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Autism screening questionnaires are sometimes used as a measure of "autism-associated traits" in samples drawn from the general population, even though such tools are primarily developed and designed for use in samples of children diagnosed with or being assessed for autism. Here, we explore the psychometric properties of the Social Communication Questionnaire (SCQ) current version reported at age 8 in a large population-based sample. Using data from the Norwegian Mother, Father and Child Cohort study (MoBa), we perform exploratory (N = 21,775) and confirmatory (N = 21,674) factor analyses on items and compare our results with previously suggested factor structure models of the SCQ. Furthermore, we test for measurement invariance across sex and registry-ascertained autism diagnostic status (N[subscript diagnosed] = 636). A 5-factor model provided best fit to the data in both children with and without autism diagnoses, though with some qualitative differences in what the factors represent across these groups. This model performed largely consistently across boys and girls in the general population. Taken together, the SCQ's measurement properties must be carefully considered when it is used in population-based samples and measurement invariance testing of other autism screening tools used in similar contexts is warranted.

Using questionnaires in research relies on the expectation that they measure the same things across different groups of individuals. If this is not true, then interpretations of results can be misleading when researchers compare responses across different groups of individuals or use in it a group that differs from that in which the questionnaire was developed. For the questionnaire we investigated, the Social Communication Questionnaire (SCQ), we found that parents of boys and girls responded to questionnaire items in largely the same way but that the SCQ measured traits and behaviors slightly differently depending on whether the children had autism. Based on these results, we concluded that researchers using this questionnaire should carefully consider these differences when deciding how to interpret findings. SCQ scores as a reflection of autism-associated traits in samples that are mostly or entirely made up of individuals without an autism diagnosis may be misleading and we encourage a more precise interpretation of scores as a broader indication of social-communicative and behavioral traits.

Children born to parents with fewer years of education are more likely to have depression, anxiety, and attention-deficit hyperactivity disorder (ADHD), but it is unclear to what extent these associations are causal. We estimated the effect of parents' educational attainment on children's depressive, anxiety, and ADHD traits at age 8 years, in a sample of 40,879 Norwegian children born in 1998-2009 and their parents. We used within-family Mendelian randomization, which employs genetic variants as instrumental variables, and controlled for direct genetic effects by adjusting for children's polygenic indexes. We found little evidence that mothers' or fathers' educational attainment independently affected children's depressive, anxiety, or ADHD traits. However, children's own polygenic scores for educational attainment were independently and negatively associated with these traits. Results suggest that differences in these traits according to parents' education may reflect direct genetic effects more than genetic nurture. Consequences of social disadvantage for children's mental health may however be more visible in samples with more socioeconomic variation, or contexts with larger socioeconomic disparities than present-day Norway. Further research is required in populations with more educational and economic inequality and in other age groups.

Abstract Background Autism and different neurodevelopmental conditions frequently co-occur, as do their symptoms at sub-diagnostic threshold levels. Overlapping traits and shared genetic liability are potential explanations. Methods In the population-based Norwegian Mother, Father, and Child Cohort study (MoBa), we leverage item-level data to explore the phenotypic factor structure and genetic architecture underlying neurodevelopmental traits at age 3 years (N = 41,708–58,630) using maternal reports on 76 items assessing children’s motor and language development, social functioning, communication, attention, activity regulation, and flexibility of behaviors and interests. Results We identified 11 latent factors at the phenotypic level. These factors showed associations with diagnoses of autism and other neurodevelopmental conditions. Most shared genetic liabilities with autism, ADHD, and/or schizophrenia. Item-level GWAS revealed trait-specific genetic correlations with autism (items r g range = − 0.27–0.78), ADHD (items r g range = − 0.40–1), and schizophrenia (items r g range = − 0.24–0.34). We find little evidence of common genetic liability across all neurodevelopmental traits but more so for several genetic factors across more specific areas of neurodevelopment, particularly social and communication traits. Some of these factors, such as one capturing prosocial behavior, overlap with factors found in the phenotypic analyses. Other areas, such as motor development, seemed to have more heterogenous etiology, with specific traits showing a less consistent pattern of genetic correlations with each other. Conclusions These exploratory findings emphasize the etiological complexity of neurodevelopmental traits at this early age. In particular, diverse associations with neurodevelopmental conditions and genetic heterogeneity could inform follow-up work to identify shared and differentiating factors in the early manifestations of neurodevelopmental traits and their relation to autism and other neurodevelopmental conditions. This in turn could have implications for clinical screening tools and programs.

Prior studies have reported associations between socioeconomic disadvantage, brain structure and mental health outcomes, but the timing of these relations is not well understood. Using prospective longitudinal data from the Avon Longitudinal Study of Parents and Children (ALSPAC), this preregistered study examined whether socioeconomic disadvantage related differentially to depressive symptoms (n=3012–3530) and cortical and subcortical structures (n=460–733) in emerging adults, depending on the timing of exposure to socioeconomic disadvantage. Family income in early childhood and own income measured concurrently were both significantly related to depressive symptoms in emerging adulthood. Similar results were observed for perceived financial strain. In contrast, only family income in early childhood was associated with brain structure in emerging adulthood, with positive associations with intracranial volume and total and regional cortical surface area. The findings suggest that both objective and subjective aspects of one’s financial standing throughout development relate to depressive symptoms in adulthood, but that specifically early life family income is related to brain structural features in emerging adulthood. This suggests that associations between socioeconomic disadvantage and brain structure originate early in neurodevelopment, highlighting the role of timing of socioeconomic disadvantage.

Abstract Background The timing of puberty may have an important impact on adolescent mental health. In particular, earlier age at menarche has been associated with elevated rates of depression in adolescents. Previous research suggests that this relationship may be causal, but replication and an investigation of whether this effect extends to other mental health domains is warranted. Methods In this Registered Report, we triangulated evidence from different causal inference methods using a new wave of data (N = 13,398) from the Norwegian Mother, Father, and Child Cohort Study. We combined multiple regression, one- and two-sample Mendelian randomisation (MR), and negative control analyses (using pre-pubertal symptoms as outcomes) to assess the causal links between age at menarche and different domains of adolescent mental health. Results Our results supported the hypothesis that earlier age at menarche is associated with elevated depressive symptoms in early adolescence based on multiple regression (β = − 0.11, 95% CI [− 0.12, − 0.09], p one-tailed

BackgroundGenetics and biology may influence the age of onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to age of onset of AN and to investigate the genetic associations between age of onset of AN and age at menarche.MethodsA secondary analysis of the Psychiatric Genomics Consortium genome-wide association study (GWAS) of AN was performed, which included 9335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age of onset, early-onset AN (

Abstract The widespread comorbidity observed across psychiatric disorders may be the result of processes such as assortative mating, gene-environment correlation, or selection into population studies. Between-family analyses of comorbidity are subject to these sources of bias, whereas within-family analyses are not. Because of Mendelian inheritance, alleles are randomly assigned within families, conditional on parental alleles. We exploit this variation to compare the structure of comorbidity across broad psychiatric polygenic scores when calculated either between-family (child polygenic scores) or within-family (child polygenic scores regressed on parental polygenic scores) in over 25,000 genotyped parent-offspring trios from the Norwegian Mother Father and Child Cohort study (MoBa). We fitted a series of factor models to the between- and within-family data, which consisted of a single genetic p-factor and a varying number of uncorrelated subfactors. The best-fitting model was identical for between- and within-family analyses and included three subfactors capturing variants associated with neurodevelopment, psychosis, and constraint, in addition to the genetic p-factor. Partner genetic correlations, indicating assortative mating, were not present for the genetic p-factor, but were substantial for the psychosis (b = 0.081;95% CI [0.038,0.124]) and constraint (b = 0.257;95% CI [0.075,0.439]) subfactors. When average factor levels for MoBa mothers and fathers were compared to a population mean of zero we found evidence of sex-specific participation bias, which has implications for the generalizability of findings from cohort studies. Our results demonstrate the power of the within-family design for better understanding the mechanisms driving psychiatric comorbidity and their consequences on population health.

Abstract Background Adverse pregnancy outcomes (APO) may unmask or exacerbate a woman’s underlying risk for coronary heart disease (CHD). We estimated associations of maternal and paternal genetically predicted liability for CHD with lifelong risk of APOs. We hypothesized that associations would be found for women, but not their male partners (negative controls). Methods We studied up to 83,969‬ women (and up to 55,568‬ male partners) from the Norwegian Mother, Father and Child Cohort Study or the Trøndelag Health Study with genotyping data and lifetime history of any APO in their pregnancies (1967–2019) in the Medical Birth Registry of Norway (miscarriage, stillbirth, hypertensive disorders of pregnancy, gestational diabetes, small for gestational age, large for gestational age, and spontaneous preterm birth). Maternal and paternal genetic risk scores (GRS) for CHD were generated using 148 gene variants (p-value

ObjectiveTo investigate the genetic architecture of internalizing symptoms in childhood and adolescence.MethodIn 22 cohorts, multiple univariate genome-wide association studies (GWASs) were performed using repeated assessments of internalizing symptoms, in a total of 64,561 children and adolescents between 3 and 18 years of age. Results were aggregated in meta-analyses that accounted for sample overlap, first using all available data, and then using subsets of measurements grouped by rater, age, and instrument.ResultsThe meta-analysis of overall internalizing symptoms (INToverall) detected no genome-wide significant hits and showed low single nucleotide polymorphism (SNP) heritability (1.66%, 95% CI = 0.84-2.48%, neffective = 132,260). Stratified analyses indicated rater-based heterogeneity in genetic effects, with self-reported internalizing symptoms showing the highest heritability (5.63%, 95% CI = 3.08%-8.18%). The contribution of additive genetic effects on internalizing symptoms appeared to be stable over age, with overlapping estimates of SNP heritability from early childhood to adolescence. Genetic correlations were observed with adult anxiety, depression, and the well-being spectrum (|rg| > 0.70), as well as with insomnia, loneliness, attention-deficit/hyperactivity disorder, autism, and childhood aggression (range |rg| = 0.42-0.60), whereas there were no robust associations with schizophrenia, bipolar disorder, obsessive-compulsive disorder, or anorexia nervosa.ConclusionGenetic correlations indicate that childhood and adolescent internalizing symptoms share substantial genetic vulnerabilities with adult internalizing disorders and other childhood psychiatric traits, which could partially explain both the persistence of internalizing symptoms over time and the high comorbidity among childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood samples will be key in paving the way to future GWAS success.

Summary: Low birth weight raises neonatal risks and lifelong health issues and is linked to maternal medication use during pregnancy. We examined data from the Norwegian Mother, Father, and Child Cohort Study and the Medical Birth Registry of Norway, including 69,828 offspring with genotype data and 81,189 with maternal genotype data. We identified genetic risk variants in placental efflux transporters, calculated genetic scores based on alleles related to transporter activity, and assessed their interaction with prenatal use of antiseizure or antidepressant medication on offspring birth weight. Our study uncovered possible genetic variants in both offspring (rs3740066) and mothers (rs10248420; rs2235015) in placental efflux transporters (MRP2-ABCC2 and MDR1-ABCB1) that modulated the association between prenatal exposure to antiseizure medication and low birth weight in the offspring. Antidepressant exposure was associated with low birth weight, but there were no gene-drug interactions. The interplay between MRP2-ABCC2 and MDR1-ABCB1 variants and antiseizure medication may impact neonatal birth weight.

Estimates from genome-wide association studies (GWAS) of unrelated individuals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indirect genetic effects, but large-scale family datasets have been lacking. We combined data from 178,086 siblings from 19 cohorts to generate population (between-family) and within-sibship (within-family) GWAS estimates for 25 phenotypes. Within-sibship GWAS estimates were smaller than population estimates for height, educational attainment, age at first birth, number of children, cognitive ability, depressive symptoms and smoking. Some differences were observed in downstream SNP heritability, genetic correlations and Mendelian randomization analyses. For example, the within-sibship genetic correlation between educational attainment and body mass index attenuated towards zero. In contrast, analyses of most molecular phenotypes (for example, low-density lipoprotein-cholesterol) were generally consistent. We also found within-sibship evidence of polygenic adaptation on taller height. Here, we illustrate the importance of family-based GWAS data for phenotypes influenced by demographic and indirect genetic effects.

Cognitive skills are a strong predictor of a wide range of later life outcomes. Genetic and epigenetic associations across the genome explain some of the variation in general cognitive abilities in the general population and it is plausible that epigenetic associations might arise from prenatal environmental exposures and/or genetic variation early in life. We investigated the association between cord blood DNA methylation at birth and cognitive skills assessed in children from eight pregnancy cohorts within the Pregnancy And Childhood Epigenetics (PACE) Consortium across overall (total N = 2196), verbal (total N = 2206) and non-verbal cognitive scores (total N = 3300). The associations at single CpG sites were weak for all of the cognitive domains investigated. One region near DUSP22 on chromosome 6 was associated with non-verbal cognition in a model adjusted for maternal IQ. We conclude that there is little evidence to support the idea that variation in cord blood DNA methylation at single CpG sites is associated with cognitive skills and further studies are needed to confirm the association at DUSP22.

BackgroundDelayed walking is common in intellectual disability (ID) but may be less common when ID occurs with autism spectrum disorder (ASD). Previous studies examining this were limited by reliance on clinical samples and exclusion of children with severe motor deficits.ObjectiveTo examine in a population-based sample if age of walking is differentially related to intellectual ability in children with ASD versus other neurodevelopmental disorders (NDD).MethodsParticipants were from the nested Autism Birth Cohort Study of the Norwegian Mother, Father and Child Cohort Study (MoBa). Cox proportional hazards regression assessed if diagnosis (ASD n = 212 vs. NDD n = 354), continuous nonverbal IQ, and their interaction, were associated with continuous age of walking.ResultsThe relationship between nonverbal IQ and age of walking was stronger for NDD than for ASD (Group × nonverbal IQ interaction, χ2  = 13.93, p = .0002). This interaction was characterized by a 21% decrease in the likelihood of walking onset at any given time during the observation period per 10-point decrease in nonverbal IQ (hazard ratio = 0.79, 95% CI: 0.78-0.85) in the NDD group compared to 8% (hazard ratio = 0.92, 95% CI: 0.86-0.98) in the ASD group.ConclusionsThe finding that age of walking is less strongly related to low intellectual ability in children with ASD than in children without other NDDs supports the hypothesis that ID in ASD may result from heterogeneous developmental pathways. Late walking may be a useful stratification variable in etiological research focused on ASD and other NDDs.

Abstract Knowledge on how genetic risk for bipolar disorder manifests in developmental, emotional or behavioral traits during childhood is lacking. This issue is important to address to inform early detection and intervention efforts. We investigated whether polygenic risk for bipolar disorder is associated with developmental outcomes during early to middle childhood in the general population, and if associations differ between boys and girls. Our sample consisted of 28 001 children from the Norwegian Mother, Father and Child Cohort study, a prospective pregnancy cohort with available genotype and developmental data. Mothers reported on a range of developmental outcomes in their children at 6 and 18 months, 3, 5 and 8 years. Polygenic risk scores reflecting common variant liability to bipolar disorder were calculated. Linear regression models were used in a multi-group framework to investigate associations between polygenic risk score and developmental outcomes, using sex as a grouping variable. We found robust evidence for an association between polygenic risk scores for bipolar disorder and conduct difficulties (β = 0.041, CI = 0.020–0.062) and oppositional defiant difficulties (β = 0.032, CI = 0.014–0.051) at 8 years. Associations with most other outcomes were estimated within the region of practical equivalence to zero (equivalence range D = −0.1 to 0.1), with the exceptions of negative association for activity levels (β = −0.028, CI = −0.047– −0.010) at age 5 and benevolence (β = −0.025, CI = –0.043 to –0.008) at age 8, and positive association for motor difficulties (β = 0.025, CI = 0.008–0.043) at age 3, inattention (β = 0.021, CI = 0.003–0.041) and hyperactivity (β = 0.025, CI = 0.006–0.044) at age 8. Our results suggest that genetic risk for bipolar disorder manifests as disruptive behaviors like oppositional defiant and conduct difficulties in childhood in the general population.

Abstract Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. To explore genetic causes of recessive lethality, we searched for sequence variants with deficit of homozygosity among 1.52 million individuals from six European populations. In this study, we identified 25 genes harboring protein-altering sequence variants with a strong deficit of homozygosity (10% or less of predicted homozygotes). Sequence variants in 12 of the genes cause Mendelian disease under a recessive mode of inheritance, two under a dominant mode, but variants in the remaining 11 have not been reported to cause disease. Sequence variants with a strong deficit of homozygosity are over-represented among genes essential for growth of human cell lines and genes orthologous to mouse genes known to affect viability. The function of these genes gives insight into the genetics of intrauterine lethality. We also identified 1077 genes with homozygous predicted loss-of-function genotypes not previously described, bringing the total set of genes completely knocked out in humans to 4785.

Abstract Background An individual's overall burden of behavioural and emotional problems across childhood is associated with increased likelihood of later mental health conditions. However, the relative extent of behavioural versus emotional problems ‐ that is, the extent to which the domains are differentiated from one another ‐ may provide additional information about who is at risk of developing a mental health condition. Here, we seek to validate differentiation as an independent predictor of later mental health conditions, and to explore its aetiology. Methods We analysed data from ~79,000 children in the population‐based Norwegian Mother, Father, and Child Cohort Study, and linked health‐care registries. In preregistered analyses, we modelled the extent and rate of differentiation of behavioural and emotional problems between ages 1.5–5 years, and estimated associations with later symptoms (age 8) and diagnoses (after age 8). We also explored the aetiology of differentiation by estimating associations with early life exposures and, in a subset of 23,945 full siblings, assessing the impact of accounting for unobserved familial confounding. Results Differentiation of behavioural and emotional problems was associated with later symptoms and diagnoses of mental health conditions, independent of total problems. Maternal at‐risk drinking (β = 0.04 [0.02, 0.06]) and parental relationship problems (β = 0.04 [0.02, 0.05]) were associated with higher behavioural relative to emotional problems at age 5. Maternal prenatal distress (|β| = 0.04 [0.03, 0.06]), concurrent distress (|β| = 0.04 [0.02, 0.06]) and parental education (|β| = 0.05 [0.04, 0.07]) predicted higher emotional relative to behavioural problems at age 5. Estimates for maternal prenatal distress and at‐risk drinking were consistent across both unadjusted and adjusted analyses accounting for unobserved familial risk. Conclusions Differentiation of behavioural and emotional problems in early childhood represents a valid source of inter‐individual variability linked to the later emergence of psychopathology and may be relevant for early detection and prevention strategies for mental health.

Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGGoverall) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGGoverall. The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E-06), PCDH7 (P = 2.0E-06), and IPO13 (P = 2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (rg) among rater-specific assessment of AGG ranged from rg = 0.46 between self- and teacher-assessment to rg = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range [Formula: see text]: 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (rg = ~-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range [Formula: see text]: 0.46-0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.

Abstract Background Guidance to improve fertility includes reducing alcohol and caffeine consumption, achieving healthy weight-range and stopping smoking. Advice is informed by observational evidence, which is often biased by confounding. Methods This study primarily used data from a pregnancy cohort, the Norwegian Mother, Father and Child Cohort Study. First, we conducted multivariable regression of health behaviours (alcohol and caffeine consumption, body-mass index (BMI), and smoking) on fertility outcomes (e.g. time to conception) and reproductive outcomes (e.g. age at first birth) (n = 84,075 females, 68,002 males), adjusting for birth year, education and attention-deficit and hyperactive-impulsive (ADHD) traits. Second, we used individual-level Mendelian randomisation (MR) to explore possible causal effects of health behaviours on fertility/reproductive outcomes (n = 63,376 females, 45,460 males). Finally, we performed summary-level MR for available outcomes in UK Biobank (n = 91,462–1,232,091) and controlled for education and ADHD liability using multivariable MR. Results In multivariable regression analyses, higher BMI associated with fertility (longer time to conception, increased odds of infertility treatment and miscarriage), and smoking was associated with longer time to conception. In individual-level MR analyses, there was strong evidence for effects of smoking initiation and higher BMI on younger age at first birth, of higher BMI on increased time to conception, and weak evidence for effects of smoking initiation on increased time to conception. Age at first birth associations were replicated in summary-level MR analysis; however, effects attenuated using multivariable MR. Conclusions Smoking behaviour and BMI showed the most consistent associations for increased time to conception and a younger age at first birth. Given that age at first birth and time to conception are positively correlated, this suggests that the mechanisms for reproductive outcomes are distinct to the mechanisms acting on fertility outcomes. Multivariable MR suggested that effects on age at first birth might be explained by underlying liability to ADHD and education.

Abstract Parental genes may indirectly influence offspring psychiatric outcomes through the environment that parents create for their children. These indirect genetic effects, also known as genetic nurture, could explain individual differences in common internalising and externalising psychiatric symptoms during childhood. Advanced statistical genetic methods leverage data from families to estimate the overall contribution of parental genetic nurture effects. This study included up to 10,499 children, 5990 mother–child pairs, and 6,222 father–child pairs from the Norwegian Mother Father and Child Study. Genome-based restricted maximum likelihood (GREML) models were applied using software packages GCTA and M-GCTA to estimate variance in maternally reported depressive, disruptive, and attention-deficit hyperactivity disorder (ADHD) symptoms in 8-year-olds that was explained by direct offspring genetic effects and maternal or paternal genetic nurture. There was no strong evidence of genetic nurture in this sample, although a suggestive paternal genetic nurture effect on offspring depressive symptoms (variance explained (V) = 0.098, standard error (SE) = 0.057) and a suggestive maternal genetic nurture effect on ADHD symptoms (V = 0.084, SE = 0.058) was observed. The results indicate that parental genetic nurture effects could be of some relevance in explaining individual differences in childhood psychiatric symptoms. However, robustly estimating their contribution is a challenge for researchers given the current paucity of large-scale samples of genotyped families with information on childhood psychiatric outcomes.

Abstract Background There has been a growing interest in the association between maternal levels of vitamin D during pregnancy and offspring autism. However, whether any associations reflect causal effects is still inconclusive. Methods We used data from a UK-based pregnancy cohort study (Avon Longitudinal Study of Parents and Children) comprising 7689 births between 1991 and 1992 with maternal blood vitamin D levels recorded during pregnancy and at least one recorded outcome measure, including autism diagnosis and autism-associated traits. The association between each outcome with seasonal and gestational age-adjusted maternal serum 25-hydroxyvitamin D during pregnancy was estimated using confounder-adjusted regression models. Multiple imputation was used to account for missing data, and restricted cubic splines were used to investigate nonlinear associations. Mendelian randomization was used to strengthen causal inference. Results No strong evidence of an association between maternal serum 25-hydroxyvitamin D during pregnancy and any offspring autism-associated outcome was found using multivariable regression analysis (autism diagnosis: adjusted OR = 0.98, 95% CI = 0.90–1.06), including with multiple imputation (autism diagnosis: adjusted OR = 0.99, 95% CI = 0.93–1.06), and no evidence of a causal effect was suggested by Mendelian randomization (autism diagnosis: causal OR = 1.08, 95% CI = 0.46–2.55). Some evidence of increased odds of autism-associated traits at lower levels of maternal serum 25-hydroxyvitamin D was found using spline analysis. Limitations Our study was potentially limited by low power, particularly for diagnosed autism cases as an outcome. The cohort may not have captured the extreme lows of the distribution of serum 25-hydroxyvitamin D, and our analyses may have been biased by residual confounding and missing data. Conclusions The present study found no strong evidence of a causal link between maternal vitamin D levels in pregnancy and offspring diagnosis or traits of autism.

Assortative mating could violate the assumption of random mating used in many genetic studies. Here, the authors study more than 25,000 Norwegian families to find genetic similarity between partners, siblings, and in-laws in genetic factors related to educational attainment, height, and depression.

Background: Sex differences in human brain anatomy have been well-documented, though remain significantly underexplored during early development. The neonatal period is a critical stage for brain development and can provide key insights into the role that prenatal and early postnatal factors play in shaping sex differences in the brain. Methods: Here, we assessed on-average sex differences in global and regional brain volumes in 514 newborns aged 0–28 days (236 birth-assigned females and 278 birth-assigned males) using data from the developing Human Connectome Project. We also assessed sex-by-age interactions to investigate sex differences in early postnatal brain development. Results: On average, males had significantly larger intracranial and total brain volumes, even after controlling for birth weight. After controlling for total brain volume, females showed significantly greater total cortical gray matter volumes, whilst males showed greater total white matter volumes. After controlling for total brain volume in regional comparisons, females had significantly increased white matter volumes in the corpus callosum and increased gray matter volumes in the bilateral parahippocampal gyri (posterior parts), left anterior cingulate gyrus, bilateral parietal lobes, and left caudate nucleus. Males had significantly increased gray matter volumes in the right medial and inferior temporal gyrus (posterior part) and right subthalamic nucleus. Effect sizes ranged from small for regional comparisons to large for global comparisons. Significant sex-by-age interactions were noted in the left anterior cingulate gyrus and left superior temporal gyrus (posterior parts). Conclusions: Our findings demonstrate that sex differences in brain structure are already present at birth and remain comparatively stable during early postnatal development, highlighting an important role of prenatal factors in shaping sex differences in the brain. Plain Language Summary: Sex differences in the human brain have attracted substantial scientific and societal interest, but less is known about whether the brain shows sex differences at birth. Studying sex differences at birth can help to understand how prenatal factors (e.g., hormone levels before birth) and early postnatal factors (e.g., exposure to the sensory environment and caregiver interactions) contribute to shaping sex differences in the brain. In this study, we investigated on-average sex differences in brain structure in a large sample of newborn infants shortly after birth. Our findings show that several on-average differences are present at birth, suggesting that factors before birth play an important role in initiating sex differences in the brain. Highlights: At birth, males on average show significantly increased total brain volumes compared to females even after accounting for sex differences in birth weight. After controlling for total brain volume, females on average show significantly increased total cortical gray matter volumes, while males show increased total white matter volumes. After controlling for total brain volume, significant on-average sex differences are observed in regions such as the corpus callosum (F > M), bilateral parietal lobes (F > M), left anterior cingulate gyrus (F > M), left caudate nucleus (F > M), and right medial and inferior temporal gyri (M > F). Fewer global and regional volumes showed significant sex-by-age interactions, except for the left anterior cingulate gyrus (F > M) and left superior temporal gyrus (M > F). Several sex differences that have previously been observed later in development are present from birth, emphasising the key role that prenatal factors play in initiating sex differences in the brain. [ABSTRACT FROM AUTHOR]

Background: Higher BMI in childhood is associated with emotional and behavioural problems, but these associations may not be causal. Results of previous genetic studies imply causal effects but may reflect influence of demography and the family environment. Methods: This study used data on 40,949 8-year-old children and their parents from the Norwegian Mother, Father and Child Cohort Study (MoBa) and Medical Birth Registry of Norway (MBRN). We investigated the impact of BMI on symptoms of depression, anxiety, and attention-deficit hyperactivity disorder (ADHD) at age 8. We applied within-family Mendelian randomization, which accounts for familial effects by controlling for parental genotype. Results: Within-family Mendelian randomization estimates using genetic variants associated with BMI in adults suggested that a child’s own BMI increased their depressive symptoms (per 5 kg/m2 increase in BMI, beta = 0.26 S.D., CI = −0.01,0.52, p=0.06) and ADHD symptoms (beta = 0.38 S.D., CI = 0.09,0.63, p=0.009). These estimates also suggested maternal BMI, or related factors, may independently affect a child’s depressive symptoms (per 5 kg/m2 increase in maternal BMI, beta = 0.11 S.D., CI:0.02,0.09, p=0.01). However, within-family Mendelian randomization using genetic variants associated with retrospectively-reported childhood body size did not support an impact of BMI on these outcomes. There was little evidence from any estimate that the parents’ BMI affected the child’s ADHD symptoms, or that the child’s or parents’ BMI affected the child’s anxiety symptoms. Conclusions: We found inconsistent evidence that a child’s BMI affected their depressive and ADHD symptoms, and little evidence that a child’s BMI affected their anxiety symptoms. There was limited evidence of an influence of parents’ BMI. Genetic studies in samples of unrelated individuals, or using genetic variants associated with adult BMI, may have overestimated the causal effects of a child’s own BMI. Funding: This research was funded by the Health Foundation. It is part of the HARVEST collaboration, supported by the Research Council of Norway. Individual co-author funding: the European Research Council, the South-Eastern Norway Regional Health Authority, the Research Council of Norway, Helse Vest, the Novo Nordisk Foundation, the University of Bergen, the South-Eastern Norway Regional Health Authority, the Trond Mohn Foundation, the Western Norway Regional Health Authority, the Norwegian Diabetes Association, the UK Medical Research Council. The Medical Research Council (MRC) and the University of Bristol support the MRC Integrative Epidemiology Unit.

Abstract Background ADHD and autism are neurodevelopmental conditions, for which non‐specific precursors or early signs include difficulties with language and motor skills, and differences in temperament in the first and second year of life. These early features have also been linked to later diagnosis of schizophrenia which is widely considered to have neurodevelopmental origins. Given that ADHD, autism and schizophrenia are all highly heritable, we tested the hypothesis that in the general population, measures of toddler language development, motor development and temperament are associated with genetic liability to ADHD, autism and/or schizophrenia. Methods Data were analysed from the Avon Longitudinal Study of Parents and Children (ALSPAC) which included motor development scores at age 18 months and language development and temperament scores at age 24 months (N = 7498). Genetic liability was indexed by polygenic risk scores (PGS) for ADHD, autism and schizophrenia. Results ADHD PGS were associated with specific temperament scales (higher activity β = 0.07, 95% CI = 0.04, 0.09 and lower withdrawal β = −0.05, 95% CI = −0.07, −0.02) as well as better gross motor scores (β = 0.04, 95% CI = 0.01, 0.06). Schizophrenia PGS were associated with one specific temperament scale (negative mood β = 0.04, 95% CI = 0.02, 0.07). We did not find strong evidence of association of autism PGS with any of the toddler measures; there was also not strong evidence of association with motor or language delays for any of the PGS. Conclusions This study suggests that some specific aspects of early temperament and gross motor differences in the general population could represent part of the early manifestation of genetic liability to neurodevelopmental conditions.