Plasma neurofilament light chain in association to late-life depression in the general population

Aim:Investigating what is underlying late-life depression is becoming increasingly important with the rapidly growing elderly population. Yet, the associations between plasma biomarkers of neuroaxonal damage and late-life depression remain largely unclear. Therefore, we determined cross-sectional and longitudinal associations of neurofilament light chain (NfL) with depression in middle-aged and elderly individuals, and total tau, β-amyloid 40 and 42 for comparison. Methods:We included 3,895 participants (71.78 years [SD = 7.37], 53.4% women) from the population-based Rotterdam Study. Between 2002 and 2005, NfL, total tau, β-amyloid 40 and β-amyloid 42 were determined in blood and depressive symptoms were measured with the Center for Epidemiologic Studies Depression scale (CES-D). Incident depressive events (clinically relevant depressive symptoms, depressive syndromes, major depressive disorders) were measured prospectively with the Center for Epidemiologic Studies Depression, a clinical interview and follow-up of medical records over a median follow-up of 7.0 years (interquartile range 1.80). We used linear and Cox proportional hazard regression models. Results: Each log2 pg./mL increase in NfL was cross-sectionally associated with more depressive symptoms (adjusted mean difference: 0.32, 95% CI 0.05–0.58), as well as with an increased risk of any incident depressive event over time (hazard ratio: 1.22, 95% CI 1.01–1.47). Further, more amyloid-β 40 was cross-sectionally associated with more depressive symptoms (adjusted mean difference: 0.70, 95% CI 0.15–1.25). Conclusion: Higher levels of NfL are cross-sectionally associated with more depressive symptoms and a higher risk of incident depressive events longitudinally. The association was stronger for NfL compared to other plasma biomarkers, suggesting a potential role of neuroaxonal damage in developing late-life depression.</p

Life stress and adiposity in mothers:A 14-year follow-up in the general population

Exposure to specific stressors has been found to associate with higher adiposity in adulthood. However, the potential overlapping effects of stress domains have been overlooked, as well as the role of parenting-related stressors that mothers are widely exposed to in mid-adulthood. Therefore, we assessed the association of overlapping effects of stress domains, including parenting-related stress, with subsequent adiposity in mothers. In 3957 mothers from the population-based Generation R Study, life stress was assessed during the first 10 years of child-rearing and measured as a reflective latent variable of stress domains. Structural equation modelling was used to assess the association of life stress and its individual domains with body mass index (BMI) and waist circumference after 14 years of follow-up. Greater life stress over the course of 10 years was associated with a higher BMI (standardized adjusted difference: 0.57 kg/m2 [95% CI: 0.41–0.72]) and a larger waist circumference (1.15 cm [0.72–1.57]). When examining individual stress domains, we found that life events was independently associated with a higher BMI (0.16 kg/m2) and contextual stress was independently associated with a higher BMI (0.43 kg/m2) and larger waist circumference (1.04 cm). Parenting stress and interpersonal stress were not independently associated with adiposity at follow-up. The overlap of multiple domains of stress in mothers is associated with a higher risk of adiposity. This effect was stronger than for individual life stress domains, reiterating the need to consider overlapping effects of different life stress domains.</p

The polygenic and reactive nature of observed parenting

In Wertz et al. (2019), parents' polygenic scores of educational attainment (PGS-EA) predicted parental sensitive responses to the child's needs for support, as observed in a dyadic task (i.e., observed sensitivity). We aimed to replicate and expand these findings by combining longitudinal data, child genotype data and several polygenic scores in the Generation R Study. Mother–child dyads participated in two developmental periods, toddlerhood (14 months old; n = 648) and early childhood (3–4 years old, n = 613). Higher maternal PGS-EA scores predicted higher observed sensitivity in toddlerhood (b = 0.12, 95% CI 0.03, 0.20) and early childhood (b = 0.16, 95% CI 0.08, 0.24). Child PGS-EA was significantly associated with maternal sensitivity in early childhood (b = 0.11, 95% CI 0.02, 0.21), and the effect of maternal PGS-EA was no longer significant when correcting for child PGS-EA. A latent factor of PGSs based on educational attainment, intelligence (IQ) and income showed similar results. These polygenic scores might be associated with maternal cognitive and behavioral skills that help shape parenting. Maternal PGSs predicted observed sensitivity over and above the maternal phenotypes, showing an additional role for PGSs in parenting research. In conclusion, we replicated the central finding of Wertz et al. (2019) that parental PGS-EA partially explains parental sensitivity. Our findings may be consistent with evocative gene–environment correlation (rGE), emphasizing the dynamic nature of parenting behavior across time, although further research using family trios is needed to adequately test this hypothesis.</p

A Longitudinal Study of Stress During Pregnancy, Children’s Sleep and Polygenic Risk for Poor Sleep in the General Pediatric Population

Early life stress is robustly associated with poor sleep across life. Preliminary studies suggest that these associations may begin already in utero. Here, we study the longitudinal associations of prenatal psychosocial stress with sleep across childhood, and assess whether prenatal stress interacts with genetic liability for poor sleep. The study is embedded in the Generation R population-based birth cohort. Caregivers reported on prenatal psychosocial stress (life events, contextual, parental or interpersonal stressors) and on children’s sleep at ages 2 months, 1.5, 2, 3 and 6 years. The study sample consisted of 4,930 children; polygenic risk scores for sleep traits were available in 2,063. Prenatal stress was consistently associated with more sleep problems across assessments. Effect sizes ranged from small (B = 0.21, 95%CI: 0.14;0.27) at 2 months to medium (B = 0.45, 95%CI: 0.38;0.53) at 2 years. Prenatal stress was moreover associated with shorter sleep duration at 2 months (Bhrs = -0.22, 95%CI: -0.32;-0.12) and at 2 years (Bhrs = -0.04, 95%CI -0.07; -0.001), but not at 3 years (Bhrs = 0.02, 95%CI: -0.02;0.06). Prenatal negative life events interacted with polygenic risk for insomnia to exacerbate sleep problems at 6 years (Binteraction = 0.07, 95%CI: 0.02;0.13). Psychosocial stress during pregnancy has negative associations with children’s sleep that persist across childhood, and are exacerbated by genetic liability for insomnia. Associations with sleep duration were more pronounced in infancy and seem to attenuate with age. These findings highlight the role of the prenatal environment for developing sleep regulation, and could inform early intervention programs targeting sleep in children from high-risk pregnancies.</p

Child mental health problems as a risk factor for academic underachievement:A multi-informant, population-based study

OBJECTIVE: To investigate whether child mental health problems prospectively associate with IQ‐achievement discrepancy (i.e., academic under‐ and over‐achievement) in emerging adolescence. The secondary aims were to test whether these associations are specific to certain mental health problems, to assess potential sex differences, and to examine whether associations are robustly observed across multiple informants (i.e., maternal and teacher‐reports). METHODS: This study included 1,577 children from the population‐based birth cohort the Generation R Study. Child mental health problems at age 6 were assessed by mothers and teachers using the Child Behavior Checklist and the Teacher's Report Form. The IQ‐achievement discrepancy was quantified as the standardized residuals of academic achievement regressed on IQ, where IQ was measured with four tasks from the Wechsler Intelligence Scale for Children‐Fifth Edition around age 13 and academic attainment was measured with the Cito test, a national Dutch academic test, at the end of elementary school (12 years of age). RESULTS: Mental health problems at age 6 were associated with IQ‐achievement discrepancy at age 12, with more problems associating with greater academic underachievement. When examining specific mental health problems, we found that attention problems was the only mental health problem to independently associate with the IQ‐achievement discrepancy (adjusted standardized difference per 1‐standard deviation, mother: −0.11, p < 0.001, 95% CI [−0.16, −0.06]; teacher: −0.13, p < 0.001, 95% CI [−0.18, −0.08]). These associations remained after adjusting for co‐occurring mental health problems. The overall pattern of associations was consistent across boys and girls and across informants. CONCLUSION: Mental health problems during the transition from kindergarten to elementary school associate with academic underachievement at the end of elementary school. These associations were primarily driven by attention problems, as rated by both mothers and teachers—suggesting that strategies targeting attention problems may be a particularly promising avenue for improving educational performance irrespective of IQ, although this should be established more thoroughly through further research

DNA methylation at birth and lateral ventricular volume in childhood:a neuroimaging epigenetics study

Background: Lateral ventricular volume (LVV) enlargement has been repeatedly linked to schizophrenia; yet, what biological factors shape LVV during early development remain unclear. DNA methylation (DNAm), an essential process for neurodevelopment that is altered in schizophrenia, is a key molecular system of interest. Methods:In this study, we conducted the first epigenome-wide association study of neonatal DNAm in cord blood with LVV in childhood (measured using T1-weighted brain scans at 10 years), based on data from a large population-based birth cohort, the Generation R Study (N = 840). Employing both probe-level and methylation profile score (MPS) approaches, we further examined whether epigenetic modifications identified at birth in cord blood are: (a) also observed cross-sectionally in childhood using peripheral blood DNAm at age of 10 years (Generation R, N = 370) and (b) prospectively associated with LVV measured in young adulthood in an all-male sample from the Avon Longitudinal Study of Parents and Children (ALSPAC, N = 114). Results: At birth, DNAm levels at four CpGs (annotated to potassium channel tetramerization domain containing 3, KCTD3; SHH signaling and ciliogenesis regulator, SDCCAG8; glutaredoxin, GLRX) prospectively associated with childhood LVV after genome-wide correction; these genes have been implicated in brain development and psychiatric traits including schizophrenia. An MPS capturing a broader epigenetic profile of LVV – but not individual top hits – showed significant cross-sectional associations with LVV in childhood in Generation R and prospectively associated with LVV in early adulthood within ALSPAC. Conclusions: This study finds suggestive evidence that DNAm at birth prospectively associates with LVV at different life stages, albeit with small effect sizes. The prediction of MPS on LVV in a childhood sample and an independent male adult sample further underscores the stability and reproducibility of DNAm as a potential marker for LVV. Future studies with larger samples and comparable time points across development are needed to further elucidate how DNAm associates with this clinically relevant brain structure and risk for neuropsychiatric disorders, and what factors explain the identified DNAm profile of LVV at birth.</p

A multivariate genome-wide association study of psycho-cardiometabolic multimorbidity

Coronary artery disease (CAD), type 2 diabetes (T2D) and depression are among the leading causes of chronic morbidity and mortality worldwide. Epidemiological studies indicate a substantial degree of multimorbidity, which may be explained by shared genetic influences. However, research exploring the presence of pleiotropic variants and genes common to CAD, T2D and depression is lacking. The present study aimed to identify genetic variants with effects on cross-trait liability to psycho-cardiometabolic diseases. We used genomic structural equation modelling to perform a multivariate genome-wide association study of multimorbidity (Neffective = 562,507), using summary statistics from univariate genome-wide association studies for CAD, T2D and major depression. CAD was moderately genetically correlated with T2D (rg = 0.39, P = 2e-34) and weakly correlated with depression (rg = 0.13, P = 3e-6). Depression was weakly correlated with T2D (rg = 0.15, P = 4e-15). The latent multimorbidity factor explained the largest proportion of variance in T2D (45%), followed by CAD (35%) and depression (5%). We identified 11 independent SNPs associated with multimorbidity and 18 putative multimorbidity-associated genes. We observed enrichment in immune and inflammatory pathways. A greater polygenic risk score for multimorbidity in the UK Biobank (N = 306,734) was associated with the co-occurrence of CAD, T2D and depression (OR per standard deviation = 1.91, 95% CI = 1.74–2.10, relative to the healthy group), validating this latent multimorbidity factor. Mendelian randomization analyses suggested potentially causal effects of BMI, body fat percentage, LDL cholesterol, total cholesterol, fasting insulin, income, insomnia, and childhood maltreatment. These findings advance our understanding of multimorbidity suggesting common genetic pathways.</p

Effects of Pre- and Postnatal Early-Life Stress on Internalizing, Adiposity, and Their Comorbidity

Objective: Depression and obesity are 2 highly prevalent and often comorbid conditions. Exposure to early-life stress (ELS) has been associated with both depression and obesity in adulthood, as well as their preclinical manifestations during development. However, it remains unclear whether (1) associations differ depending on the timing of stress exposure (prenatal vs postnatal), and whether (2) ELS is a shared risk factor underlying the comorbidity between the 2 conditions. Method: Leveraging data from 2 large population-based birth cohorts (ALSPAC: n = 8,428 [52% male participants]; Generation R: n = 4,268 [48% male participants]), we constructed comprehensive cumulative measures of prenatal (in utero) and postnatal (from birth to 10 years) ELS. At age 13.5 years, we assessed the following: internalizing symptoms (using maternal reports); fat mass percentage (using dual-energy X-ray absorptiometry); and their comorbidity, defined as the co-occurrence of high internalizing and high adiposity. Results: Both prenatal (total effect [95% CI] = 0.20 [0.16; 0.22]) and postnatal stress (β [95%CI] = 0.22 [0.17; 0.25]) were associated with higher internalizing symptoms, with evidence of a more prominent role of postnatal stress. A weaker association (driven primarily by prenatal stress) was observed between stress and adiposity (prenatal: 0.07 [0.05; 0.09]; postnatal: 0.04 [0.01; 0.07]). Both prenatal (odds ratio [95%CI] = 1.70 [1.47; 1.97]) and postnatal (1.87 [1.61; 2.17]) stress were associated with an increased risk of developing comorbidity. Conclusion: We found evidence of timing and shared causal effects of ELS on psycho-cardiometabolic health in adolescence; however, future research is warranted to clarify how these associations may unfold over time. Diversity &amp; Inclusion Statement: We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. We actively worked to promote sex and gender balance in our author group.</p

DNA Methylation at Birth and Fine Motor Ability in Childhood:An Epigenome-wide Association Study with Replication

Lower fine motor performance in childhood has been associated with poorer cognitive development and neurodevelopmental conditions such as autism spectrum disorder, yet, biological underpinnings remain unclear. DNA methylation (DNAm), an essential process for healthy neurodevelopment, is a key molecular system of interest. In this study, we conducted the first epigenome-wide association study of neonatal DNAm with childhood fine motor ability and further examined the replicability of epigenetic markers in an independent cohort. The discovery study was embedded in Generation R, a large population-based prospective cohort, including a subsample of 924 ~ 1026 European-ancestry singletons with available data on DNAm in cord blood and fine motor ability at a mean (SD) age of 9.8 (0.4) years. Fine motor ability was measured using a finger-tapping test (3 subtests including left-, right-hand and bimanual), one of the most frequently used neuropsychological instruments of fine motor function. The replication study comprised 326 children with a mean (SD) age of 6.8 (0.4) years from an independent cohort, the INfancia Medio Ambiente (INMA) study. Four CpG sites at birth were prospectively associated with childhood fine motor ability after genome-wide correction. Of these, one CpG (cg07783800 in GNG4) was replicated in INMA, showing that lower levels of methylation at this site were associated with lower fine motor performance in both cohorts. GNG4 is highly expressed in the brain and has been implicated in cognitive decline. Our findings support a prospective, reproducible association between DNAm at birth and fine motor ability in childhood, pointing to GNG4 methylation at birth as a potential biomarker of fine motor ability.The EWAS data was funded by a grant from the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA; project nr. 050-060-810), funds from the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, and a grant from the National Institute of Child and Human Development (R01HD068437). HT was supported by a grant of the Dutch Ministry of Education, Culture, and Science and the Netherlands Organization for Scientific Research (NWO grant No. 024.001.003, Consortium on Individual Development). FS was supported by a Royal Netherlands Academy of Science and Art (KNAW) Van Leersum fellowship. ML is supported by the scholarship from the China Scholarship Council (201706990036). CC is supported by the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme under grant agreements No 101039672 (TEMPO) and No 848158 (EarlyCause). This project received funding from the European Union’s Horizon 2020 research and innovation programme (733206, LifeCycle).The epigenetic studies in INMA were mainly funded by grants from Instituto de Salud Carlos III (Red INMA G03/176, CB06/02/0041, CP18/00018), Spanish Ministry of Health (FIS-PI04/1436, FIS-PI08/1151 including FEDER funds, FIS-PI11/00610, FIS-FEDER-PI06/0867, FIS-FEDER-PI03-1615) Generalitat de Catalunya-CIRIT 1999SGR 00241, Fundació La marató de TV3 (090430), EU Commission (261357-MeDALL: Mechanisms of the Development of ALLergy), and European Research Council (268479-BREATHE: BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn)