predictor are warranted to determine its utility in clinical settings and for research purposes. When clinical estimates are available this measure may increase accuracy in the testing of hypotheses related to developmental age and other early life circumstances.

Maternal prenatal anxiety is an important risk factor for altered child neurodevelopment but there is uncertainty concerning the biological mechanisms involved and sources of individual differences in children's responses. We sought to determine the role of functional genetic variation in COMT, which encodes catechol-O-methyltransferase, in the association between maternal prenatal anxiety and child symptoms of ADHD and working memory. We used the prospectively-designed ALSPAC cohort (n = 6,969) for our primary data analyses followed by replication analyses in the PREDO cohort (n = 425). Maternal prenatal anxiety was based on self-report measures; child symptoms of ADHD were collected from 4-15 years of age; working memory was assessed from in-person testing at age 8 years; and genetic variation in COMT at rs4680 was determined in both mothers and children. The association between maternal prenatal anxiety and child attention/hyperactivity symptoms and working memory was moderated by the child's rs4680 genotype, with stronger effects obtained for the val/val (G:G) genotype relative to val/met (A:G) (all p<0.01) and met/met (A:A) groups (all p<0.05). Similar findings were observed in the PREDO cohort where maternal prenatal anxiety interacted with child rs4680 to predict symptoms of ADHD at 3.5 years of age. The findings, from two cohorts, show a robust gene-environment interaction, which may contribute to inter-individual differences in the effects of maternal prenatal anxiety on developmental outcomes from childhood to mid-adolescence.

To investigate whether expression-based polygenic risk scores for the insulin receptor gene network (ePRS-IRs) modifiy the association between type of depressive symptoms and health-related quality of life (HRQoL). This cross-sectional study includes 1558 individuals from the Helsinki Birth Cohort Study. Between 2001 and 2004, the Short Form-36 questionnaire was employed to assess mental and physical components of HRQoL and Beck Depression Inventory (BDI) to assess depressive symptoms. Depressive symptoms were categorized into minimal (BDI < 10), non-melancholic and melancholic types of depression. The ePRS-IRs were calculated for the hippocampal (hePRS-IR) and the mesocorticolimbic (mePRS-IR) regions of the brain. General linear regression models adjusted for age, sex, population stratification, lifestyle factors and body mass index were applied to analyze the data. Both types of depressive symptoms were associated with lower HRQoL (p < 0.0001). HePRS-IR modified the association between the types of depression and mental HRQoL (p for interaction = 0.005). Melancholic type of depressive symptoms was associated with higher mental HRQoL compared to the non-melancholic symptoms among individuals with low hePRS-IR (adjusted mean 4.1, 95% CI 0.7–7.4, p = 0.018). However, no such difference was evident in moderate or high hePRS-IR groups as higher hePRS-IR was associated with lower mental HRQoL (B = − 3.4, 95% CI − 5.6 to − 1.2) in individuals with melancholic type of depressive symptoms. No direct associations were detected between the ePRS-IRs and type of depressive symptoms or HRQoL. Variations in the glucose-insulin metabolism can lower HRQoL in individuals with melancholic depressive symptoms.

Attention-deficit and hyperactivity disorder (ADHD) is a common childhood disorder with a substantial genetic component. However, the extent to which epigenetic mechanisms play a role in the etiology of the disorder is unknown. We performed epigenome-wide association studies (EWAS) within the Pregnancy And Childhood Epigenetics (PACE) Consortium to identify DNA methylation sites associated with ADHD symptoms at two methylation assessment periods: birth and school age. We examined associations of both DNA methylation in cord blood with repeatedly assessed ADHD symptoms (age 4–15 years) in 2477 children from 5 cohorts and of DNA methylation at school age with concurrent ADHD symptoms (age 7–11 years) in 2374 children from 9 cohorts, with 3 cohorts participating at both timepoints. CpGs identified with nominal significance ( p  < 0.05) in either of the EWAS were correlated between timepoints ( ρ  = 0.30), suggesting overlap in associations; however, top signals were very different. At birth, we identified nine CpGs that predicted later ADHD symptoms ( p  < 1 × 10 –7 ), including ERC2 and CREB5 . Peripheral blood DNA methylation at one of these CpGs (cg01271805 in the promoter region of ERC2 , which regulates neurotransmitter release) was previously associated with brain methylation. Another (cg25520701) lies within the gene body of CREB5 , which previously was associated with neurite outgrowth and an ADHD diagnosis. In contrast, at school age, no CpGs were associated with ADHD with p  < 1 × 10 −7 . In conclusion, we found evidence in this study that DNA methylation at birth is associated with ADHD. Future studies are needed to confirm the utility of methylation variation as biomarker and its involvement in causal pathways.

Lasting effects of adversity, such as exposure to childhood adversity (CA) on disease risk, may be embedded via epigenetic mechanisms but findings from human studies investigating the main effects of such exposure on epigenetic measures, including DNA methylation (DNAm), are inconsistent. Studies in perinatal tissues indicate that variability of DNAm at birth is best explained by the joint effects of genotype and prenatal environment. Here, we extend these analyses to postnatal stressors. We investigated the contribution of CA, cis genotype (G), and their additive (G + CA) and interactive (G × CA) effects to DNAm variability in blood or saliva from five independent cohorts with a total sample size of 1074 ranging in age from childhood to late adulthood. Of these, 541 were exposed to CA, which was assessed retrospectively using self-reports or verified through social services and registries. For the majority of sites (over 50%) in the adult cohorts, variability in DNAm was best explained by G + CA or G × CA but almost never by CA alone. Across ages and tissues, 1672 DNAm sites showed consistency of the best model in all five cohorts, with G × CA interactions explaining most variance. The consistent G × CA sites mapped to genes enriched in brain-specific transcripts and Gene Ontology terms related to development and synaptic function. Interaction of CA with genotypes showed the strongest contribution to DNAm variability, with stable effects across cohorts in functionally relevant genes. This underscores the importance of including genotype in studies investigating the impact of environmental factors on epigenetic marks.

The stress hormone cortisol modulates fuel metabolism, cardiovascular homoeostasis, mood, inflammation and cognition. The CORtisol NETwork (CORNET) consortium previously identified a single locus associated with morning plasma cortisol. Identifying additional genetic variants that explain more of the variance in cortisol could provide new insights into cortisol biology and provide statistical power to test the causative role of cortisol in common diseases. The CORNET consortium extended its genome-wide association meta-analysis for morning plasma cortisol from 12,597 to 25,314 subjects and from ~2.2 M to ~7 M SNPs, in 17 population-based cohorts of European ancestries. We confirmed the genetic association with SERPINA6/SERPINA1 . This locus contains genes encoding corticosteroid binding globulin (CBG) and α1-antitrypsin. Expression quantitative trait loci (eQTL) analyses undertaken in the STARNET cohort of 600 individuals showed that specific genetic variants within the SERPINA6/SERPINA1 locus influence expression of SERPINA6 rather than SERPINA1 in the liver. Moreover, trans-eQTL analysis demonstrated effects on adipose tissue gene expression, suggesting that variations in CBG levels have an effect on delivery of cortisol to peripheral tissues. Two-sample Mendelian randomisation analyses provided evidence that each genetically-determined standard deviation (SD) increase in morning plasma cortisol was associated with increased odds of chronic ischaemic heart disease (0.32, 95% CI 0.06–0.59) and myocardial infarction (0.21, 95% CI 0.00–0.43) in UK Biobank and similarly in CARDIoGRAMplusC4D. These findings reveal a causative pathway for CBG in determining cortisol action in peripheral tissues and thereby contributing to the aetiology of cardiovascular disease.