Paola Pesenti-Gritti

Unstable maternal environment, separation anxiety, and heightened CO2 sensitivity induced by gene-by-environment interplay

Background In man, many different events implying childhood separation from caregivers/unstable parental environment are associated with heightened risk for panic disorder in adulthood. Twin data show that the occurrence of such events in childhood contributes to explaining the covariation between separation anxiety disorder, panic, and the related psychobiological trait of CO2 hypersensitivity. We hypothesized that early interference with infant-mother interaction could moderate the interspecific trait of response to CO2 through genetic control of sensitivity to the environment. Methodology Having spent the first 24 hours after birth with their biological mother, outbred NMRI mice were cross-fostered to adoptive mothers for the following 4 post-natal days. They were successively compared to normally-reared individuals for: number of ultrasonic vocalizations during isolation, respiratory physiology responses to normal air (20%O2), CO2-enriched air (6% CO2), hypoxic air (10%O2), and avoidance of CO2-enriched environments. Results Cross-fostered pups showed significantly more ultrasonic vocalizations, more pronounced hyperventilatory responses (larger tidal volume and minute volume increments) to CO2-enriched air and heightened aversion towards CO2-enriched environments, than normally-reared individuals. Enhanced tidal volume increment response to 6%CO2 was present at 16–20, and 75–90 postnatal days, implying the traits stability. Quantitative genetic analyses of unrelated individuals, sibs and half-sibs, showed that the genetic variance for tidal volume increment during 6%CO2 breathing was significantly higher (Bartlett χ = 8.3, p = 0.004) among the cross-fostered than the normally-reared individuals, yielding heritability of 0.37 and 0.21 respectively. These results support a stress-diathesis model whereby the genetic influences underlying the response to 6%CO2 increase their contribution in the presence of an environmental adversity. Maternal grooming/licking behaviour, and corticosterone basal levels were similar among cross-fostered and normally-reared individuals. Conclusions A mechanism of gene-by-environment interplay connects this form of early perturbation of infant-mother interaction, heightened CO2 sensitivity and anxiety. Some non-inferential physiological measurements can enhance animal models of human neurodevelopmental anxiety disorders.

The co-occurrence between internalizing and externalizing behaviors

Although Internalized and Externalized problem behaviors are described as separate phenomena at the psychometric and clinical levels, they frequently co-occur. Only few studies, however, have investigated the causes of such covariation. In a sample of 398 twin pairs aged 8–17 drawn from the general population-based Italian Twin Registry, we applied bivariate genetic analyses to parent-rated CBCL/6–18 Internalization and Externalization scores. Covariation of Internalizing and Externalizing problem behaviors was best explained by genetic and common environmental factors, while the influence of unique environmental factors upon covariance appeared negligible. Odds ratio values showed that a borderline/clinical level of Externalization is a robust predictor of co-existing Internalizing problems in the same child, or within a sibship. Our findings help to approximate individual risks (e.g., in clinical practice, predicting the presence of Internalization in an externalizing child, and vice-versa), and to recognize that several shared environmental and genetic factors can simultaneously affect a child’s proneness to suffer from both types of problem behaviors.

Clumsiness and psychopathology: Causation or shared etiology? A twin study with the CBCL 6–18 questionnaire in a general school-age population sample

In a sample of 398 twin pairs aged 8-17 belonging to the Italian Twin Registry we explored the extent to which physical clumsiness/motor problems covary with a broad spectrum of behavioral problems identified by the Child Behavior Checklist 6-18/DSM oriented scales, and the causes of such covariation. Only Anxiety and Attention Deficit Hyperactivity (ADH) Problems maintained significant correlation with Clumsiness after partialling out the effects of the other problem scales. By the co-twin control method we found no indication of clear, direct causal effect of Clumsiness upon Anxiety or ADH Problems, or vice versa. Twin bivariate analyses showed that the co-occurrence of motor problems and Anxiety/ADH Problems is best explained by genetic factors shared between Clumsiness and the behavioral problems phenotypes.

The role of genes and environment in shaping co-occurrence of DSM-IV defined anxiety dimensions among Italian twins aged 8–17

This study investigated the ultimate causes of co-variation between symptoms of four common DSM-IV anxiety dimensions - Generalized Anxiety, Panic, Social Phobia and Separation Anxiety disorder - assessed with the Italian version of the Screen for Child Anxiety-Related Emotional Disorders questionnaire in a sample of 378 twin pairs aged 8-17 from the population-based Italian Twin Register. Genetic and environmental proportions of covariance between the targeted anxiety dimensions were estimated by multivariate twin analyses. Genetic influences (explaining from 58% to 99% of covariance) and unique environmental factors were the sole sources of co-variation for all phenotypes under study. Genetic influences associated with different anxiety dimensions coincide remarkably, as indicated by genetic correlations ranging from 0.40 to 0.61, while unique environmental overlap is less substantial. Thus, while additive genetic effects are important in explaining why children report symptoms from multiple anxiety disorders, environmental idiosyncratic factors seem to play a marginal role in shaping the co-occurrence of different anxiety dimensions in childhood.

A Genetically Informed Study of the Covariation Between the CBCL/6-18 DSM-Oriented Problem Scales and the Competence Scales

In 398 twin pairs belonging to the population-based Italian Registry, we investigated by the monozygotic twin intrapair differences model and bivariate designs whether the phenotypic correlations between CBCL/6–18 problem behaviours and competencies could better be accounted for by direct, causal effects, or by the presence of latent etiological factors, acting simultaneously as elements of risk/protection for psychopathology and competencies. All zero-order correlations between six CBCL DSM-oriented scales (DOS) and three competence scales (CS) were negative and small-to-moderate. After implementing multiple regressions we found robust enough prediction only for ADH DOS on school CS, and for anxiety DOS on social CS. Results from the intrapair differences model indicated shared elements of liability, rather than direct causation, as more likely explanations for the negative phenotypic correlations between these emotional/behavioural problem and competencies scores. Bivariate analyses indicated shared genetic factors that influence simultaneously the emotional/behavioural problems and the competencies domains as the best explanations for the phenotypic covariations between DOS and CS.