Developmental milestones in earlychildhood and genetic liability toneurodevelopmental disorders

Background: Timing of developmental milestones, such as age at first walking, is associated with later diagnoses of neurodevelopmental disorders. However, its relationship to genetic risk for neurodevelopmental disorders in the general population is unknown. Here, we investigate associations between attainment of early-life language and motor development milestones and genetic liability to autism, attention deficit hyperactivity disorder (ADHD), and schizophrenia. Methods: We use data from a genotyped sub-set (N = 25699) of children in the Norwegian Mother, Father and Child Cohort Study (MoBa). We calculate polygenic scores (PGS) for autism, ADHD, and schizophrenia and predict maternal reports of children's age at first walking, first words, and first sentences, motor delays (18 months), and language delays and a generalised measure of concerns about development (3 years). We use linear and probit regression models in a multi-group framework to test for sex differences. Results: We found that ADHD PGS were associated with earlier walking age (β = −0.033, padj < 0.001) in both males and females. Additionally, autism PGS were associated with later walking (β = 0.039, padj = 0.006) in females only. No robust associations were observed for schizophrenia PGS or between any neurodevelopmental PGS and measures of language developmental milestone attainment. Conclusions: Genetic liabilities for neurodevelopmental disorders show some specific associations with the age at which children first walk unsupported. Associations are small but robust and, in the case of autism PGS, differentiated by sex. These findings suggest that early-life motor developmental milestone attainment is associated with genetic liability to ADHD and autism in the general population

Genetic liability for schizophrenia and childhood psychopathology in the general population

Abstract Genetic liability for schizophrenia is associated with psychopathology in early life. It is not clear if these associations are time dependent during childhood, nor if they are specific across different forms of psychopathology. Using genotype and questionnaire data on children (N = 15 105) from the Norwegian Mother, Father and Child Cohort Study, we used schizophrenia polygenic risk scores to test developmental stability in associations with measures of emotional and behavioral problems between 18 months and 5 years, and domain specificity in associations with symptoms of depression, anxiety, conduct problems, oppositionality, inattention, and hyperactivity at 8 years. We then sought to identify symptom profiles—across development and domains—associated with schizophrenia polygenic liability. We found evidence for developmental stability in associations between schizophrenia polygenic risk scores and emotional and behavioral problems, with the latter being mediated specifically via the rate of change in symptoms (β slope = 0.032; 95% CI: 0.007–0.057). At age 8, associations were better explained by a model of symptom-specific polygenic effects rather than effects mediated via a general psychopathology factor or by domain-specific factors. Overall, individuals with higher schizophrenia polygenic risk scores were more likely (OR = 1.310 [95% CIs: 1.122–1.528]) to have a profile of increasing behavioral and emotional symptoms in early childhood, followed by elevated symptoms of conduct disorder, oppositionality, hyperactivity, and inattention by age 8. Schizophrenia-associated alleles are linked to specific patterns of early-life psychopathology. The associations are small, but findings of this nature can help us better understand the developmental emergence of schizophrenia

Clinical Features of Children With Autism Who Passed 18-Month Screening

OBJECTIVES: We compared sex-stratified developmental and temperamental profiles at 18 months in children screening negative for autism spectrum disorder (ASD) on the Modified Checklist for Autism in Toddlers (M-CHAT) but later receiving diagnoses of ASD (false-negative group) versus those without later ASD diagnoses (true-negative group). METHODS: We included 68 197 screen-negative cases from the Norwegian Mother and Child Cohort Study (49.1% girls). Children were screened by using the 6 critical items of the M-CHAT at 18 months. Groups were compared on domains of the Ages and Stages Questionnaire and the Emotionality Activity Sociability Temperament Survey. RESULTS: Despite passing M-CHAT screening at 18 months, children in the false-negative group exhibited delays in social, communication, and motor skills compared with the true-negative group. Differences were more pronounced in girls. However, with regard to shyness, boys in the false-negative group were rated as more shy than their true-negative counterparts, but girls in the false-negative group were rated as less shy than their counterparts in the true-negative group. CONCLUSIONS: This is the first study to reveal that children who pass M-CHAT screening at 18 months and are later diagnosed with ASD exhibit delays in core social and communication areas as well as fine motor skills at 18 months. Differences appeared to be more pronounced in girls. With these findings, we underscore the need to enhance the understanding of early markers of ASD in boys and girls, as well as factors affecting parental report on early delays and abnormalities, to improve the sensitivity of screening instruments. </jats:sec

Clinical Features of Children With Autism Who Passed 18-Month Screening

We examine birth-cohort trends behind recent changes in the prevalence of functional disability in the older population living in private households in the United Kingdom (UK). By using three different socio-economic indicators available in the nationally representative cross-sectional data on older individuals interviewed between 2002 and 2012 in the Family Resource Survey (FRS) (96,733 respondents), we investigate the extent to which the overall trends have been more favourable among more advantaged than disadvantaged socioeconomic groups. Compared to the cohort of people born in 1924, successive cohorts of older men have lower odds of having at least one functional difficulty (FD), whereas no significant trend was found for women. Among people with at least one FD, however, the number of disabilities increases for each successive cohort of older women (incidence rate ratio 1.027, 95% confidence interval 1.023 to 1.031, P<0.001) and men (incidence rate ratio 1.028, 95% confidence interval 1.024 to 1.033, P<0.001). By allowing interactions between birth cohort and SES indicators, a significant increasing cohort trend in the number of reported FDs was found among older men and women at lower SES, whereas an almost stable pattern was observed at high SES. Our results suggest that the overall slightly increasing birth-cohort trend in functional difficulties observed among current cohorts of older people in the UK hides underlying increases among low SES individuals and a relative small reduction among high SES individuals. Further studies are needed to understand the causes of such trends and to propose appropriate interventions. However, if the SES differentials in trends in FDs observed in the past continue, this could have important implications for the future costs of the public system of care and support for people with care needs

Diagnostisering av autismespekterforstyrrelser hos barn i Norge

Diagnosing autism spectrum disorder among children in Norwa

Multidimensional Influences on Autism Symptom Measures:Implications for Use in Etiological Research

OBJECTIVE: Growing awareness that symptoms of autism spectrum disorder (ASD) transcend multiple diagnostic categories, and major advances in the identification of genetic syndromes associated with ASD, has led to widespread use of ASD symptom measures in etiological studies of neurodevelopmental disorders. Insufficient consideration of potentially confounding factors such as cognitive ability or behavior problems can have important negative consequences in interpretation of findings, including erroneous estimation of associations between ASD and etiological factors. METHOD: Participants were 388 children aged 2–13 years with diagnoses of ASD or another neurodevelopmental disorder without ASD. Receiver operating characteristics methods were used to assess the influence of IQ and emotional/behavioral problems on the discriminative ability of three widely used ASD symptom measures; the Social Responsiveness Scale (SRS), the Autism Diagnostic Interview-Revised (ADI-R), and the Autism Diagnostic Observation Schedule (ADOS). RESULTS: IQ influenced the discriminative thresholds of the SRS and ADI-R, and emotional/behavioral problems affected the discriminative thresholds of the SRS, ADI-R, and ADOS. This resulted in low specificity of ASD cut-offs on the SRS and ADI-R for children with intellectual disability without ASD (27–42%), and low specificity across all three instruments for children without ASD with elevated emotional/behavioral problems (36–59%). Adjustment for these characteristics resulted in improved discriminative ability for all three ASD measures. CONCLUSION: The findings indicate that scores on ASD symptom measures reflect far more than ASD symptoms. Valid interpretation of these measures requires steps to account for the influences of IQ and emotional/behavioral problems

The autism birth cohort (ABC): A study of autism spectrum disorders in MoBa

Background: Autism spectrum disorders (ASDs) are characterized by persistent deficits in social communication and interaction and restricted, repetitive patterns of behavior, interests or activities. In most cases, the cause of ASD is likely to be a combination of genetic predisposition and environmental exposures occurring in fetal life or early infancy. Consequently, a prospective pregnancy cohort like MoBa represents an ideal platform for studies of ASDs in children. Methods: The Autism Birth Cohort (ABC) Study has identified potential ASD cases in MoBa through questionnaire- based screening, parental and professional referrals, and linkages to the Norwegian Patient Register. ASD diagnoses have been ascertained through in-person clinical assessments and medical record reviews. Current results: By the end of 2012, the ABC Study had identified 518 ASD cases in MoBa. The ASD prevalence in school-age children is 0.7-0.8%, which is in line with nationwide estimates for Norway. The most important source of ASD case identification was registry linkages, while only a minority was detected through early screening. Published findings show that screening at 18 months misses the majority of ASD cases. Analyses of risk factors for ASDs have shown that maternal use of folic acid supplements in early pregnancy may lower the child’s risk of developing ASDs and that paternal obesity appears to increase the child’s risk of ASDs. Future plans: ASD case identification will continue through annual registry linkages and subsequent reviews of medical records. Analyses of plasma samples and RNA samples will be conducted to investigate prenatal and perinatal microbial exposures, innate immune and inflammatory responses, biomarkers of autism risk, and exposures to xenobiotics. Analyses of deciduous teeth will also investigate the effect of medications and environmental toxins. Exome sequencing of DNA from ASD cases and their parents is ongoing, and will elucidate the role of de novo DNA mutations in the pathogenesis of ASDs. Future epidemiological analyses will explore the results of the 36-month screening for ASDs, the diagnostic stability and developmental trajectories in ASD children, and psychiatric and medical comorbidities in ASDs