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Abstract Bipolar disorder (BD) has been associated with premature cellular aging with shortened telomere length (TL) as compared to the general population. We recently identified a subgroup of young individuals with prematurely shortened TL. The aims of the present study were to replicate this observation in a larger sample and analyze the expression levels of genes associated with age or TL in a subsample of these individuals. TL was measured on peripheral blood DNA using quantitative polymerase chain reaction in a sample of 542 individuals with BD and clustering analyses were performed. Gene expression level of 29 genes, associated with aging or with telomere maintenance, was analyzed in RNA samples from a subsample of 129 individuals. Clustering analyses identified a group of young individuals (mean age 29.64 years), with shorter TL. None of the tested clinical variables were significantly associated with this subgroup. Gene expression level analyses showed significant downregulation of MYC, POT1, and CD27 in the prematurely aged young individuals compared to the young individuals with longer TL. After adjustment only POT1 remained significantly differentially expressed between the two groups of young individuals. This study confirms the existence of a subgroup of young individuals with BD with shortened TL. The observed decrease of POT1 expression level suggests a newly described cellular mechanism in individuals with BD, that may contribute to telomere shortening.

Abstract Emotion dysregulation is central to the development and maintenance of psychopathology, and is common across many psychiatric disorders. Neurobiological models of emotion dysregulation involve the fronto-limbic brain network, including in particular the amygdala and prefrontal cortex (PFC). Neural variability has recently been suggested as an index of cognitive flexibility. We hypothesized that within-subject neural variability in the fronto-limbic network would be related to inter-individual variation in emotion dysregulation in the context of low affective control. In a multi-site cohort (N = 166, 93 females) of healthy individuals and individuals with emotional dysregulation (attention deficit/hyperactivity disorder (ADHD), bipolar disorder (BD), and borderline personality disorder (BPD)), we applied partial least squares (PLS), a multivariate data-driven technique, to derive latent components yielding maximal covariance between blood-oxygen level-dependent (BOLD) signal variability at rest and emotion dysregulation, as expressed by affective lability, depression and mania scores. PLS revealed one significant latent component (r = 0.62, p = 0.044), whereby greater emotion dysregulation was associated with increased neural variability in the amygdala, hippocampus, ventromedial, dorsomedial and dorsolateral PFC, insula and motor cortex, and decreased neural variability in occipital regions. This spatial pattern bears a striking resemblance to the fronto-limbic network, which is thought to subserve emotion regulation, and is impaired in individuals with ADHD, BD, and BPD. Our work supports emotion dysregulation as a transdiagnostic dimension with neurobiological underpinnings that transcend diagnostic boundaries, and adds evidence to neural variability being a relevant proxy of neural efficiency.