Nadine Forget-Dubois

Rare mutations in N-methyl-D-aspartate glutamate receptors in autism spectrum disorders and schizophrenia

Pharmacological, genetic and expression studies implicate N-methyl-D-aspartate (NMDA) receptor hypofunction in schizophrenia (SCZ). Similarly, several lines of evidence suggest that autism spectrum disorders (ASD) could be due to an imbalance between excitatory and inhibitory neurotransmission. As part of a project aimed at exploring rare and/or de novo mutations in neurodevelopmental disorders, we have sequenced the seven genes encoding for NMDA receptor subunits (NMDARs) in a large cohort of individuals affected with SCZ or ASD (n=429 and 428, respectively), parents of these subjects and controls (n=568). Here, we identified two de novo mutations in patients with sporadic SCZ in GRIN2A and one de novo mutation in GRIN2B in a patient with ASD. Truncating mutations in GRIN2C, GRIN3A and GRIN3B were identified in both subjects and controls, but no truncating mutations were found in the GRIN1, GRIN2A, GRIN2B and GRIN2D genes, both in patients and controls, suggesting that these subunits are critical for neurodevelopment. The present results support the hypothesis that rare de novo mutations in GRIN2A or GRIN2B can be associated with cases of sporadic SCZ or ASD, just as it has recently been described for the related neurodevelopmental disease intellectual disability. The influence of genetic variants appears different, depending on NMDAR subunits. Functional compensation could occur to counteract the loss of one allele in GRIN2C and GRIN3 family genes, whereas GRIN1, GRIN2A, GRIN2B and GRIN2D appear instrumental to normal brain development and function.

Prenatal Methylmercury, Postnatal Lead Exposure, and Evidence of Attention Deficit/Hyperactivity Disorder among Inuit Children in Arctic Québec

Background: Prenatal exposure to methylmercury (MeHg) and polychlorinated biphenyls (PCBs) has been associated with impaired performance on attention tasks in previous studies, but the extent to which these cognitive deficits translate into behavioral problems in the classroom and attention deficit/hyperactivity disorder (ADHD) remains unknown. By contrast, lead (Pb) exposure in childhood has been associated with ADHD and disruptive behaviors in several studies. Objectives: In this study we examined the relation of developmental exposure to MeHg, PCBs, and Pb to behavioral problems at school age in Inuit children exposed through their traditional diet. Methods: In a prospective longitudinal study conducted in the Canadian Arctic, exposure to contaminants was measured at birth and at school age. An assessment of child behavior (n = 279; mean age = 11.3 years) was obtained from the child’s classroom teacher on the Teacher Report Form (TRF) from the Child Behavior Checklist, and the Disruptive Behavior Disorders Rating Scale (DBD). Results: Cord blood mercury concentrations were associated with higher TRF symptom scores for attention problems and DBD scores consistent with ADHD. Current blood Pb concentrations were associated with higher TRF symptom scores for externalizing problems and with symptoms of ADHD (hyperactive-impulsive type) based on the DBD. Conclusions: To our knowledge, this study is the first to identify an association between prenatal MeHg and ADHD symptomatology in childhood and the first to replicate previously reported associations between low-level childhood Pb exposure and ADHD in a population exposed to Pb primarily from dietary sources.

Early Child Language Mediates the Relation Between Home Environment and School Readiness

Home environment quality is a well-known predictor of school readiness (SR), although the underlying processes are little known. This study tested two hypotheses: (a) child language mediates the association between home characteristics (socioeconomic status and exposure to reading) and SR, and (b) genetic factors partly explain the association between language and SR. Data were collected between 6 and 63 months in a large sample of twins. Results showed that home characteristics had direct effects on SR and indirect effects through child language. No genetic correlation was found between language and SR. These results suggest that home characteristics affect SR in part through their effect on early language skills, and show that this process is mainly environmental rather than genetic in nature.

Associations Between Sleep-Wake Consolidation and Language Development in Early Childhood: A Longitudinal Twin Study

STUDY OBJECTIVES The objectives were (1) to assess associations between sleep consolidation at 6, 18 and 30 months and language skills at 18, 30, and 60 months; and (2) to investigate the genetic/environmental etiology of these associations. DESIGN Longitudinal study of a population-based twin cohort. PARTICIPANTS 1029 twins from the Quebec Newborn Twin Study. MEASUREMENTS AND RESULTS Sleep consolidation was derived from parental reports of day/night consecutive sleeping durations. Language skills were assessed with the MacArthur Communicative Development Inventory at 18 and 30 months and the Peabody Picture Vocabulary Test at 60 months. The day/night sleep ratio decreased significantly from 6 to 30 months. The 6- and 18-month ratios were negatively correlated with subsequent language skills. Children with language delays at 60 months had less mature sleep consolidation at both 6 and 18 months than children without delays and those with transient early delays. Genetic and regression analyses revealed that the sleep ratio at 6 months was highly heritable (64%) and predicted 18-month (B = -0.06) and 30-month language (B = -0.11) mainly through additive genetic influences (R(Gs) = 0.32 and 0.33, respectively). By contrast, the sleep ratio at 18 months was mainly due to shared environment influences (58%) and predicted 60-month language (B = -0.08) through shared environment influences (R(Cs) = 0.24). CONCLUSIONS Poor sleep consolidation during the first 2 years of life may be a risk factor for language learning, whereas good sleep consolidation may foster language learning through successive genetic and environmental influences.

Heritability of Response Inhibition in Children

We report the heritability of response inhibition, latency, and variability, which are potential markers of genetic risk in neuropsychiatric conditions. Genetic and environmental influences on cancellation and restraint, response latency, and variability measured in a novel variant of the stop signal task were studied in 139 eight-year-old twin pairs from a birth cohort. Cancellation (50%), restraint (27%), and response latency (41%) showed significant heritability, the balance being non-shared environmental influences and/or error. Response variability was not heritable, with 23% of the variance attributable to shared environmental influences and 77% to non-shared environmental risk or error. The phenotypic correlation between response cancellation and restraint was -.44 and between response latency and restraint was .21. These phenotypic correlations were entirely genetic in origin. The phenotypic correlation between response variability and % successful inhibition was .27, but was not genetic. Cancellation and restraint were heritable and shared genetic influences, indicating that they may be influenced by a common gene or genes. Response latency was moderately heritable and shared genetic influences with restraint, but was not correlated with cancellation. Response variability was not heritable. These results support the potential of response inhibition and latency as endophenotypes in genetic research.

Exposure to organochlorines and mercury through fish and marine mammal consumption: Associations with growth and duration of gestation among Inuit newborns

BACKGROUND Several studies have reported negative associations of polychlorinated biphenyls (PCBs), hexachlorobenzene (HCB) and mercury (Hg) with duration of gestation and fetal growth in fish eating populations. Docosahexaenoic acid (DHA) from fish, seafood and marine mammal intake has been reported to be positively related with pregnancy duration and fetal growth. So far, it remains unclear, however, if the associations of environmental contaminants (ECs) with growth are direct or mediated through their relation with the duration of gestation and the degree to which DHA intake during pregnancy attenuates the negative association of ECs with fetal growth. OBJECTIVES To investigate direct and indirect associations of in utero exposure to ECs with fetal growth and pregnancy duration while taking into account the possible positive effects of DHA. METHODS Pregnant Inuit women (N=248) from Arctic Quebec were recruited and cord blood samples were analyzed for PCBs, HCB, Hg and DHA. Anthropometric measurements were assessed at birth. Path models were used to evaluate direct and indirect associations. RESULTS Cord concentrations of PCB 153, HCB and Hg were significantly associated with shorter duration of pregnancy (β varying from -0.17 to -0.20, p<0.05). Path models indicated that the associations of PCBs, HCB and Hg with reduced fetal growth (β varying from -0.09 to -0.13, p<0.05) were mediated through their relations with shorter gestation duration. Cord DHA was indirectly related to greater growth parameters (β varying from 0.17 to 0.20, p<0.05) through its positive association with gestation duration. CONCLUSION Prenatal exposure to ECs was associated with reduced gestation duration, which is a recognized determinant of fetal growth. DHA intake during pregnancy appeared to have independent positive association with fetal growth by prolonging gestation. Whether these associations are causal remains to be elucidated.

De Novo Truncating Mutation in Kinesin 17 Associated with Schizophrenia

BACKGROUND Schizophrenia (SCZ) is one of the most disabling psychiatric disorders. It is thought to be due to a complex interplay between polygenic and various environmental risk factors, although recent reports on genomic copy number variations suggest that a fraction of the cases could result from variably penetrant de novo variants. The gene encoding the synaptic motor protein kinesin 17 (KIF17) involved in glutamatergic synapse is a candidate gene for SCZ. METHODS As part of our Synapse to Disease project, we resequenced KIF17 in a cohort of individuals with sporadic SCZ (188 subjects). Additional populations included autism spectrum disorder (142 subjects), nonsyndromic mental retardation (95 subjects), and control subjects (568 subjects). Functional validation of the human mutation was done in developing zebrafish. RESULTS Here we report the identification of a de novo nonsense truncating mutation in one patient with SCZ, in kinesin 17, a synaptic motor protein. No de novo or truncating KIF17 mutations were found in the additional samples. We further validated the pathogenic nature of this mutation by knocking down its expression in zebrafish embryos, which resulted in a developmental defect. CONCLUSIONS Together our findings suggest that disruption of KIF17, although rare, could result in a schizophrenia phenotype and emphasize the possible involvement of rare de novo mutations in this disorder.

Genetic and environmental influences on daytime and nighttime sleep duration in early childhood

OBJECTIVES: To determine the relative contributions of genetic and environmental factors on daytime and nighttime continuous sleep duration at 6, 18, 30, and 48 months of age, and to identify different subgroups of children who followed different daytime and nighttime sleep duration trajectories and to investigate their etiology. METHODS: The current study included 995 twins (405 monozygotic and 586 dizygotic) of the Quebec Newborn Twin Study recruited from the birth records of the Quebec Statistics Institute. Daytime and nighttime sleep was assessed through maternal reports at 6, 18, 30, and 48 months of age. A semiparametric modeling strategy was used to estimate daytime and nighttime sleep duration trajectories. Quantitative genetic models were used to examine to what extent genetic and environmental factors influenced daytime and nighttime continuous sleep duration. RESULTS: Genetic modeling analyses revealed environmental influences for all daytime sleep duration trajectories. In contrast, strong genetic influences were found for consolidated nighttime sleep duration (except at 18 months and for the short-increasing sleep duration trajectory). CONCLUSIONS: This is the first indication that early childhood daytime sleep duration may be driven by environmental settings, whereas the variance in consolidated nighttime sleep duration is largely influenced by genetic factors with a critical environmental time-window influence at ∼18 months.

Maternal self-efficacy and hostile-reactive parenting from infancy to toddlerhood

A longitudinal study of maternal self-efficacy (SE) and hostile-reactive parenting (HRP) was conducted with a community sample of 1836 mothers. Mothers completed questionnaires when their child was 4.5, 16.6 and 28.5 months of age. Maternal SE showed little change, whereas HRP sharply increased from 4.5 to 28.5 months. Structural equation models suggest these initially correlated variables did not influence each other over time, but rather became increasingly independent. Three distinct developmental trajectories were fitted for both maternal SE and HRP. In contrast to the overall portrait of stability, 12.6% of mothers followed a trajectory of declining SE. Likewise, 12.1% of mothers showed initially high and sharply increasing HRP. Few mothers (3.1%) simultaneously followed both of these trajectories, yet overall, SE and HRP trajectories were modestly associated (tau(b)=-.23, p<.0001). Failure to support the expected reciprocal influences between SE and HRP over time, as well as maternal and child contributions to early manifestations of maternal HRP and their evolution are discussed.

Growth in Inuit children exposed to polychlorinated biphenyls and lead during fetal development and childhood

BACKGROUND Because of their geographical location and traditional lifestyle, Canadian Inuit children are highly exposed to polychlorinated biphenyls (PCBs) and lead (Pb), environmental contaminants that are thought to affect fetal and child growth. We examined the associations of these exposures with the fetal and postnatal growth of Inuit children. METHODS We conducted a prospective cohort study among Inuit from Nunavik (Arctic Québec). Mothers were recruited at their first prenatal visit; children (n=290) were evaluated at birth and at 8-14 years of age. Concentrations of PCB 153 and Pb were determined in umbilical cord and child blood. Weight, height and head circumference were measured at birth and during childhood. RESULTS Cord blood PCB 153 concentrations were not associated with anthropometric measurements at birth or school age, but child blood PCB 153 concentrations were associated with reduced weight, height and head circumference during childhood. There was no association between cord Pb levels and anthropometric outcomes at birth, but cord blood Pb was related to smaller height and shows a tendency of a smaller head circumference during childhood. INTERPRETATION Our results suggest that chronic exposure to PCBs during childhood is negatively associated with skeletal growth and weight, while prenatal Pb exposure is related to reduced growth during childhood. This study is the first to link prenatal Pb exposure to poorer growth in school-age children.