Association between prenatal alcohol exposure and children's facial shape: a prospective population-based cohort study.

STUDY QUESTION: Is there an association between low-to-moderate levels of prenatal alcohol exposure (PAE) and children's facial shape? SUMMARY ANSWER: PAE before and during pregnancy, even at low level (<12 g of alcohol per week), was found associated with the facial shape of children, and these associations were found attenuated as children grow older. WHAT IS KNOWN ALREADY: High levels of PAE during pregnancy can have significant adverse associations with a child's health development resulting in recognizably abnormal facial development. STUDY DESIGN, SIZE, DURATION: This study was based on the Generation R Study, a prospective cohort from fetal life onwards with maternal and offspring data. We analyzed children 3-dimensional (3D) facial images taken at ages 9 (n = 3149) and 13 years (n = 2477) together with the data of maternal alcohol consumption. PARTICIPANTS/MATERIALS, SETTING, METHODS: We defined six levels of PAE based on the frequency and dose of alcohol consumption and defined three tiers based on the timing of alcohol exposure of the unborn child. For the image analysis, we used 3D graph convolutional networks for non-linear dimensionality reduction, which compressed the high-dimensional images into 200 traits representing facial morphology. These 200 traits were used for statistical analysis to search for associations with PAE. Finally, we generated heatmaps to display the facial phenotypes associated with PAE. MAIN RESULTS AND THE ROLE OF CHANCE: The results of the linear regression in the 9-year-old children survived correction for multiple testing with false discovery rate (FDR). In Tier 1 where we examined PAE only before pregnancy (exposed N = 278, unexposed N = 760), we found three traits survived FDR correction. The lowest FDR-P is 1.7e-05 (beta = 0.021, SE = 0.0040) in Trait #29; In Tier 2b where we examine any PAE during first trimester (exposed N = 756; unexposed N = 760), we found eight traits survived FDR correction. The lowest FDR-P is 9.0e-03 (beta = -0.013, SE = 0.0033) in Trait #139. Moreover, more statistically significant facial traits were found in higher levels of PAE. No FDR-significant results were found in the 13-year-old children. We map these significant traits back to the face, and found the most common detected facial phenotypes included turned-up nose tip, shortened nose, turned-out chin, and turned-in lower-eyelid-related regions. LIMITATIONS, REASONS FOR CAUTION: We had no data for alcohol consumption more than three months prior to pregnancy and thus do not know if maternal drinking had chronic effects. The self-reported questionnaire might not reflect accurate alcohol measurements because mothers may have denied their alcohol consumption. WIDER IMPLICATIONS OF THE FINDINGS: Our results imply that facial morphology, such as quantified by the approach we proposed here, can be used as a biomarker in further investigations. Furthermore, our study suggests that for women who are pregnant or want to become pregnant soon, should quit alcohol consumption several months before conception and completely during pregnancy to avoid adverse health outcomes in the offspring. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Erasmus Medical Centre, Rotterdam, the Erasmus University Rotterdam, and the Netherlands Organization for Health Research. V.W.V.J. reports receipt of funding from the Netherlands Organization for Health Research (ZonMw 90700303). W.J.N. is a founder, a scientific lead, and a shareholder of Quantib BV. TRIAL REGISTRATION NUMBER: N/A.

Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation.

Mitochondrial DNA copy number (mtDNA-CN) measured from blood specimens is a minimally invasive marker of mitochondrial function that exhibits both inter-individual and intercellular variation. To identify genes involved in regulating mitochondrial function, we performed a genome-wide association study (GWAS) in 465,809 White individuals from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (UKB). We identified 133 SNPs with statistically significant, independent effects associated with mtDNA-CN across 100 loci. A combination of fine-mapping, variant annotation, and co-localization analyses was used to prioritize genes within each of the 133 independent sites. Putative causal genes were enriched for known mitochondrial DNA depletion syndromes (p = 3.09 × 10-15) and the gene ontology (GO) terms for mtDNA metabolism (p = 1.43 × 10-8) and mtDNA replication (p = 1.2 × 10-7). A clustering approach leveraged pleiotropy between mtDNA-CN associated SNPs and 41 mtDNA-CN associated phenotypes to identify functional domains, revealing three distinct groups, including platelet activation, megakaryocyte proliferation, and mtDNA metabolism. Finally, using mitochondrial SNPs, we establish causal relationships between mitochondrial function and a variety of blood cell-related traits, kidney function, liver function and overall (p = 0.044) and non-cancer mortality (p = 6.56 × 10-4).

Fetal-placental blood flow and neurodevelopment in childhood: population-based neuroimaging study.

OBJECTIVE: Antenatal Doppler measurements of the fetal umbilical and cerebral circulations can predict perinatal complications; however, it is unclear if subtle variations in antenatal Doppler measurements are associated with long-term neurodevelopmental outcome. In this study, we examined whether antenatal Doppler measurements of the fetal-placental circulation are associated with cognitive and motor abilities and brain morphology in childhood. METHODS: To evaluate differences in long-term sequelae across the continuum of the umbilical and cerebral artery circulations in the general population, we utilized a population-based longitudinal cohort study approach. In women from the Generation R study, we measured second- and third-trimester umbilical artery pulsatility index (UA-PI). Children underwent non-verbal intelligence testing at 4-8 years of age, and at 8-12 years they underwent finger-tapping tests to measure fine motor skills, balance beam tests to measure gross motor skills and brain magnetic resonance imaging. We assessed the relationships between prenatal UA-PI and neurodevelopmental outcome using linear regression. We adjusted for child age and sex, maternal age, education, parity and smoking status. RESULTS: The study sample included 2803 pregnancies. Higher third-trimester UA-PI was associated with poorer fine motor performance (0.41 (95% CI, 0.11-0.70) fewer taps on the finger-tapping test per 1 SD higher UA-PI) and gross motor performance (0.64 (95% CI, 0.20-1.08) fewer steps on the balance beam test per 1 SD higher UA-PI). One SD higher third-trimester UA-PI was also associated with 0.65 (95% CI, 0.04-1.25) points lower intelligence quotient; however, unlike the associations with motor abilities, this finding did not persist after correction for multiple testing. Higher second-trimester UA-PI was associated with smaller brain volume (6.1 (95% CI, 1.0-11.3) cm3 reduction per 1 SD higher UA-PI), but the association did not persist after correction for multiple testing. CONCLUSION: Higher placental vascular resistance may have mild adverse effects on neurodevelopmental outcome at school age. While these effects are subtle at population level, we encourage future research into the role of early circulation in brain development. This information could be used to develop targeted interventions. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

[Disruptive behaviour problems in childhood: studies on phenotypic heterogeneity and neurobiology from the Generation R Study]. / Disruptieve gedragsproblemen op de kinderleeftijd: studies naar fenotypische heterogeniteit en neurobiologie in de Generation R Studie.

BACKGROUND: Disruptive behaviour problems in childhood are strongly predictive of physical and mental health problems and criminality. A better understanding of the development of children with disruptive behaviour problems will help improve our understanding of later severe mental illnesses.
AIM: To gain insights into the neurodevelopment of children with disruptive behaviour problems. Here, we focused on their phenotypic heterogeneity and the underlying neurobiological substrates of disruptive behaviour problems.
METHOD: All studies described in the discussed thesis were embedded in the Generation R Study, a prospective population-based birth cohort from Rotterdam, the Netherlands. Data were, amongst others, collected through multi-informant questionnaires and neuroimaging.
RESULTS: Empirically obtained dimensions of disruptive behaviour problems included oppositional/disobedient behaviour, physical aggression, irritability, and delinquent behaviour. Less white matter microstructure was related to more delinquent behaviour, taking into account the multi-dimensionality of disruptive behaviour problems. Callous traits were characterised by widespread macro- and microstructural differences across the brain.
CONCLUSION: These studies have shown that disruptive behaviour problems in childhood can be best conceptualized as a complex multi-dimensional phenotype. Taking into account this multi-dimensional heterogeneity has proven beneficial for the finding of underlying neurobiological mechanisms. Considering disruptive behaviour problems are predictive of later severe mental disorders, it is paramount to acknowledge the neurodevelopmental perspective on behaviour problems.

Gestational vitamin D deficiency and autism-related traits: the Generation R Study.

There is intense interest in identifying modifiable risk factors associated with autism-spectrum disorders (ASD). Autism-related traits, which can be assessed in a continuous fashion, share risk factors with ASD, and thus can serve as informative phenotypes in population-based cohort studies. Based on the growing body of research linking gestational vitamin D deficiency with altered brain development, this common exposure is a candidate modifiable risk factor for ASD and autism-related traits. The association between gestational vitamin D deficiency and a continuous measure of autism-related traits at ~6 years (Social Responsiveness Scale; SRS) was determined in a large population-based cohort of mothers and their children (n=4229). 25-hydroxyvitamin D (25OHD) was assessed from maternal mid-gestation sera and from neonatal sera (collected from cord blood). Vitamin D deficiency was defined as 25OHD concentrations less than 25 nmol l-1. Compared with the 25OHD sufficient group (25OHD>50 nmol l-1), those who were 25OHD deficient had significantly higher (more abnormal) SRS scores (mid-gestation n=2866, ß=0.06, P<0.001; cord blood n=1712, ß=0.03, P=0.01). The findings persisted (a) when we restricted the models to offspring with European ancestry, (b) when we adjusted for sample structure using genetic data, (c) when 25OHD was entered as a continuous measure in the models and (d) when we corrected for the effect of season of blood sampling. Gestational vitamin D deficiency was associated with autism-related traits in a large population-based sample. Because gestational vitamin D deficiency is readily preventable with safe, cheap and accessible supplements, this candidate risk factor warrants closer scrutiny.

A rare missense variant in RCL1 segregates with depression in extended families.

Depression is the most prevalent psychiatric disorder with a complex and elusive etiology that is moderately heritable. Identification of genes would greatly facilitate the elucidation of the biological mechanisms underlying depression, however, its complex etiology has proved to be a major bottleneck in the identification of its genetic risk factors, especially in genome-wide association-like studies. In this study, we exploit the properties of a genetic isolate and its family-based structure to explore whether relatively rare exonic variants influence the burden of depressive symptoms in families. Using a multistep approach involving linkage and haplotype analyses followed by exome sequencing in the Erasmus Rucphen Family (ERF) study, we identified a rare (minor allele frequency (MAF)=1%) missense c.1114C>T mutation (rs115482041) in the RCL1 gene segregating with depression across multiple generations. Rs115482041 showed significant association with depressive symptoms (N=2393, ßT-allele=2.33, P-value=1 × 10-4) and explained 2.9% of the estimated genetic variance of depressive symptoms (22%) in ERF. Despite being twice as rare (MAF<0.5%), c.1114C>T showed similar effect and significant association with depressive symptoms in samples from the independent population-based Rotterdam study (N=1604, ßT-allele=3.60, P-value=3 × 10-2). A comparison of RCL1 expression in human and mouse brain revealed a striking co-localization of RCL1 with the layer 1 interlaminar subclass of astrocytes found exclusively in higher-order primates. Our findings identify RCL1 as a novel candidate gene for depression and offer insights into mechanisms through which RCL1 may be relevant for depression.

Exome-sequencing in a large population-based study reveals a rare Asn396Ser variant in the LIPG gene associated with depressive symptoms.

Despite a substantial genetic component, efforts to identify common genetic variation underlying depression have largely been unsuccessful. In the current study we aimed to identify rare genetic variants that might have large effects on depression in the general population. Using high-coverage exome-sequencing, we studied the exonic variants in 1265 individuals from the Rotterdam study (RS), who were assessed for depressive symptoms. We identified a missense Asn396Ser mutation (rs77960347) in the endothelial lipase (LIPG) gene, occurring with an allele frequency of 1% in the general population, which was significantly associated with depressive symptoms (P-value=5.2 × 10-08, ß=7.2). Replication in three independent data sets (N=3612) confirmed the association of Asn396Ser (P-value=7.1 × 10-03, ß=2.55) with depressive symptoms. LIPG is predicted to have enzymatic function in steroid biosynthesis, cholesterol biosynthesis and thyroid hormone metabolic processes. The Asn396Ser variant is predicted to have a damaging effect on the function of LIPG. Within the discovery population, carriers also showed an increased burden of white matter lesions (P-value=3.3 × 10-02) and a higher risk of Alzheimer's disease (odds ratio=2.01; P-value=2.8 × 10-02) compared with the non-carriers. Together, these findings implicate the Asn396Ser variant of LIPG in the pathogenesis of depressive symptoms in the general population.

Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group.

The neuro-anatomical substrates of major depressive disorder (MDD) are still not well understood, despite many neuroimaging studies over the past few decades. Here we present the largest ever worldwide study by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Major Depressive Disorder Working Group on cortical structural alterations in MDD. Structural T1-weighted brain magnetic resonance imaging (MRI) scans from 2148 MDD patients and 7957 healthy controls were analysed with harmonized protocols at 20 sites around the world. To detect consistent effects of MDD and its modulators on cortical thickness and surface area estimates derived from MRI, statistical effects from sites were meta-analysed separately for adults and adolescents. Adults with MDD had thinner cortical gray matter than controls in the orbitofrontal cortex (OFC), anterior and posterior cingulate, insula and temporal lobes (Cohen's d effect sizes: -0.10 to -0.14). These effects were most pronounced in first episode and adult-onset patients (>21 years). Compared to matched controls, adolescents with MDD had lower total surface area (but no differences in cortical thickness) and regional reductions in frontal regions (medial OFC and superior frontal gyrus) and primary and higher-order visual, somatosensory and motor areas (d: -0.26 to -0.57). The strongest effects were found in recurrent adolescent patients. This highly powered global effort to identify consistent brain abnormalities showed widespread cortical alterations in MDD patients as compared to controls and suggests that MDD may impact brain structure in a highly dynamic way, with different patterns of alterations at different stages of life.

Psychotic-like experiences in pre-adolescence: what precedes the antecedent symptoms of severe mental illness?

OBJECTIVE: Adolescent psychotic-like experiences predict the onset of psychosis, but also predict subsequent non-psychotic disorders. Therefore, it is crucial to better understand the aetiology of psychotic-like experiences. This study examined whether (a) child emotional and behavioural problems at 3 and 6 years, or (b) childhood adversities were associated with psychotic-like experiences at age 10 years. METHOD: This prospective study was embedded in the Generation R Study; 3984 children (mean age 10 years) completed a psychotic-like experiences questionnaire. Mothers reported problems of their child at ages 3, 6 and 10 years. Additionally, mothers were interviewed about their child's adversities. RESULTS: Psychotic-like experiences were endorsed by ~20% of children and predicted by both emotional and behavioural problems at 3 years (e.g. emotional-reactive problems: ORadjusted = 1.10, 95% CI: 1.06-1.15, aggressive behaviour: ORadjusted = 1.03, 95% CI: 1.02-1.05) and 6 years (e.g. anxious/depressed problems: ORadjusted = 1.11, 95% CI: 1.06-1.15, aggressive behaviour: ORadjusted = 1.04, 95% CI: 1.04-1.05). Childhood adversities were associated with psychotic-like experiences (>2 adversities: ORadjusted = 2.24, 95% CI: 1.72-2.92), which remained significant after adjustment for comorbid psychiatric problems. CONCLUSION: This study demonstrated associations between early adversities, childhood emotional and behavioural problems and pre-adolescent psychotic-like experiences, which will improve the understanding of children at increased risk of severe mental illness.

Maternal psychiatric symptoms during pregnancy and risk of childhood atopic diseases.

BACKGROUND: Maternal psychiatric symptoms during pregnancy might affect the developing immune system and subsequent risk of childhood atopic diseases. OBJECTIVE: Our aim was to examine the associations of maternal psychiatric symptoms during pregnancy with allergic sensitization, allergy and eczema in children until age 10 years. METHODS: This study among 5205 children was performed in a population-based prospective cohort from foetal life onwards. We assessed maternal and paternal psychiatric symptoms (overall, depressive, anxiety) during pregnancy and at 36 months after delivery, and maternal psychiatric symptoms at 2 and 6 months after delivery using the Brief Symptom Inventory. Inhalant and food allergic sensitization were measured by skin prick tests, and physician-diagnosed inhalant and food allergy or eczema by questionnaires from birth until age 10 years. We used multivariate logistic regression, multinomial logistic regression or generalized estimating equation models where appropriate. RESULTS: We observed no association of maternal psychiatric symptoms during pregnancy with allergic sensitization. Maternal overall psychiatric, depressive and anxiety symptoms during pregnancy were associated with an increased risk of inhalant allergy only (adjusted odds ratio (95% confidence interval) 1.96 (1.44, 2.65), 1.58 (1.25, 1.98) and 1.61 (1.27, 2.03), respectively, per 1-unit increase). Maternal overall psychiatric and anxiety symptoms during pregnancy were associated with an increased risk of eczema (1.21 (1.05, 1.39) and 1.15 (1.02, 1.29), respectively, per 1-unit increase). Effect estimates did not materially change when maternal psychiatric symptoms after delivery, or paternal psychiatric symptoms during pregnancy and after delivery were taken into account. CONCLUSIONS AND CLINICAL RELEVANCE: Maternal psychiatric symptoms during pregnancy were associated with increased risks of childhood inhalant allergy and eczema, independent of maternal psychiatric symptoms after delivery and of paternal psychiatric symptoms.

Subjective measures of health and all-cause mortality - the Rotterdam Study.

BACKGROUND: Subjectively assessed health is related to mortality. Various subjective indicators of health have been studied, but it is unclear whether perceived physical functioning or mental health best accounts for the relation with mortality. METHOD: We studied the relation of subjective measures of health with all-cause mortality in 5538 participants of age 55 to 96 years at baseline from the Rotterdam Study. Various instruments of subjectively assessed health were used, that included basic activities of daily living (BADL), instrumental activities of daily living (IADL), quality of life (QoL), positive affect, somatic symptoms and negative affect. All participants completed questionnaires for each subjective measure of health and were followed for mortality for a mean of 12.2 (s.e. = 0.09) years. Cox regression analysis was conducted in the total sample. RESULTS: In this cohort, 2021 persons died during 48 534 person-years of follow-up. All measures of subjective health were related to mortality after adjusting for age, gender, education, cognition, prevalent chronic diseases and cardiovascular risk [BADL hazard ratio (HR, calculated per Z-score) = 1.35, 95% confidence interval (CI) 1.29-1.41; IADL HR = 1.27, 95% CI 1.22-1.32; QoL HR = 0.85, 95% CI 0.81-0.89; positive affect HR = 0.92, 95% CI 0.88-0.96; somatic symptoms HR = 1.11, 95% CI 1.06-1.16; and negative affect HR = 1.05, 95% CI 1.01-1.10]. In the mutually adjusted model, only BADL (HR = 1.24, 95% CI 1.16-1.32) and IADL (HR = 1.10, 95% CI 1.04-1.17) remained independently associated with mortality. CONCLUSIONS: Measures of subjectively assessed health are important indicators of mortality. Our study shows that of the different measures of subjective health, perceived physical health predicts mortality over and above mental health. Conversely, the association between mental health and mortality may partly be explained by poor perceived physical health.

The impact of education, country, race and ethnicity on the self-report of postpartum depression using the Edinburgh Postnatal Depression Scale.

BACKGROUND: Universal screening for postpartum depression is recommended in many countries. Knowledge of whether the disclosure of depressive symptoms in the postpartum period differs across cultures could improve detection and provide new insights into the pathogenesis. Moreover, it is a necessary step to evaluate the universal use of screening instruments in research and clinical practice. In the current study we sought to assess whether the Edinburgh Postnatal Depression Scale (EPDS), the most widely used screening tool for postpartum depression, measures the same underlying construct across cultural groups in a large international dataset. METHOD: Ordinal regression and measurement invariance were used to explore the association between culture, operationalized as education, ethnicity/race and continent, and endorsement of depressive symptoms using the EPDS on 8209 new mothers from Europe and the USA. RESULTS: Education, but not ethnicity/race, influenced the reporting of postpartum depression [difference between robust comparative fit indexes (∆*CFI) 0.01), but not between European countries (∆*CFI < 0.01). CONCLUSIONS: Investigators and clinicians should be aware of the potential differences in expression of phenotype of postpartum depression that women of different educational backgrounds may manifest. The increasing cultural heterogeneity of societies together with the tendency towards globalization requires a culturally sensitive approach to patients, research and policies, that takes into account, beyond rhetoric, the context of a person's experiences and the context in which the research is conducted.

Meta-analysis of genome-wide association studies of anxiety disorders.

Anxiety disorders (ADs), namely generalized AD, panic disorder and phobias, are common, etiologically complex conditions with a partially genetic basis. Despite differing on diagnostic definitions based on clinical presentation, ADs likely represent various expressions of an underlying common diathesis of abnormal regulation of basic threat-response systems. We conducted genome-wide association analyses in nine samples of European ancestry from seven large, independent studies. To identify genetic variants contributing to genetic susceptibility shared across interview-generated DSM-based ADs, we applied two phenotypic approaches: (1) comparisons between categorical AD cases and supernormal controls, and (2) quantitative phenotypic factor scores (FS) derived from a multivariate analysis combining information across the clinical phenotypes. We used logistic and linear regression, respectively, to analyze the association between these phenotypes and genome-wide single nucleotide polymorphisms. Meta-analysis for each phenotype combined results across the nine samples for over 18 000 unrelated individuals. Each meta-analysis identified a different genome-wide significant region, with the following markers showing the strongest association: for case-control contrasts, rs1709393 located in an uncharacterized non-coding RNA locus on chromosomal band 3q12.3 (P=1.65 × 10(-8)); for FS, rs1067327 within CAMKMT encoding the calmodulin-lysine N-methyltransferase on chromosomal band 2p21 (P=2.86 × 10(-9)). Independent replication and further exploration of these findings are needed to more fully understand the role of these variants in risk and expression of ADs.

Subcortical brain alterations in major depressive disorder: findings from the ENIGMA Major Depressive Disorder working group.

The pattern of structural brain alterations associated with major depressive disorder (MDD) remains unresolved. This is in part due to small sample sizes of neuroimaging studies resulting in limited statistical power, disease heterogeneity and the complex interactions between clinical characteristics and brain morphology. To address this, we meta-analyzed three-dimensional brain magnetic resonance imaging data from 1728 MDD patients and 7199 controls from 15 research samples worldwide, to identify subcortical brain volumes that robustly discriminate MDD patients from healthy controls. Relative to controls, patients had significantly lower hippocampal volumes (Cohen's d=-0.14, % difference=-1.24). This effect was driven by patients with recurrent MDD (Cohen's d=-0.17, % difference=-1.44), and we detected no differences between first episode patients and controls. Age of onset ⩽21 was associated with a smaller hippocampus (Cohen's d=-0.20, % difference=-1.85) and a trend toward smaller amygdala (Cohen's d=-0.11, % difference=-1.23) and larger lateral ventricles (Cohen's d=0.12, % difference=5.11). Symptom severity at study inclusion was not associated with any regional brain volumes. Sample characteristics such as mean age, proportion of antidepressant users and proportion of remitted patients, and methodological characteristics did not significantly moderate alterations in brain volumes in MDD. Samples with a higher proportion of antipsychotic medication users showed larger caudate volumes in MDD patients compared with controls. This currently largest worldwide effort to identify subcortical brain alterations showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.

Vitamin D serum levels are cross-sectionally but not prospectively associated with late-life depression.

OBJECTIVE: The evidence for a prospective association of vitamin D deficiency with the occurrence of late-life depression is limited. We aimed to study the long-term association between vitamin D serum levels and depression in a large population-based study of older adults. METHOD: We included 3251 participants from the Rotterdam Study, aged 55 and older with 32 400 person-years follow-up for depression. Baseline 25-hydroxyvitamin D (25(OH)D) serum levels were analyzed continuously and categorically. Repeated depressive symptoms' questionnaire assessments were used to assess the change of depressive symptoms. Semistructured psychiatric interviews, and GP records were used to assess incident major depressive disorder according to DSM-IV criteria. RESULTS: Low serum vitamin D levels were cross-sectionally associated with more depressive symptoms. However, low 25(OH)D serum levels were not prospectively associated with change of depressive symptoms (unstandardized beta = 0.02, 95% CI = -0.23; 0.26) or incident MDD (hazard ratio = 0.95, 95% CI = 0.86; 1.05). CONCLUSION: We observed a cross-sectional but no prospective association between serum vitamin D levels and depression. A cross-sectional association in the absence of the longitudinal association can mostly be attributed to reverse causality or residual confounding. Probably, vitamin D deficiency is not an independent risk factor for depression but co-occurs with late-life depression.

Intelligence quotient scores at the age of 6 years in children anaesthetised before the age of 5 years.

We analysed the association of independent variables with non-verbal cognition at 6 years in children with complete data (3441 from a cohort of 9901), of whom 415 were anaesthetised before the age of 5 years. Using multivariable regression, cognition was reduced by a mean (95% CI) score for children: anaesthetised before the age of 5 years, 2.1 (0.7-3.5), p = 0.004; born prematurely, 9.8 (4.1-15.4), p = 0.001; whose mothers smoked while pregnant, 2.3 (0.8-3.8), p = 0.004; whose mothers had lower IQ scores, 0.3 (0.2-0.3) for each unit reduction in maternal IQ, p < 0.0001. The association of child IQ with exposure to anaesthetic drugs was sensitive to missing data.

Obesity in older adults and life expectancy with and without cardiovascular disease.

BACKGROUND: The prevalence of overweight and obesity is increasing globally and is an established risk factor for cardiovascular disease (CVD). Our objective was to evaluate the impact of overweight and obesity on life expectancy and years lived with and without CVD in older adults. METHODS: The study included 6636 individuals (3750 women) aged 55 years and older from the population-based Rotterdam Study. We developed multistate life tables by using prevalence, incidence rate and hazard ratios (HR) for three transitions (free-of-CVD-to-CVD, free-of-CVD-to-death and CVD-to-death), stratifying by the categories of body mass index (BMI) at baseline and adjusting for confounders. RESULTS: During 12 years of follow-up, we observed 1035 incident CVD events and 1902 overall deaths. Obesity was associated with an increased risk of CVD among men (HR 1.57 (95% confidence interval (CI) 1.17, 2.11)) and women (HR 1.49 (95% CI 1.19, 1.86)), compared with normal weight individuals. Overweight and obesity were not associated with mortality in men and women without CVD. Among men with CVD, obesity compared with normal weight, was associated with a lower risk of mortality (HR 0.67 (95% CI 0.49, 0.90)). Overweight and obesity did not influence total life expectancy. However, obesity was associated with 2.6 fewer years (95% CI -4.8, -0.4) lived free from CVD in men and 1.9 (95% CI -3.3, -0.9) in women. Moreover, men and women with obesity lived 2.9 (95% CI 1.1, 4.8) and 1.7 (95% CI 0.6, 2.8) more years suffering from CVD compared with normal weight counterparts. CONCLUSIONS: Obesity had no effect on total life expectancy in older individuals, but increased the risk of having CVD earlier in life and consequently extended the number of years lived with CVD. Owing to increasing prevalence of obesity and improved treatment of CVD, we might expect more individuals living with CVD and for a longer period of time.

Associations of maternal and fetal 25-hydroxyvitamin D levels with childhood lung function and asthma: the Generation R Study.

BACKGROUND: Exposure to low levels of vitamin D in fetal life might be a risk factor for childhood asthma. OBJECTIVE: We examined whether 25-hydroxyvitamin D levels in mid-gestation and at birth were associated with higher airway resistance and inflammation, and increased risks of wheezing and asthma in school-age children. METHODS: We performed a population-based prospective cohort study among 3130 mothers and their children. Maternal blood samples in mid-gestation and umbilical cord blood samples at birth were used to determine 25-hydroxyvitamin D levels. At age of 6, airway resistance (Rint) was measured by interrupter technique and airway inflammation by fractional exhaled nitric oxide (FENO) using NIOX chemiluminescence analyser. Wheezing and asthma were prospectively assessed by annual questionnaires until age 6. RESULTS: Maternal levels of 25-hydroxyvitamin D in mid-gestation were not associated with Rint, FeNO, wheezing patterns, or asthma. Children in the lowest tertile of 25-hydroxyvitamin D levels at birth had a higher Rint (Z-score (95% confidence interval [95% CI]): -0.42 (-0.84, -0.01), P-value for trend< 0.05), compared to those in the highest tertile group. The effect estimate attenuated when child's current 25-hydroxyvitamin D level was taken into account [Z-score (95% CI): -0.55 (-1.08, 0.01)]. CONCLUSION AND CLINICAL RELEVANCE: Low levels of 25-hydroxyvitamin D at birth were associated with a higher airway resistance in childhood. Additional adjustment for child's current 25-hydroxyvitamin D level reduced the effect size of the association. Further studies are needed to replicate these findings and to examine mechanisms underlying the observed association and the long-term consequences.

Maternal fatty acid levels during pregnancy, childhood lung function and atopic diseases. The Generation R Study.

BACKGROUND: Maternal fatty acid status during pregnancy might influence foetal immunological development and subsequently the risk of childhood atopic diseases. OBJECTIVE: To examine the associations of maternal fatty acid levels during pregnancy with airway resistance and inflammation, asthma and eczema, in school-age children. METHODS: This study among 4976 subjects was embedded in a population-based prospective cohort study. We measured maternal plasma glycerophospholipid fatty acid levels by gas chromatography during the second trimester of pregnancy (mean gestational age: 20.7 (± 1.1) weeks). At the age of 6 years, airway resistance and inflammation were measured by interrupter technique (Rint) and fractional exhaled nitric oxide (FeNO), and current physician-diagnosed asthma and eczema were assessed by ISAAC-based questionnaires. Multiple linear and logistic regression models were adjusted for socio-demographic, lifestyle and anthropometric factors. RESULTS: We did not observe consistent associations of maternal total polyunsaturated fatty acid (PUFA), total n-6 PUFA, total n-3 PUFA levels and n-6/n-3 PUFA ratio during pregnancy with child's Rint and FeNO. Higher maternal total PUFA and total n-6 PUFA levels were associated with a decreased risk of childhood asthma (odds ratios (95% confidence interval): 0.76 (0.60, 0.97) and 0.71 (0.52, 0.96) per standard deviation score (SDS) increase of total PUFA and total n-6 PUFA levels, respectively) and with an increased risk of childhood eczema (1.16 (1.05, 1.28) and 1.21 (1.07, 1.37)). The observed associations were partly explained by Linoleic acid (LA, C18:2n-6) levels. Maternal total n-3 PUFA levels and n-6/n-3 PUFA ratio were not associated with current asthma and eczema. The observed associations were not explained by child's PUFA intake. CONCLUSIONS AND CLINICAL RELEVANCE: Higher maternal total PUFA and total n-6 PUFA levels during pregnancy seem to influence the risk of atopic diseases in childhood. The underlying mechanisms need to be further explored.

The long-term risk of recognized and unrecognized myocardial infarction for depression in older men.

BACKGROUND: The association between myocardial infarction (MI) and depression is well described. Yet, the underlying mechanisms are unclear and the contribution of psychological factors is uncertain. We aimed to determine the risk of recognized (RMI) and unrecognized (UMI) myocardial infections on depression, as both have a similar impact on cardiovascular health but differ in psychological epiphenomena. METHOD: Participants of the Rotterdam Study, 1823 men aged ⩾55 years, were followed for the occurrence of depression. RMI and UMI were ascertained using electrocardiography and medical history at baseline. We determined the strength of the association of RMI and UMI with mortality, and we studied the relationship of RMI and UMI with depressive symptoms and the occurrence of major depression. RESULTS: The risk of mortality was similar in men with RMI [adjusted hazard ratio (aHR) 1.71, 95% confidence interval (CI) 1.45-2.03] and UMI (aHR 1.58, 95% CI 1.27-1.97). Men with RMI had on average [unstandardized regression coefficient (B) 1.14, 95% CI 0.07-2.21] higher scores for depressive symptoms. By contrast, we found no clear association between UMI and depressive symptoms (B 0.55, 95% CI -0.51 to 1.62) in men. Analysis including occurrence of major depression as the outcome were consistent with the pattern of association. CONCLUSION: The discrepant association of RMI and UMI with mortality compared to depression suggests that the psychological burden of having experienced an MI contributes to the long-term risk of depression.