Gene–environment interactions in panic disorder and CO₂ sensitivity: Effects of events occurring early in life

Abstract

Heterogeneous life events (LE) precede the onset of-and potentially increase the susceptibility to-panic disorder (PD). It remains unknown whether LE can act as moderators in the context of gene-by-environment interactions (G×E) that alter the susceptibility to PD and the related trait of CO₂ sensitivity, nor it is known whether such moderation may depend on occurrence of events at different epochs in life. In 712 general population twins we analyzed by Maximum Likelihood analyses of ordinal data whether life (major- and stressful) events moderate the genetic risk for PD and CO₂ sensitivity, as indexed by the 35% CO₂ /65% O₂ challenge. For CO₂ sensitivity, best-fitting models encompassed both additive and interactional effects that increased linearly with the cumulative number and severity (SEV) of events in lifetime. By analyzing the moderation effect of cumulative SEV separately for events that had occurred in adulthood (between age 18 and 37) or during childhood-adolescence (before the 18th birthday), we found evidence of G×E only within the childhood-adolescence window of risk, although twins had rated the childhood-adolescence events as significantly (P = 0.001) less severe than those having occurred during adulthood. For PD, all interactional terms could be dropped without significant worsening of the models' fit. Consistently with a diathesis-stress model, LE appear to act as moderators of the genetic variance for CO₂ sensitivity. Childhood-adolescence appears to constitute a sensitive period to the action of events that concur to alter the susceptibility to this panic-related trait.

Translational approach to studying panic disorder in rats: Hits and misses

“…In particular, Roberson-Nay et al (2012a) showed that although PD and CSA share a common genetic diathesis, childhood environment adversities account for only 1.2% of adult-onset panic attacks. Conversely, however, Spatola et al (2011) found that early-life adversities do correlate with CO 2 hypersensitivity in adulthood provided that the stressful events took place before 18 years of age. Accordingly, the influence of the early-life adversities in the later development of PD remains unclear.…”

The carbon dioxide challenge test in panic disorder: a systematic review of preclinical and clinical research

“…Battaglia et al reported three experiments [86][87][88] in which another variable was added to the twins' equation: the occurrence of traumatic events such as those leading to childhood separation anxiety, death of parents, and a history of generally stressful situations in childhood. The first of these, 86 with 700 twins, suggested the existence of a continuum of childhood separation anxiety and PD, and the association of both disorders with hypersensitivity to CO 2 .…”

“…Following this report, a study of 712 subjects 87 concluded that the opposite could also be true: that ''genetic susceptibility to CO 2 response may influence the sensitivity to environmental hazard.'' The next trial, 88 also with 712 twins, suggested the existence of a relation between the occurrence of adverse life events, susceptibility to CO 2 , and later development of PD.…”

Animal Models of Human Anxiety Disorders: Reappraisal From a Developmental Psychopathology Vantage Point

“…The use of well-validated human endophenotypes that share part of the susceptibility with a corresponding diagnosis, but are at least partially independent of the clinical manifestation of the disorder, may become one "gold standard" in the field. These endophenotypes can be used as tools to investigate the mechanisms of illness while circumventing some of the limits connected with the inferential nature of behavioral testing (46,(72)(73)(74).…”