Ted Reichborn-Kjennerud

The Autism Birth Cohort: a paradigm for gene–environment–timing research

The reported prevalence of autism spectrum disorders (ASDs) has increased by 5- to 10-fold over the past 20 years. Whether ASDs are truly more frequent is controversial; nonetheless, the burden is profound in human and economic terms. Although autism is among the most heritable of mental disorders, its pathogenesis remains obscure. Environmental factors are proposed; however, none is implicated. Furthermore, there are no biomarkers to screen for ASD or risk of ASD. The Autism Birth Cohort (ABC) was initiated to analyze gene × environment × timing interactions and enable early diagnosis. It uses a large, unselected birth cohort in which cases are prospectively ascertained through population screening. Samples collected serially through pregnancy and childhood include parental blood, maternal urine, cord blood, milk teeth and rectal swabs. More than 107u2009000 children are continuously screened through questionnaires, referral, and a national registry. Cases are compared with a control group from the same cohort in a ‘nested case–control’ design. Early screening and diagnostic assessments and re-assessments are designed to provide a rich view of longitudinal trajectory. Genetic, proteomic, immunologic, metagenomic and microbiological tools will be used to exploit unique biological samples. The ABC is a paradigm for analyzing the role of genetic and environmental factors in complex disorders.

Parental Obesity and Risk of Autism Spectrum Disorder

OBJECTIVES: The objective of the study was to investigate the associations among maternal prepregnancy BMI, paternal BMI, and the risk of autism spectrum disorders (ASDs) in children. METHODS: The study sample of 92u2009909 children was derived from the population-based, prospective Norwegian Mother and Child Cohort Study. The age range was 4.0 through 13.1 (mean 7.4) years. Relative risks of ASDs were estimated by odds ratios (ORs) and 95% confidence intervals (CIs) from logistic regression models. RESULTS: At the end of follow-up on December 31, 2012, 419 children in the study sample had been diagnosed with ASDs: 162 with autistic disorder, 103 with Asperger disorder, and 154 with pervasive developmental disorder not otherwise specified. Maternal obesity (BMI ≥30) was only weakly associated with ASD risk, whereas paternal obesity was associated with an increased risk of autistic disorder and Asperger disorder. The risk of autistic disorder was 0.27% (25 of 9267) in children of obese fathers and 0.14% (59 of 41u2009603) in children of fathers with normal weight (BMI <25), generating an adjusted OR of 1.73 (95% CI: 1.07–2.82). For Asperger disorder, analyses were limited to children aged ≥7 years (n = 50u2009116). The risk was 0.38% (18 of 4761) in children of obese fathers and 0.18% (42 of 22u2009736) in children of normal-weight fathers, and the adjusted OR was 2.01 (95% CI: 1.13–3.57). No associations were found for pervasive developmental disorder not otherwise specified. CONCLUSIONS: Paternal obesity is an independent risk factor for ASDs in children. The associations should be investigated further in genetic and epigenetic studies.

Later Emotional and Behavioral Problems Associated With Sleep Problems in Toddlers: A Longitudinal Study

IMPORTANCEnChildhood sleep problems have been linked to a range of adverse health outcomes, but there is limited knowledge as to the temporal association between sleep problems and subsequent emotional and behavioral problems in young children.nnnOBJECTIVEnTo examine whether sleep problems in toddlers aged 18 months are related to both concurrent and subsequent emotional and behavioral problems in preschool children aged 5 years.nnnDESIGN, SETTING, AND PARTICIPANTSnA large population-based longitudinal study was conducted in September 2014 using data from the Norwegian Mother and Child Cohort Study conducted at the Norwegian Institute of Public Health from June 1, 1999, to December 31, 2008. A total of 32u202f662 children or pregnancies were included.nnnEXPOSURESnSleep was assessed by mother-reported child sleep duration and nocturnal awakenings.nnnMAIN OUTCOMES AND MEASURESnEmotional and behavioral problems were measured with items from the Child Behavior Checklist and operationalized according to recommended clinical cutoffs, corresponding to T scores of greater than 65 (93rd percentile). Risk ratios (RRs) were calculated using negative binomial regression, controlling for emotional and behavioral problems at 18 months and other relevant covariates.nnnRESULTSnShort sleep duration (≤10 hours) in 556 children (1.7%) and frequent nocturnal awakenings (≥3 times) in 1033 children (3.2%) at 18 months significantly predicted both concurrent and later incidence of emotional and behavioral problems at 5 years. The longitudinal RRs were generally larger for internalizing problems, with adjusted RRs of 1.59 (95% CI, 1.23-2.08) for both short sleep duration and 1.57 (95% CI, 1.28-1.93) for nocturnal awakenings; RRs for externalizing problems were 1.77 (95% CI, 1.37-2.30) and 1.25 (95% CI, 1.00-1.58), respectively. Additional adjustment for emotional and behavioral problems at 18 months slightly reduced the strength of these associations, and all RRs remained significant in the fully adjusted models.nnnCONCLUSIONS AND RELEVANCEnEarly sleep problems predict later development of emotional and behavioral problems. Intervention studies are needed to examine whether sleep programs targeting early childhood may avert the onset of later adverse outcomes.

Identifying Children with Autism Spectrum Disorder at 18 Months in a General Population Sample

BACKGROUNDnPrevious research on clinical and high-risk samples suggests that signs of autism spectrum disorder (ASD) can be detected between 1 and 2 years of age. We investigated signs of ASD at 18 months in a population-based sample and the association with later ASD diagnosis.nnnMETHODSnThe study sample includes 52,026 children born 2003 through 2008 and is a subset of children that participated in the Norwegian Mother and Child Cohort (MoBa), a population-based longitudinal study, and the Autism Birth Cohort (ABC), a sub-study on ASD. Parents completed all 23 items from the Modified Checklist for Autism in Toddlers (M-CHAT) at 18 months.nnnRESULTSnThe M-CHAT 6-critical-item criterion and the 23-item criterion had a specificity of 97.9% and 92.7% and a sensitivity of 20.8% and 34.1%, respectively. In the 173 children diagnosed with ASD to date, 60 children (34.7%) scored above the cut-off on either of the screening criteria. The items with the highest likelihood ratios were interest in other children, show objects to others and response to name.nnnCONCLUSIONnEven though one-third of the children who later received an ASD diagnosis were identified through M-CHAT items, the majority scored below cut-off on the screening criteria at 18 months. The results imply that it might not be possible to detect all children with ASD at this age.

Substance use disorders in schizophrenia, bipolar disorder, and depressive illness: a registry-based study

PurposeTo compare the prevalence and pattern of comorbid substance use disorders (SUD) between patients with schizophrenia, bipolar disorder, and depressive illness.MethodsData on presence of alcohol use disorder (AUD) and non-alcohol drug use disorder (DUD) were retrieved from the Norwegian Patient Register for individuals born between 1950 and 1989 who in the period 2009–2013 were diagnosed with schizophrenia, bipolar disorder or depressive illness according to the 10th version of the WHO International Classification of Diseases. The prevalence of AUD only, DUD only, or both was compared between men and women across age and diagnostic groups.ResultsThe prevalence of SUD was 25.1xa0% in schizophrenia (AUD: 4.6xa0%, DUD: 15.6xa0%, AUD and DUD: 4.9xa0%), 20.1xa0% in bipolar disorder (AUD: 8.1xa0%, DUD: 7.6xa0%, AUD and DUD: 4.4xa0%), and 10.9xa0% in depressive illness (AUD: 4.4xa0%, DUD: 4.3xa0%, AUD and DUD: 2.2xa0%). Middle-aged men with bipolar disorder had the highest prevalence of AUD (19.1xa0%) and young men with schizophrenia had the highest prevalence of DUD (29.6xa0%). Of the specific DUDs, all but sedative use disorder were more prevalent in schizophrenia than the other groups. Cannabis and stimulant use disorder was found among 8.8 and 8.9xa0%, respectively, of the men with schizophrenia.ConclusionsThe alarmingly high prevalence of DUD among young patients with severe mental disorders should encourage preventive efforts to reduce illicit drug use in the adolescent population.

Genome-Wide Analysis of Attention Deficit Hyperactivity Disorder in Norway

Background Attention deficit hyperactivity disorder (ADHD) is a highly heritable neuropsychiatric condition, but it has been difficult to identify genes underlying this disorder. This study aimed to explore genetics of ADHD in an ethnically homogeneous Norwegian population by means of a genome-wide association (GWA) analysis followed by examination of candidate loci. Materials and Methods Participants were recruited through Norwegian medical and birth registries as well as the general population. Presence of ADHD was defined according to DSM-IV criteria. Genotyping was performed using Illumina Human OmniExpress-12v1 microarrays. Statistical analyses were divided into several steps: (1) genome-wide association in the form of logistic regression in PLINK and follow-up pathway analyses performed in DAPPLE and INRICH softwares, (2) SNP-heritability calculated using genome-wide complex trait analysis (GCTA) tool, (3) gene-based association tests carried out in JAG software, and (4) evaluation of previously reported genome-wide signals and candidate genes of ADHD. Results In total, 1.358 individuals (478 cases and 880 controls) and 598.384 autosomal SNPs were subjected to GWA analysis. No single polymorphism reached genome-wide significance. The strongest signal was observed at rs9949006 in the ENSG00000263745 gene (OR=1.51, 95% CI 1.28–1.79, p=1.38E-06). Pathway analyses of the top SNPs implicated genes involved in the regulation of gene expression, cell adhesion and inflammation. Among previously identified ADHD candidate genes, prominent association signals were observed for SLC9A9 (rs1393072, OR=1.46, 95% CI = 1.21–1.77, p=9.95E-05) and TPH2 (rs17110690, OR = 1.38, 95% CI = 1.14–1.66, p=8.31E-04). Conclusion This study confirms the complexity and heterogeneity of ADHD etiology. Taken together with previous findings, our results point to a spectrum of biological mechanisms underlying the symptoms of ADHD, providing targets for further genetic exploration of this complex disorder.

Reliability of triclosan measures in repeated urine samples from Norwegian pregnant women

Triclosan (TCS) is a synthetic antibacterial chemical that is used in personal care products and is measurable in urine. Urinary TCS has been associated with allergy in children in Norway and the United States. A reasonable degree of temporal reliability of TCS urinary concentrations has been reported among US children as well as for Puerto Rican pregnant women. We examined the reliability of TCS measures in urine among Norwegian pregnant women. TCS was measured in spot urine samples collected in gestational weeks 17, 23, and 29 from 45 women in The Norwegian Mother and Child Cohort Study (MoBa) enrolled in 2007 and 2008. Spearman’s rank correlation coefficient (rs) and intraclass correlation coefficient (ICC) statistics were calculated. Fifty-six percent of the 45 women had a least one sample with a value above the method limit of detection (2.3u2009μg/l). The correlation coefficients were 0.61 for TCS concentrations at 17 and 23 weeks and 0.49 for concentrations at 17 and 29 weeks. For the three time points, the ICC was 0.49. The reliability of TCS concentrations in repeated urine samples from pregnant Norwegian women was reasonably good, suggesting a single urine sample can adequately represent TCS exposure during pregnancy.

Association of Maternal Report of Infant and Toddler Gastrointestinal Symptoms With Autism: Evidence From a Prospective Birth Cohort

IMPORTANCEnGastrointestinal (GI) comorbidities are frequently described in association with autism spectrum disorder (ASD). However, the prevalence of GI disturbances and the age at which such problems first appear are unclear, and their specificity for ASD compared with other neurodevelopmental disorders is uncertain.nnnOBJECTIVEnTo compare maternal report of GI symptoms during the first 3 years of life in children with ASD, developmental delay (DD), and typical development (TD).nnnDESIGN, SETTING, AND PARTICIPANTSnThis large prospective cohort study consists of participants in the Norwegian Mother and Child Cohort Study. During a 10-year period (January 1, 1999, through December 31, 2008), women throughout Norway were recruited at the first prenatal ultrasonographic visit (approximately 18 weeks gestation). The study enrolled 95,278 mothers, 75,248 fathers, and 114,516 children. Our analyses are based on MoBa data released through October 1, 2013, and NPR diagnoses registered through December 31, 2012, and include children born from January 1, 2002, through December 31, 2008, with completed age 18- and 36-month questionnaires.nnnEXPOSURESnWe defined 3 groups of children: children with ASD (n = 195), children with DD and delayed language and/or motor development (n = 4636), and children with TD (n = 40u202f,95).nnnMAIN OUTCOMES AND MEASURESnThe GI symptoms were based on maternal report of constipation, diarrhea, and food allergy/intolerance.nnnRESULTSnChildren with ASD were at significantly increased odds of maternally reported constipation (adjusted odds ratio [aOR], 2.7; 95% CI, 1.9-3.8; P < .001) and food allergy/intolerance (aOR, 1.7; 95% CI, 1.1-2.6; P = .01) in the 6- to 18-month-old age period and diarrhea (aOR, 2.3; 95% CI, 1.5-3.6; P < .001), constipation (aOR, 1.6; 95% CI, 1.2-2.3; P < .01), and food allergy/intolerance (aOR, 2.0; 95% CI, 1.3-3.1; P < .01) in the 18- to 36-month-old age period compared with children with TD. Similar results for these symptom categories were observed in comparisons with children with DD, but ORs were slightly lower. Mothers of children with ASD were significantly more likely to report 1 or more GI symptom in either the 6- to 18-month or the 18- to 36-month-old age period and more than twice as likely to report at least 1 GI symptom in both age periods compared with mothers of children with TD or DD.nnnCONCLUSIONS AND RELEVANCEnIn this large prospective cohort, maternally reported GI symptoms are more common and more often persistent during the first 3 years of life in children with ASD than in children with TD or DD.

Measurement of Total and Free Urinary Phenol and Paraben Concentrations over the Course of Pregnancy: Assessing Reliability and Contamination of Specimens in the Norwegian Mother and Child Cohort Study.

Background Exposures to environmental phenols and parabens may be harmful, especially in utero. Prior studies have demonstrated high within-person variability of urinary concentrations across pregnancy. Objectives We sought to measure phenol and paraben biomarker concentrations for the Norwegian Mother and Child Cohort (MoBa) study, assess within-person variability, and investigate any possible external phenol or paraben contamination of specimens. Methods We collected three spot urine samples at approximately 17, 23, and 29 weeks gestation in a hospital setting and added a preservative containing ethyl paraben. We measured urinary concentrations and within-person variability for phenols and parabens in a MoBa sample (n = 45), including a subgroup of 15 participants previously randomly selected for a bisphenol A (BPA) exposure study who had unusually high total BPA concentrations. Additionally, we compared reliability results for total, conjugated, and free concentrations of phenolic compounds. Results We detected total and free BPA, butyl paraben, propyl paraben, and methyl paraben in 100% of samples, total benzophenone-3 in 95% of samples, and infrequently detected free benzophenone-3 and total and free 2,4-dichlorophenol and 2,5-dichlorophenol. Intraclass correlation coefficients (ICCs) for total, conjugated, and free concentrations ranged from relatively low for BPA to moderate for propyl paraben. ICCs were generally similar overall and by subgroup. Conclusions Using conjugated concentrations improved reliability estimates only for BPA. Measuring total and free concentrations, an approach that may be useful for future studies, allowed us to identify likely BPA and butyl paraben contamination of archived MoBa urine specimens. Citation Guidry VT, Longnecker MP, Aase H, Eggesbø M, Zeiner P, Reichborn-Kjennerud T, Knudsen GP, Bertelsen RJ, Ye X, Calafat AM, Engel SM. 2015. Measurement of total and free urinary phenol and paraben concentrations over the course of pregnancy: assessing reliability and contamination of specimens in the Norwegian Mother and Child Cohort Study. Environ Health Perspect 123:705–711;u2002http://dx.doi.org/10.1289/ehp.1408325

Prenatal fever and autism risk

Some studies suggest that prenatal infection increases risk of autism spectrum disorders (ASDs). This study was undertaken in a prospective cohort in Norway to examine whether we could find evidence to support an association of the prenatal occurrence of fever, a common manifestation of infection, with ASD risk. Prospective questionnaires provided maternal exposure data; case status was established from clinical assessments and registry linkages. In a large, prospectively ascertained cohort of pregnant mothers and their offspring, we examined infants born ⩾32 weeks for associations between fever exposure in each trimester and ASD risk using logistic regression. Maternal exposure to second-trimester fever was associated with increased ASD risk, adjusting for presence of fever in other trimesters and confounders (adjusted odds ratio (aOR), 1.40; 95% confidence interval, 1.09–1.79), with a similar, but nonsignificant, point estimate in the first trimester. Risk increased markedly with exposure to three or more fever episodes after 12 weeks gestation (aOR, 3.12; 1.28–7.63). ASD risk appears to increase with maternal fever, particularly in the second trimester. Risk magnified dose dependently with exposure to multiple fevers after 12 weeks gestation. Our findings support a role for gestational maternal infection and innate immune responses to infection in the pathogenesis of at least some cases of ASD.