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BACKGROUND: The prevalence of sleep problems among pregnant women is over 50%, and daytime sleepiness is among the most common sleep problems. Previous studies have associated antenatal sleep problems with adverse maternal health and neonatal outcomes, but the consequences of antenatal sleep problems and particularly daytime sleepiness on child psychological development have not been assessed prospectively. METHODS: In this prospective cohort study including 111 mother-child dyads, we examined the associations of maternal daytime sleepiness during pregnancy, assessed at 17 and 28 weeks of gestation using the Epworth Sleepiness Scale, with child neuropsychiatric problems and neuropsychological development, assessed with mother-rated questionnaires and individually administered neuropsychological tests, at child age 2.6-5.7 years (mean = 4.3 years). RESULTS: Independently of sociodemographic and perinatal covariates and maternal depressive and anxiety symptoms during and/or after pregnancy, maternal antenatal daytime sleepiness was associated with increased total [unstandardized regression coefficient (B) = 0.25 standard deviation (s.d.) units; 95% confidence interval (CI) 0.01-0.48] and internalizing (B = 0.25 s.d.s: 95% CI 0.01-0.49) psychiatric problems and ADHD symptoms (B = 0.27 s.d.s: 95% CI 0.04-0.50) in children, and with poorer executive function, particularly in the areas of attention, working memory and inhibitory control (B = -0.39 s.d.s: 95% CI -0.69 to -0.10). CONCLUSIONS: Maternal antenatal daytime sleepiness carries adverse consequences for offspring psychological development. The assessment of sleep problems may be an important addition to standard antenatal care.
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Transtornos do Neurodesenvolvimento/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Transtornos do Sono-Vigília/epidemiologia , Sonolência , Adulto , Pré-Escolar , Feminino , Humanos , Modelos Lineares , Masculino , Relações Mãe-Filho , Transtornos do Neurodesenvolvimento/etiologia , Testes Neuropsicológicos , Obesidade/complicações , Gravidez , Estudos Prospectivos , Escócia , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Global prevalence of overweight/obesity and gestational diabetes (GDM) is increasing. In pregnant women both conditions affect offspring's later health. Overweight/obesity is a risk factor of GDM; to what extent maternal overweight/obesity explains long-term effects of GDM in offspring is unknown. OBJECTIVE: To evaluate effects of maternal pre-pregnancy overweight/obesity (body mass index (BMI) ⩾25 kg m-2) and GDM, occurring together or separately, on body composition among adult offspring. METHODS: Participants include 891 individuals aged 24.1 years (s.d. 1.4) from two longitudinal cohort studies (ESTER and AYLS). Adult offspring of normoglycemic mothers with overweight/obesity (ONOO, n=153), offspring of mothers with GDM (OGDM; n=191) and controls (n=547) underwent anthropometric measurements and bioimpedance analysis. Gestational diabetes mellitus was diagnosed by oral glucose tolerance test. Data were analyzed by linear regression models adjusted for confounders. RESULTS: Compared with controls, ONOO-participants showed higher BMI (men 1.64 kg m-2 (95% confidence interval 0.57, 2.72); women 1.41 kg m-2 (0.20, 2.63)) and fat percentage (men 2.70% (0.99, 4.41); women 2.98% (0.87, 5.09)) with larger waist circumferences (men 3.34 cm (0.68, 5.99); women 3.09 cm (0.35, 5.83)). Likewise, OGDM-participants showed higher fat percentage (men 1.97% (0.32, 3.61); women 2.32% (0.24, 4.41)). Body mass index was non-significantly different between OGDM-participants and controls (men 0.88 kg m-2 (-0.17, 1.92); women 0.82 kg m-2 (-0.39, 2.04)). Also waist circumferences were larger (men 2.63 cm (-0.01, 5.28); women 3.39 cm (0.60, 6.18)); this difference was statistically significant in OGDM-women only. Differences in body composition measures were stronger among offspring of women with both GDM and overweight/obesity. For instance, fat mass was higher among OGDM-participants of overweight mothers (men 4.24 kg (1.36, 7.11) vs controls; women 5.22 kg (1.33, 9.11)) than OGDM participants of normal weight mothers (men 1.50 kg (-2.11, 5.11) higher vs controls; women 1.57 kg (-3.27, 6.42)). CONCLUSIONS: Maternal pre-pregnancy overweight and GDM are associated with unhealthy body size and composition in offspring over 20 years later. Effects of maternal pre-pregnancy overweight appear more pronounced.
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Filhos Adultos/estatística & dados numéricos , Composição Corporal/fisiologia , Diabetes Gestacional/epidemiologia , Sobrepeso/epidemiologia , Adulto , Índice de Massa Corporal , Tamanho Corporal , Estudos de Coortes , Feminino , Humanos , Estudos Longitudinais , Obesidade/epidemiologia , Gravidez , Adulto JovemRESUMO
BACKGROUND: Being breastfed in infancy has been shown to benefit neurodevelopment. However, whether the benefits persist to old age remains unclear. METHODS: We examined the associations between breastfeeding and its duration on cognitive ability in young adulthood and old age, and on aging-related cognitive change over five decades. In total, 931 men from the Helsinki Birth Cohort Study born in 1934-1944 in Finland took the Finnish Defence Forces Basic Intellectual Ability Test (total and verbal, arithmetic and visuospatial subtest scores) twice, at ages 20.2 and 67.9 years, and had data on breastfeeding (yes v. no) and its duration ('never breastfed', 'up to 3', '3 to 6' and '6 or more months'). Linear and mixed model regressions tested the associations. RESULTS: At 20.2 years, breastfed men had higher cognitive ability total and visuospatial subtest scores [mean differences (MDs) ranged between 3.0-3.9, p values < 0.013], and its longer duration predicted higher cognitive ability total and arithmetic and visuospatial subtest scores (MDs ranged between 3.0 and 4.8, p values < 0.039). At 67.9 years, breastfed men had higher total cognitive ability and all subtest scores (MDs ranged between 2.6 and 3.4, p values < 0.044) and its longer duration predicted all cognitive ability scores (MDs ranged between 3.1 and 4.7, p values < 0.050). Verbal subtest scores decreased over five decades in men who were never breastfed or were breastfed for 3 months or less, and increased in those breastfed for longer than 3 months. CONCLUSIONS: Neurodevelopmental advantages of breastfeeding and its longer duration persist into old age, and longer duration of breastfeeding may benefit aging-related change, particularly in verbal reasoning ability.
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Aleitamento Materno , Envelhecimento Cognitivo/fisiologia , Envelhecimento Cognitivo/psicologia , Inteligência/fisiologia , Adulto , Idoso , Cognição , Finlândia , Humanos , Modelos Lineares , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Fatores de Tempo , Adulto JovemRESUMO
The epigenome is associated with biological factors, such as disease status, and environmental factors, such as smoking, alcohol consumption and body mass index. Although there is a widespread perception that environmental influences on the epigenome are pervasive and profound, there has been little evidence to date in humans with respect to environmental factors that are biologically distal. Here we provide evidence on the associations between epigenetic modifications-in our case, CpG methylation-and educational attainment (EA), a biologically distal environmental factor that is arguably among the most important life-shaping experiences for individuals. Specifically, we report the results of an epigenome-wide association study meta-analysis of EA based on data from 27 cohort studies with a total of 10 767 individuals. We find nine CpG probes significantly associated with EA. However, robustness analyses show that all nine probes have previously been found to be associated with smoking. Only two associations remain when we perform a sensitivity analysis in the subset of never-smokers, and these two probes are known to be strongly associated with maternal smoking during pregnancy, and thus their association with EA could be due to correlation between EA and maternal smoking. Moreover, the effect sizes of the associations with EA are far smaller than the known associations with the biologically proximal environmental factors alcohol consumption, body mass index, smoking and maternal smoking during pregnancy. Follow-up analyses that combine the effects of many probes also point to small methylation associations with EA that are highly correlated with the combined effects of smoking. If our findings regarding EA can be generalized to other biologically distal environmental factors, then they cast doubt on the hypothesis that such factors have large effects on the epigenome.
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Sucesso Acadêmico , Epigênese Genética , Ilhas de CpG , Metilação de DNA , Estudos de Associação Genética , Humanos , Herança MultifatorialRESUMO
This corrects the article DOI: 10.1038/mp.2016.244.
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The complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (~8M single-nucleotide polymorphisms (SNP) with minor allele frequency ⩾1%) to general cognitive function in a sample of 35 298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT). In addition, we utilized individual SNP lookups and polygenic score analyses to identify genetic overlap with other relevant neurobehavioral phenotypes. Our primary GWAS meta-analysis identified two novel SNP loci (top SNPs: rs76114856 in the CENPO gene on chromosome 2 and rs6669072 near LOC105378853 on chromosome 1) associated with cognitive performance at the genome-wide significance level (P<5 × 10-8). Gene-based analysis identified an additional three Bonferroni-corrected significant loci at chromosomes 17q21.31, 17p13.1 and 1p13.3. Altogether, common variation across the genome resulted in a conservatively estimated SNP heritability of 21.5% (s.e.=0.01%) for general cognitive function. Integration with prior GWAS of cognitive performance and educational attainment yielded several additional significant loci. Finally, we found robust polygenic correlations between cognitive performance and educational attainment, several psychiatric disorders, birth length/weight and smoking behavior, as well as a novel genetic association to the personality trait of openness. These data provide new insight into the genetics of neurocognitive function with relevance to understanding the pathophysiology of neuropsychiatric illness.
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Cognição/fisiologia , Transtornos Neurocognitivos/genética , Adulto , Alelos , Feminino , Frequência do Gene/genética , Estudos de Associação Genética/métodos , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único/genética , População Branca/genéticaRESUMO
BACKGROUND: Evidence suggests that early life stress (ELS) may extend its effect into adulthood and predispose an individual to adverse health outcomes. We investigated whether wartime parental separation, an indicator of severe ELS, would be associated with frailty in old age. METHODS: Of the 972 participants belonging to the present sub-study of the Helsinki Birth Cohort Study, 117 (12.0%) had been evacuated abroad unaccompanied by their parents in childhood during World War II. Frailty was assessed at a mean age of 71 years according to Fried's criteria. RESULTS: Thirteen frail men (4 separated and 9 non-separated) and 20 frail women (2 separated and 18 non-separated) were identified. Compared to the non-separated men, men who had been separated had an increased relative risk ratio (RRR) of frailty (age-adjusted RRR 3.93, 95% CI 1.02, 15.11) that persisted after adjusting for several confounders. No associations were observed among women (RRR 0.62; 95% CI 0.13, 2.94). CONCLUSIONS: These preliminary results suggest that ELS might extend its effects not just into adulthood but also into old age, and secondly, that men may be more vulnerable to the long-term effects of ELS.
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Idoso Fragilizado/psicologia , Fragilidade/epidemiologia , Fragilidade/psicologia , Estresse Psicológico/epidemiologia , Estresse Psicológico/psicologia , II Guerra Mundial , Idoso , Idoso de 80 Anos ou mais , Criança , Estudos de Coortes , Feminino , Finlândia/epidemiologia , Seguimentos , Fragilidade/diagnóstico , Humanos , Masculino , Estresse Psicológico/diagnósticoRESUMO
BACKGROUND: Prenatal maternal obesity has been linked to adverse childhood neuropsychiatric outcomes, including increased symptoms of attention deficit hyperactivity disorder (ADHD), internalizing and externalizing problems, affective disorders and neurodevelopmental problems but few studies have studied neuropsychiatric outcomes among offspring born to very severely obese women or assessed potential familial confounding by maternal psychological distress. METHOD: We evaluated neuropsychiatric symptoms in 112 children aged 3-5 years whose mothers had participated in a longitudinal study of obesity in pregnancy (50 very severe obesity, BMI ⩾40 kg/m2, obese class III and 62 lean, BMI 18.5-25 kg/m2). The mothers completed the Conners' Hyperactivity Scale, Early Symptomatic Syndrome Eliciting Neurodevelopmental Clinical Examination Questionnaire (ESSENCE-Q), Child's Sleep Habits Questionnaire (CSHQ), Strengths and Difficulties Questionnaire (SDQ), and Child Behavior Checklist (CBCL) to assess child neuropsychiatric symptoms. Covariates included child's sex, age, birthweight, gestational age, socioeconomic deprivation levels, maternal age, parity, smoking status during pregnancy, gestational diabetes and maternal concurrent symptoms of anxiety and depression assessed using State Anxiety of Spielberger State-Trait Anxiety Index (STAI) and General Health Questionnaire (GHQ), respectively. RESULTS: Children exposed to prenatal maternal very severe obesity had significantly higher scores in the Conners' Hyperactivity Scale; ESSENCE-Q; total sleep problems in CSHQ; hyperactivity, conduct problems and total difficulties scales of the SDQ; higher externalizing and total problems, anxious/depressed, aggressive behaviour and other problem syndrome scores and higher DSM-oriented affective, anxiety and ADHD problems in CBCL. Prenatal maternal very severe obesity remained a significant predictor of child neuropsychiatric problems across multiple scales independent of demographic factors, prenatal factors and maternal concurrent symptoms of anxiety and depression. CONCLUSIONS: Prenatal maternal very severe obesity is a strong predictor of increased neuropsychiatric problems in early childhood.
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Transtornos de Deficit da Atenção e do Comportamento Disruptivo/epidemiologia , Transtornos do Comportamento Infantil/epidemiologia , Obesidade/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Adulto , Assistência ao Convalescente , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/etiologia , Transtornos do Comportamento Infantil/etiologia , Pré-Escolar , Feminino , Humanos , Obesidade/complicações , GravidezRESUMO
BACKGROUND: Results of adulthood mental health of those born late-preterm (34 + 0-36 + 6 weeks + days of gestation) are mixed and based on national registers. We examined if late-preterm birth was associated with a higher risk for common mental disorders in young adulthood when using a diagnostic interview, and if this risk decreased as gestational age increased. METHOD: A total of 800 young adults (mean = 25.3, s.d. = 0.62 years), born 1985-1986, participated in a follow-up of the Arvo Ylppö Longitudinal Study. Common mental disorders (mood, anxiety and substance use disorders) during the past 12 months were defined using the Composite International Diagnostic Interview (Munich version). Gestational age was extracted from hospital birth records and categorized into early-preterm (<34 + 0, n = 37), late-preterm (34 + 0-36 + 6, n = 106), term (37 + 0-41 + 6, n = 617) and post-term (⩾42 + 0, n = 40). RESULTS: Those born late-preterm and at term were at a similar risk for any common mental disorder [odds ratio (OR) 1.11, 95% confidence interval (CI) 0.67-1.84], for mood (OR 1.11, 95% CI 0.54-2.25), anxiety (OR 1.00, 95% CI 0.40-2.50) and substance use (OR 1.31, 95% CI 0.74-2.32) disorders, and co-morbidity of these disorders (p = 0.38). While the mental disorder risk decreased significantly as gestational age increased, the trend was driven by a higher risk in those born early-preterm. CONCLUSIONS: Using a cohort born during the advanced neonatal and early childhood care, we found that not all individuals born preterm are at risk for common mental disorders in young adulthood - those born late-preterm are not, while those born early-preterm are at a higher risk. Available resources for prevention and intervention should be targeted towards the preterm group born the earliest.
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Transtornos de Ansiedade/epidemiologia , Idade Gestacional , Recém-Nascido Prematuro , Transtornos do Humor/epidemiologia , Sistema de Registros/estatística & dados numéricos , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Adulto , Feminino , Finlândia/epidemiologia , Humanos , Estudos Longitudinais , Masculino , Adulto JovemRESUMO
BACKGROUND: Maternal prenatal depression predicts post-partum depression and increases risk of prematurity and low birth weight. These effects may be mediated by altered placental function. We hypothesized that placental function would be influenced by the gestational week of experiencing depressive symptoms and aimed to examine associations between maternal depressive symptoms during pregnancy and placental expression of genes involved in glucocorticoid and serotonin transfer between mother and fetus. METHOD: We studied women participating in a prospective pregnancy cohort: the Prediction and Prevention of Preeclampsia (PREDO) Study, Helsinki, Finland. Maternal depressive symptoms were assessed at 2-week intervals throughout pregnancy in 56 healthy women with singleton, term pregnancies. Messenger ribonucleic acid (mRNA) levels of glucocorticoid (GR) and mineralocorticoid (MR) receptors and serotonin transporter (SLC6A4), 11ß-hydroxysteroid dehydrogenase type 1 (HSD1) and 2 (HSD2) were quantified in placental biopsies. RESULTS: In adjusted analyses women who reported higher depressive symptoms across the whole pregnancy had higher mRNA levels of GR [effect size 0.31 s.d. units, 95% confidence interval (CI) 0.01-0.60, p = 0.042] and MR (effect size 0.34 s.d. units, 95% CI 0.01-0.68, p = 0.047). These effects were significant for symptoms experienced in the third trimester of pregnancy for GR; findings for MR were also significant for symptoms experienced in the second trimester. GR and MR mRNA levels increased linearly by having the trimester-specific depressive symptoms scores 0, 1 or 2-3 times above the clinical cut-off for depression (p = 0.003, p = 0.049, respectively, and p = 0.004, p = 0.15 in adjusted analyses). CONCLUSIONS: Our findings offer potential gestational-age-specific mechanisms linking maternal depressive symptoms during pregnancy via placental biology. Future studies will test whether these also link with adverse offspring outcomes.
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Depressão/fisiopatologia , Glucocorticoides/metabolismo , Complicações na Gravidez/fisiopatologia , RNA Mensageiro/metabolismo , 11-beta-Hidroxiesteroide Desidrogenases/análise , Adulto , Feminino , Finlândia , Glucocorticoides/genética , Humanos , Modelos Lineares , Placenta/química , Gravidez , Trimestres da Gravidez , Escalas de Graduação Psiquiátrica , RNA Mensageiro/análise , RNA Mensageiro/genética , Receptores de Mineralocorticoides/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas da Membrana Plasmática de Transporte de Serotonina/análise , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Adulto JovemRESUMO
BACKGROUND: Glucocorticoids and serotonin may mediate the link between maternal environment, fetal brain development and 'programming' of offspring behaviors. The placenta regulates fetal exposure to maternal hormonal signals in animal studies, but few data address this in humans. We measured prospectively maternal depressive symptoms during pregnancy and mRNAs encoding key gene products determining glucocorticoid and serotonin function in term human placenta and explored associations with infant regulatory behaviors. METHOD: Bi-weekly self-ratings of the Center for Epidemiologic Studies Depression Scale from 12th to 13th gestational week onwards and term placental mRNAs of 11beta-hydroxysteroid dehydrogenase type 2 (HSD2B11), type 1 (HSD1B11), glucocorticoid (NR3C1), mineralocorticoid receptors (NR3C2) and serotonin transporter (SLC6A4) were obtained from 54 healthy mothers aged 32.2 ± 5.3 years with singleton pregnancies and without pregnancy complications. Infant regulatory behaviors (crying, feeding, spitting, elimination, sleeping and predictability) were mother-rated at 15.6 ± 4.2 days. RESULTS: Higher placental mRNA levels of HSD2B11 [0.41 standard deviation (s.d.) unit increase per s.d. unit increase; 95% confidence interval (CI) 0.13-0.69, p = 0.005], HSD1B11 (0.30, 0.03-0.57, p = 0.03), NR3C1 (0.44, 0.19-0.68, p = 0.001) and SLC6A4 (0.26, 0.00-0.53, p = 0.05) were associated with more regulatory behavioral challenges of the infant. Higher placental NR3C1 mRNA partly mediated the association between maternal depressive symptoms during pregnancy and infant regulatory behaviors (p < 0.05). CONCLUSIONS: Higher placental expression of genes regulating feto-placental glucocorticoid and serotonin exposure is characteristic of infants with more regulatory behavioral challenges. Maternal depression acts, at least partly, via altering glucocorticoid action in the placenta to impact on offspring regulatory behaviors.
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Depressão/metabolismo , Glucocorticoides/metabolismo , Comportamento do Lactente/fisiologia , Placenta/metabolismo , Complicações na Gravidez/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Comportamento Problema , Serotonina/metabolismo , Adulto , Feminino , Seguimentos , Expressão Gênica , Glucocorticoides/genética , Humanos , Lactente , Masculino , Gravidez , RNA Mensageiro/metabolismo , Serotonina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismoRESUMO
BACKGROUND: Late preterm births constitute the majority of preterm births. However, most evidence suggesting that preterm birth predicts the risk of mental disorders comes from studies on earlier preterm births. We examined if late preterm birth predicts the risks of severe mental disorders from early to late adulthood. We also studied whether adulthood mental disorders are associated with post-term birth or with being born small (SGA) or large (LGA) for gestational age, which have been previously associated with psychopathology risk in younger ages. METHOD: Of 12 597 Helsinki Birth Cohort Study participants, born 1934-1944, 664 were born late preterm, 1221 post-term, 287 SGA, and 301 LGA. The diagnoses of mental disorders were identified from national hospital discharge and cause of death registers from 1969 to 2010. In total, 1660 (13.2%) participants had severe mental disorders. RESULTS: Individuals born late preterm did not differ from term-born individuals in their risk of any severe mental disorder. However, men born late preterm had a significantly increased risk of suicide. Post-term birth predicted significantly increased risks of any mental disorder in general and particularly of substance use and anxiety disorders. Individuals born SGA had significantly increased risks of any mental and substance use disorders. Women born LGA had an increased risk of psychotic disorders. CONCLUSIONS: Although men born late preterm had an increased suicide risk, late preterm birth did not exert widespread effects on adult psychopathology. In contrast, the risks of severe mental disorders across adulthood were increased among individuals born SGA and individuals born post-term.
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Retardo do Crescimento Fetal/epidemiologia , Macrossomia Fetal/epidemiologia , Transtornos Mentais/epidemiologia , Nascimento Prematuro/epidemiologia , Adulto , Idoso , Estudos de Coortes , Feminino , Finlândia/epidemiologia , Humanos , Recém-Nascido , Criança Pós-Termo , Recém-Nascido Prematuro , Recém-Nascido Pequeno para a Idade Gestacional , Masculino , Pessoa de Meia-Idade , Gravidez , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
It has long been recognized that generalized deficits in cognitive ability represent a core component of schizophrenia (SCZ), evident before full illness onset and independent of medication. The possibility of genetic overlap between risk for SCZ and cognitive phenotypes has been suggested by the presence of cognitive deficits in first-degree relatives of patients with SCZ; however, until recently, molecular genetic approaches to test this overlap have been lacking. Within the last few years, large-scale genome-wide association studies (GWAS) of SCZ have demonstrated that a substantial proportion of the heritability of the disorder is explained by a polygenic component consisting of many common single-nucleotide polymorphisms (SNPs) of extremely small effect. Similar results have been reported in GWAS of general cognitive ability. The primary aim of the present study is to provide the first molecular genetic test of the classic endophenotype hypothesis, which states that alleles associated with reduced cognitive ability should also serve to increase risk for SCZ. We tested the endophenotype hypothesis by applying polygenic SNP scores derived from a large-scale cognitive GWAS meta-analysis (~5000 individuals from nine nonclinical cohorts comprising the Cognitive Genomics consorTium (COGENT)) to four SCZ case-control cohorts. As predicted, cases had significantly lower cognitive polygenic scores compared to controls. In parallel, polygenic risk scores for SCZ were associated with lower general cognitive ability. In addition, using our large cognitive meta-analytic data set, we identified nominally significant cognitive associations for several SNPs that have previously been robustly associated with SCZ susceptibility. Results provide molecular confirmation of the genetic overlap between SCZ and general cognitive ability, and may provide additional insight into pathophysiology of the disorder.
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Cognição , Esquizofrenia/genética , Adolescente , Adulto , Idoso , Alelos , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Humanos , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Testes Neuropsicológicos , Polimorfismo de Nucleotídeo Único , Risco , Esquizofrenia/epidemiologia , Adulto JovemRESUMO
OBJECTIVE: To study whether pre-eclampsia and hypertension without proteinuria during pregnancy are associated with adaptive functioning, and psychiatric and psychological problems, of older offspring. DESIGN: Retrospective longitudinal cohort study. SETTING: Participants in the Helsinki Birth Cohort 1934-44 Study. POPULATION: A cohort of 778 participants born after normotensive, pre-eclamptic, or hypertensive pregnancies, defined based on the mother's blood pressure and urinary protein measurements at maternity clinics and birth hospitals. METHODS: Pearson's chi-squared tests and multivariable logistic regression. MAIN OUTCOME MEASURES: Achenbach System of Empirically Based Assessment Older Adult Self-Report scores, completed at age 69.3 years (SD 3.1 years). RESULTS: Compared with offspring born after normotensive pregnancies, offspring born after pre-eclamptic pregnancies had increased odds of reporting total problems (aOR 4.00, 95%CI 1.64-9.77) and problems of particular concern to clinicians (critical items; aOR 5.28, 95%CI 1.87-14.96), as well as: anxious/depressed, functional impairment, memory, thought, and irritable/disinhibited problems on syndrome scales; depressive, somatic, and psychotic problems on Diagnostic and Statistical Manual of Mental Disorders scales; and adjustment problems in relationship satisfaction with spouse/partner. Maternal hypertension without proteinuria was not consistently associated with adjustment and problems (total problems, aOR 1.08, 95%CI 0.75-1.57; critical items, aOR 1.58, 95%CI 0.91-2.72). CONCLUSIONS: Maternal hypertensive disorders in pregnancy, during a period of expectant treatment, carry an increased risk of problems in adaptive functioning and mental wellbeing in the offspring seven decades later. Being the longest follow-up on transgenerational consequences of maternal hypertensive disorders reported thus far, our study points to the life-time increased risk of an adverse intrauterine environment.
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Adaptação Psicológica , Hipertensão Induzida pela Gravidez , Transtornos Mentais/etiologia , Efeitos Tardios da Exposição Pré-Natal/etiologia , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Modelos Logísticos , Masculino , Transtornos Mentais/psicologia , Pessoa de Meia-Idade , Gravidez , Efeitos Tardios da Exposição Pré-Natal/psicologia , Proteinúria , Testes Psicológicos , Estudos Retrospectivos , Fatores de Risco , AutorrelatoRESUMO
Background: Autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and schizophrenia (SCZ) are highly heritable and linked to disruptions in foetal (neuro)development. While epigenetic processes are considered an important underlying pathway between genetic susceptibility and neurodevelopmental conditions, it is unclear (i) whether genetic susceptibility to these conditions is associated with epigenetic patterns, specifically DNA methylation (DNAm), already at birth; (ii) to what extent DNAm patterns are unique or shared across conditions, and (iii) whether these neonatal DNAm patterns can be leveraged to enhance genetic prediction of (neuro)developmental outcomes. Methods: We conducted epigenome-wide meta-analyses of genetic susceptibility to ASD, ADHD, and schizophrenia, quantified using polygenic scores (PGSs) on cord blood DNAm, using four population-based cohorts (n pooled=5,802), all North European. Heterogeneity statistics were used to estimate overlap in DNAm patterns between PGSs. Subsequently, DNAm-based measures of PGSs were built in a target sample, and used as predictors to test incremental variance explained over PGS in 130 (neuro)developmental outcomes spanning birth to 14 years. Outcomes: In probe-level analyses, SCZ-PGS associated with neonatal DNAm at 246 loci (p<9×10-8), predominantly in the major histocompatibility complex. Functional characterization of these DNAm loci confirmed strong genetic effects, significant blood-brain concordance and enrichment for immune-related pathways. 8 loci were identified for ASD-PGS (mapping to FDFT1 and MFHAS1), and none for ADHD-PGS. Regional analyses indicated a large number of differentially methylated regions for all PGSs (SCZ-PGS: 157, ASD-PGS: 130, ADHD-PGS: 166). DNAm signals showed little overlap between PGSs. We found suggestive evidence that incorporating DNAm-based measures of genetic susceptibility at birth increases explained variance for several child cognitive and motor outcomes over and above PGS. Interpretation: Genetic susceptibility for neurodevelopmental conditions, particularly schizophrenia, is detectable in cord blood DNAm at birth in a population-based sample, with largely distinct DNAm patterns between PGSs. These findings support an early-origins perspective on schizophrenia. Funding: HorizonEurope; European Research Council.
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OBJECTIVE: To study the effect of aspirin in the prevention of pre-eclampsia in high-risk women. DESIGN: Randomised, double-blinded, placebo-controlled trial. SETTING: Maternity clinics in ten Finnish hospitals participating in the PREDO Project. SAMPLE: A total of 152 women with risk factors for pre-eclampsia and abnormal uterine artery Doppler velocimetry. METHODS: Participants were randomised to start either aspirin 100 mg/day or placebo at 12 + 0 to 13 + 6 weeks + days of gestation. Because of the limited power of this trial, we also conducted a meta-analysis of randomised controlled trials that included data on 346 women with abnormal uterine artery Doppler flow velocimetry, and aspirin 50-150 mg/day started at or before 16( ) weeks of gestation. MAIN OUTCOME MEASURE: Pre-eclampsia, gestational hypertension and birthweight standard deviation (SD) score. Outcome measures for the meta-analysis were pre-eclampsia, severe pre-eclampsia, preterm (diagnosed <37 + 0 weeks of gestation) and term pre-eclampsia. RESULTS: From the 152 randomised women, 121 were included in the final analysis. Low-dose aspirin did not reduce the rate of pre-eclampsia (relative risk [RR] 0.7, 95% CI 0.3-1.7); gestational hypertension (RR 1.6, 95% CI 0.6-4.2); early-onset pre-eclampsia (diagnosed <34 + 0 weeks of gestation) (RR 0.2, 95% CI 0.03-2.1); or severe pre-eclampsia (RR 0.4, 95% CI 0.1-1.3); and the results were not statistically significant in an intention-to-treat analysis. However, our meta-analysis, including the current data, suggested that low-dose aspirin initiated before 16 weeks of gestation reduces the risk of pre-eclampsia (RR 0.6, 95% CI 0.4-0.8) and severe pre-eclampsia (RR 0.3, 95% CI 0.1-0.7). CONCLUSIONS: Our trial showed no statistically significant effect of aspirin in preventing pre-eclampsia in high-risk women. However, our meta-analysis suggested that aspirin may reduce the incidence of pre-eclampsia.
Assuntos
Aspirina/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Pré-Eclâmpsia/prevenção & controle , Adolescente , Adulto , Método Duplo-Cego , Feminino , Finlândia , Humanos , Pré-Eclâmpsia/diagnóstico por imagem , Gravidez , Gravidez de Alto Risco , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Ultrassonografia Doppler em Cores , Adulto JovemRESUMO
BACKGROUND: Patients with schizophrenia have excess cardiovascular morbidity and mortality. Previous studies suggest that this may be partly due to inadequate somatic treatment and care, such as non-optimal use of lipid-lowering and antihypertensive pharmacotherapy, but longitudinal studies on such aetiological pathways are scarce. METHOD: We investigated the use of lipid-lowering and antihypertensive pharmacotherapy, and the risk of hospitalization for and death from coronary heart disease and stroke among patients with schizophrenia in a birth cohort of 12 939 subjects (Helsinki Birth Cohort Study). This cohort was followed for over 30 adult years by using national databases on cardio- and cerebrovascular hospitalizations and mortality and on reimbursement entitlements and use of drugs for treatment of hypertension, dyslipidaemia, coronary heart disease and diabetes. RESULTS: Individuals with schizophrenia had a higher risk of hospitalization for coronary heart disease [hazard ratio (HR) 1.65, 95% confidence interval (CI) 1.03-2.57], and mortality from this disease was markedly higher (HR 2.92, 95% CI 1.70-5.00), particularly among women (p=0.001 for women, p=0.008 for men). Women with schizophrenia had also marginally increased stroke mortality (p=0.06). However, patients with schizophrenia used less lipid-lowering (odds ratio 0.47, 95% CI 0.27-0.80) and antihypertensive drug treatment (HR 0.37, 95% CI 0.22-0.61). CONCLUSIONS: In this longitudinal study, coronary heart disease morbidity was increased and coronary heart disease mortality markedly increased in patients, especially in women with schizophrenia. These patients nevertheless received less antihypertensive and lipid-lowering treatment.
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Doença das Coronárias , Sistema de Registros/estatística & dados numéricos , Esquizofrenia/epidemiologia , Idoso , Comorbidade , Doença das Coronárias/tratamento farmacológico , Doença das Coronárias/epidemiologia , Doença das Coronárias/mortalidade , Feminino , Finlândia/epidemiologia , Humanos , Masculino , Fatores Sexuais , Acidente Vascular CerebralRESUMO
A suboptimal prenatal environment may induce permanent changes in cells, organs and physiology that alter social, emotional and cognitive functioning, and increase the risk of cardiometabolic and mental disorders in subsequent life ("developmental programming"). Although animal studies have provided a wealth of data on programming and its mechanisms, including on the role of stress and its glucocorticoid mediators, empirical evidence of these mechanisms in humans is still scanty. We review the existing human evidence on the effects of prenatal maternal stress, anxiety and depression, glucocorticoids and intake of liquorice (which inhibits the placental barrier to maternal glucocorticoids) on offspring developmental outcomes including, for instance, alterations in psychophysiological and neurocognitive functioning and mental health. This work lays the foundations for biomarker discovery and affords opportunities for prevention and interventions to ameliorate adverse outcomes in humans.
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Ansiedade/psicologia , Depressão/complicações , Glucocorticoides/efeitos adversos , Glycyrrhiza/efeitos adversos , Complicações na Gravidez/psicologia , Efeitos Tardios da Exposição Pré-Natal , Estresse Psicológico/complicações , Criança , Pré-Escolar , Feminino , Glucocorticoides/fisiologia , Humanos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/fisiologia , Recém-Nascido de Baixo Peso , Recém-Nascido , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/fisiologia , GravidezRESUMO
OBJECTIVE: Trait anxiety may predispose to anxiety disorders and cardiovascular events. We tested whether prenatal growth or postnatal growth from birth to 11 years of age and in adulthood predict trait anxiety in late adulthood. METHOD: Women (n = 951) and men (n = 753) reported trait anxiety using the Spielberger Trait Anxiety Scale at an average age of 63.4 years and growth was estimated from records. RESULTS: Higher trait anxiety was predicted by smaller body size at birth, in infancy and in adulthood. Moreover, faster growth particularly from seven to 11 years of age and slower growth between 11 and 63 years predicted higher trait anxiety. CONCLUSION: We found a pattern of pre- and postnatal growth that predisposed to higher trait anxiety in late adulthood. This pattern resembles that found to increase the risk of cardiovascular events and, thus, points to a shared common origin in a suboptimal prenatal and childhood developmental milieu.
Assuntos
Ansiedade/fisiopatologia , Desenvolvimento Humano , Adolescente , Adulto , Idoso , Ansiedade/epidemiologia , Transtornos de Ansiedade/epidemiologia , Transtornos de Ansiedade/fisiopatologia , Tamanho Corporal , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/fisiopatologia , Causalidade , Criança , Pré-Escolar , Estudos de Coortes , Suscetibilidade a Doenças , Feminino , Finlândia , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Fatores de Tempo , Adulto JovemRESUMO
OBJECTIVE: We studied whether pre-eclampsia predicts depressive symptoms in offspring. DESIGN: Retrospective longitudinal cohort study. SETTING: Participants in the Helsinki Birth Cohort 1934-44 Study. POPULATION: We classed 788 women and men born at term after a normotensive, hypertensive or pre-eclamptic pregnancy, by using the mother's blood pressure and urinary protein measurements, at maternity clinics and birth hospitals. METHODS: Linear and logistic regression analyses. We made adjustments for the mother's age and body mass index (BMI) at delivery, the participant's body size at birth/length of gestation, sex and childhood socio-economic status, age and educational attainment at testing. MAIN OUTCOME MEASURES: Beck depression inventory (BDI) scores completed twice, at the ages of 60 and 63 years. RESULT: Participants born after a primiparous pregnancy complicated by pre-eclampsia had over 30% (P < 0.04) higher depressive symptom scores in adulthood compared with those born after a primiparous normotensive pregnancy. We found no evidence of the association between pre-eclampsia and depression among participants born after multiparous pregnancies. Gestational hypertension and depressive symptoms were not significantly associated. The models adjusting for mother's age and BMI at delivery, the participant's body size at birth/length of gestation, sex, childhood socio-economic status, age and educational attainment at testing did not change the results. CONCLUSION: Pre-eclampsia is associated with later depressive symptoms in individuals born at term and after a primiparous pregnancy. These findings are compatible with the adverse fetal 'programming' by a suboptimal prenatal environment.