Irina Pokhvisneva

Effects of Genotype and Sleep on Temperament.

BACKGROUND AND OBJECTIVES: Sleep problems are frequent in young children; however, children vary in the degree to which they are affected by poor sleep quality. We investigated whether a polymorphism in the serotonin transporter gene, which is linked to emotional function, is a potential moderator of the influences of sleep duration on infant temperament using longitudinal data. METHODS: We examined the interactive effects of average sleep duration between 6 and 36 months of age and the 5-HTTLPR genotype on negative emotionality/behavioral dysregulation at 36 months in 209 children recruited into a longitudinal birth cohort study. Triallelic genotyping of 5-HTTLPR was performed by looking at SLC6A4 genotype, focusing on the serotonin transporter-linked polymorphic region (5-HTTLPR) including the SNP polymorphism (rs23351). Child sleep habits were assessed with a maternal self-report questionnaire. RESULTS: After controlling for demographics and both previous and concurrent maternal depression, multiple linear regression analyses revealed a significant interaction effect of average sleep duration for the first 3 years of life and 5-HTTLPR genotype on child negative emotionality/behavioral dysregulation such that the effects were exclusive to those with low-expressing 5-HTTLPR genotypes. CONCLUSIONS: The results suggest differential susceptibility to the effect of sleep duration early in life, which reiterates that the short allele of the 5-HTTLPR represents a marker of increased environmental sensitivity regarding emotional development. Differential susceptibility theory posits that certain factors may increase an individual’s susceptibility to the environment, in either a positive or negative fashion.

Cumulative prenatal exposure to adversity reveals associations with a broad range of neurodevelopmental outcomes that are moderated by a novel, biologically informed polygenetic score based on the serotonin transporter solute carrier family C6, member 4 (SLC6A4) gene expression

While many studies focus on the association between early life adversity and the later risk for psychopathology, few simultaneously explore diverse forms of environmental adversity. Moreover, those studies that examined the cumulative impact of early life adversity focus uniquely on postnatal influences. The objective of this study was to focus on the fetal period of development to construct and validate a cumulative prenatal adversity score in relation to a wide range of neurodevelopmental outcomes. We also examined the interaction of this adversity score with a biologically informed genetic score based on the serotonin transporter gene. Prenatal adversities were computed in two community birth cohorts using information on health during pregnancy, birth weight, gestational age, income, domestic violence/sexual abuse, marital strain, as well as maternal smoking, anxiety, and depression. A genetic score based on genes coexpressed with the serotonin transporter in the amygdala, hippocampus, and prefrontal cortex during prenatal life was constructed with an emphasis on functionally relevant single nucleotide polymorphisms, that is, expression quantitative trait loci. Prenatal adversities predicted a wide range of developmental and behavioral alterations in children as young as 2 years of age in both cohorts. There were interactions between the genetic score and adversities for several domains of the Child Behavior Checklist (CBCL), with pervasive developmental problems remaining significant adjustment for multiple comparisons. Scores combining different prenatal adverse exposures predict childhood behavior and interact with the genetic background to influence the risk for psychopathology.

Systematic Overestimation of Reflection Impulsivity in the Information Sampling Task: Age Dependency in Children

We read with great interest the letter recently published in Biological Psychiatry regarding the systematic overestimation of reflection impulsivity in the Information Sampling Task (IST) (1). The IST is a task in which the participants gather a variable amount of information prior to making a decision about an uncertain outcome (2). One of the main outcomes in this task is the P(correct), which estimates the level of uncertainty tolerated by the participant at the point of decision. Bennett et al. (1) proposed a new way to compute the IST outcome measure [P(correct)] and the use of this new formula was encouraged by the original designers of the task (3). However, as we have been using IST (incorporated into the Cambridge Neuropsychological Test Automated Battery) (4,5) in our community-based birth cohort for many years now (6), we observe that the relationship between the original and revised P(correct) is age specific. As impulsivity is a core feature in many prevalent neuropsychiatric conditions affecting youth, such as attention-deficit/hyperactivity disorder (7), eating disorders (8), and substance use disorders (9), and is a marker

A novel, biologically-informed polygenic score reveals role of mesocorticolimbic insulin receptor gene network on impulsivity and addiction

Abstract Conventional polygenic scores derived from genome-wide association studies do not reflect gene networks that code for biological functions. We present an alternative approach creating a biologically-informed polygenic score based on the insulin receptor (IR) gene networks in the mesocorticolimbic system and hippocampus that regulate reward sensitivity/inhibitory control and memory, respectively. Across multiple samples (n = 4300) our biologically-informed IR-PRS score showed better prediction of child impulsivity and cognitive performance, as well as risk for early addiction onset and Alzheimer’s disease in comparison to conventional polygenic scores for ADHD, addiction and dementia. This novel, biologically-informed approach enables the use of genomic datasets to probe relevant biological processes involved in neural function and disorders. One Sentence Summary A polygenic score based on genes co-expressed with the insulin receptor predicts childhood behavior and adult disease.Importance Activation of brain insulin receptors occurs on mesocorticolimbic regions, modulating reward sensitivity and inhibitory control. Variations in the functioning of this mechanism likely associate with individual differences in the risk for related psychopathologies (attention-deficit hyperactivity disorder, addiction), an idea that agrees with the high comorbidity between insulin resistant states and psychiatric conditions. While genetic studies comprise an interesting tool to explore neurobiological mechanisms in community samples, the conventional genome-wide association studies and polygenic risk score methodologies completely ignore the fact that genes operate in networks, and code for precise biological functions in specific tissues. Objective We propose a novel, biologically informed genetic score reflecting the mesocorticolimbic insulin receptor-related gene network, and investigate if it predicts dopamine-related psychopathology (impulsivity and addiction) in community samples. Design Birth cohort (Maternal Adversity, Vulnerability and Neurodevelopment, MAVAN) and adult cohort (Study of Addiction, Genes and Environment, SAGE). Setting General community. Participants 212 4-year-old children (MAVAN), and 1626 adults (SAGE). Exposure The biologically informed, mesocorticolimbic specific, insulin receptor polygenic score was created based on levels of co-expression with the insulin receptor in striatum and prefrontal cortex, and calculated in the two samples using the genotype data (Psychip/Psycharray). Main outcome childhood impulsivity in the Information Sampling task, and risk for early addiction onset. Results The insulin receptor polygenic score showed improved prediction of childhood impulsivity in boys and risk for early addiction onset in males in comparison to conventional polygenic risk scores for attention-deficit hyperactivity disorder or addiction. Conclusions and relevance This novel genomic approach reveals insulin action as a relevant biological process involved in the risk for dopamine-related psychopathology. Key points Question Considering the modulation of mesocorticolimbic dopaminergic pathways by insulin through the action on its receptors (IR), we investigated if a novel, region specific polygenic score on the IR-related gene network (ePRS-IR) is associated with dopamine-related behaviors (impulsivity and addiction). Findings The ePRS-IR showed improved prediction of childhood impulsivity and risk for early addiction onset in comparison to conventional polygenic risk scores for ADHD or addiction. Meaning This novel genomic approach reveals insulin action as a biological process involved in the risk for dopamine-related psychopathology.

Birth weight and catch up growth are associated with childhood impulsivity in two independent cohorts

Individuals born after intrauterine growth restriction (IUGR) are more impulsive towards palatable foods, but it is not clear 1) if IUGR-related impulsivity is specific for foods and solely based on response inhibition and 2) if the development of impulsivity is due to being born IUGR per se or to growing up fast in the first few years of life (catch up growth). Children were classified in the IUGR group if the birth weight ratio was below 0.85. Delta z score for BMI was used as a measure of catch up growth. In MAVAN (N = 274), impulsivity was measured by the Information Sampling Task from the Cambridge Neuropsychological Test Automated Battery (IST - CANTAB), and in GUSTO using the Sticker Delay Task (N = 327). There is a significant effect of interaction between being born IUGR and the magnitude of catch up growth on the reflection impulsivity from IST-CANTAB at 60 months, in which greater catch up growth associates with greater impulsivity in the IST fixed condition in IUGR children. The finding was reproduced in children from the GUSTO cohort using the Sticker Delay Task. We confirmed that catch up growth interacts with IUGR, having a major role in the development of impulsivity in the first years of life and influencing inhibitory control and decision making processes.

Maternal characteristics and behavioural/emotional problems in preschoolers: how they relate to sleep rhythmic movements at sleep onset

Sleep rhythmic movements have been speculated to be a form of self‐soothing. While this sleep‐related movement has been associated with lower socioeconomic status, psychopathologies and maternal characteristics, prospective studies with sizeable sample and objective measurements are lacking. The objectives were: (a) to identify maternal characteristics predicting sleep rhythmic movements in children; and (b) to document behavioural/emotional problems in preschoolers with sleep rhythmic movements. Participants were mother–child dyads (N = 529) from the Adversity: Maternal Adversity, Vulnerability and Neurodevelopment cohort. Questionnaires evaluating socioeconomic status (prenatal), maternal depressive symptoms (prenatal, 48 months), sleep rhythmic movements (12, 18, 24, 36, 48 months), maternal anxiety trait (24 months) and childrens behavioural/emotional problems (48 months) were used. Maternal sensitivity (accuracy and appropriateness of mothers responses to her babys needs) was assessed objectively with a filmed mother–infant interaction (6 months). Generalized estimating equation was used to investigate associations between sleep rhythmic movements and maternal characteristics (depression, anxiety and sensitivity). Linear regressions were used to assess associations between sleep rhythmic movements and behavioural/emotional problems in children. Lower maternal sensitivity, higher maternal depressive symptoms and lower socioeconomic status predicted sleep rhythmic movements in children (p < 0.05). To our knowledge, this is the first study showing that sleep rhythmic movements are associated with lower maternal sensitivity, measured objectively. This study also builds on previous reports, by documenting an association between sleep rhythmic movements and behavioural/emotional problems even in preschoolers. The presence of psychosocial factors in sleep rhythmic movements aetiology should be considered in treatment.

Community study found that cutaneous allergies in childhood were associated with conduct problems in girls

Several studies have shown that children with eczema, which is the most common form of cutaneous allergy, have an increased prevalence of psychological and behavioural problems or mental health disorders (1). Higher rates of anxiety and depression have been found in females than males with eczema (2) in adult studies, but the role that sex plays in influencing the association between eczema and the risk for mental health problems has not been extensively studied in young children. Our goal was to determine whether cutaneous allergies during childhood were associated with socioemotional outcomes in young girls and boys. Our community-based sample consisted of 630 mother–child dyads who were recruited in Montr eal and Hamilton, Canada, at 13– 20 weeks of gestation from antenatal care clinics during routine ultrasound visits or through advertisements displayed at local hospitals. The demographic information is in Table S1. The participants were part of the Maternal Adversity, Vulnerability, and Neurodevelopment study, which examined the development of individual differences in phenotypes associated with multiple forms of psychopathology. The study was conducted between 2003 and 2016. Mothers were first assessed during their pregnancy, between 24 and 36 weeks, and then followed at multiple time points, which included home visits and laboratory sessions. Written informed consent was obtained from all the participants. Ethics approval was obtained from the Douglas Mental Health University Institute at McGill University, Montreal, and St. Joseph’s Healthcare Hamilton at McMaster University, Hamilton. Mothers were asked to report on the state of their child’s health at different time points by answering questions on the Child’s Health Questions questionnaire (CHQ). The CHQ questionnaire was designed by Louise S eguin, MD, based on questions used for the Longitudinal Study of Child Development study in Quebec from1998 to 2002 and theNational Longitudinal Survey of Children and Youth study, (NLSCY 1994-present) which started in 1994 and is still continuing. This questionnaire was administered to themothers when their study child was 3, 6, 12 and 18 months and in the months they turned three, four, five and six years of age. The mothers were asked if their child had been diagnosedwith an allergy in the last six months at each time point, and the answers were dichotomised into yes or no. We also identified the presence or absence of cutaneous allergies, with eczema being the most common form. Therefore, a cutaneous allergy was used as a proxy for eczema. Socio-emotional development was assessed using the mother-reported Child Behavior Checklist (CBCL) at four and five years and the Strengths and Difficulties Questionnaire (SDQ) at five and six years. From the original 630 mother–child pairs recruited into the study, we were able to collect mother reports of child socio-emotional outcomes from 369 children at four years (41% attrition), 325 children at five years (48% attrition) and 260 children at six years (59% attrition). A generalised estimating equations analysis was used to account for repeated measurements of cutaneous allergies and socio-emotional outcome assessments at different times in boys and girls separately. An a priori split of the data on the boys and girls was conducted as previous findings showed differences in the risk for eczema, severity of eczema symptoms and impairments in quality of life between males and females with eczema (3). The presence of a childhood cutaneous allergy was the independent variable, and the dependent variables were the various socioemotional outcomes reported by the mother using the SDQ scores at five and six years and the CBCL scores at four and five years. Adjustments for maternal depression, gathered using the scores from the Center for Epidemiologic Studies Depression Scale Revised questionnaire, and family socio-economic status were added to the models. The data were analysed using the R statistical package (R Core Team, Vienna, Austria) and the Statistical Package for the Social Sciences version 20.0 (IBM Corp, Armonk, NY, USA). The Bonferroni–Holm correction was applied to adjust for multiple comparisons. The data are presented as beta values. Beta is an estimated regression coefficient representing the effect of the presence of a cutaneous allergy on a behavioural or psychological outcome. A p value of less than 0.05 was regarded as statistically significant. In addition to the demographic information on the mother–child dyads (Table S1), our data show that girls with a cutaneous allergy had higher emotional reactivity (Table S2) and higher emotional symptoms scores and higher conduct problems (Table 1) than girls without

Dynamic interaction between fetal adversity and a genetic score reflecting dopamine function on developmental outcomes at 36 months

Background Fetal adversity, evidenced by poor fetal growth for instance, is associated with increased risk for several diseases later in life. Classical cut-offs to characterize small (SGA) and large for gestational age (LGA) newborns are used to define long term vulnerability. We aimed at exploring the possible dynamism of different birth weight cut-offs in defining vulnerability in developmental outcomes (through the Bayley Scales of Infant and Toddler Development), using the example of a gene vs. fetal adversity interaction considering gene choices based on functional relevance to the studied outcome. Methods 36-month-old children from an established prospective birth cohort (Maternal Adversity, Vulnerability, and Neurodevelopment) were classified according to birth weight ratio (BWR) (SGA ≤0.85, LGA >1.15, exploring a wide range of other cut-offs) and genotyped for polymorphisms associated with dopamine signaling (TaqIA-A1 allele, DRD2-141C Ins/Ins, DRD4 7-repeat, DAT1-10- repeat, Met/Met-COMT), composing a score based on the described function, in which hypofunctional variants received lower scores. Results There were 251 children (123 girls and 128 boys). Using the classic cut-offs (0.85 and 1.15), there were no statistically significant interactions between the neonatal groups and the dopamine genetic score. However, when changing the cut-offs, it is possible to see ranges of BWR that could be associated with vulnerability to poorer development according to the variation in the dopamine function. Conclusion The classic birth weight cut-offs to define SGA and LGA newborns should be seen with caution, as depending on the outcome in question, the protocols for long-term follow up could be either too inclusive—therefore most costly, or unable to screen true vulnerabilities—and therefore ineffective to establish early interventions and primary prevention.