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Impulsivity is a key feature of bipolar disorder (BD) associated with various negative outcomes. Recent use of ecological momentary assessment (EMA) has allowed for nuanced examination of the mechanisms of mood and impulsivity dysregulation. However, few existing studies have used an ecological momentary assessment of impulsivity in multiplex families with BD and examined its associations with mood. Using EMA, this study investigated the concurrent and predictive relationships between impulsivity and mood. Multiplex family members with BD (BDF, n = 8), unaffected family members (FC, n = 6), individuals with BD not from families (BDC, n = 8) and healthy controls (HC, n = 8), completed daily EMA surveys about mood and impulsivity for 6-12 weeks. Mixed-effects regression concurrent and lagged models were employed to analyze the relationship between impulsivity and mood. The BDF (Diff = -31.70, p = 0.001) and BDC (Diff = -25.74, p = 0.007) groups had a significantly lower mean in mood scores compared to the HC group but not compared to the FC group. There were no significant differences in the mean impulsivity scores between the groups. Time-lagged analyses revealed a significant negative association between prior impulsivity and mood at the next assessment independent of diagnosis (OR=0.939, p = 0.002). However, the opposite relationship between prior mood and impulsivity was not significant (OR=0.996, p = 0.135). These results contribute to the understanding of the complex interactions between BD, the genetic load of the disorder, impulsivity and mood. Furthermore, these findings indicate the potential benefits of addressing impulsivity as a means to improve mood outcomes at an early stage.

Major Depression and Bipolar Disorder Type I (BIP-I) and Type II (BIP-II), are characterized by depressed, manic, and hypomanic episodes in which specific changes of physical activity, circadian rhythm, and sleep are observed. It is known that genetic factors contribute to variation in mood disorders and biological rhythms, but unclear to what extent there is an overlap between their underlying genetics. In the present study, data from genome-wide association studies were used to examine the genetic relationship between mood disorders and biological rhythms. We tested the genetic correlation of depression, BIP-I, and BIP-II with physical activity (overall physical activity, moderate activity, sedentary behaviour), circadian rhythm (relative amplitude), and sleep features (sleep duration, daytime sleepiness). Genetic correlations of depression, BIP-I, and BIP-II with biological rhythms were compared to discover commonalities and differences. A gene-based analysis tested for associations of single genes and common circadian genes with mood disorders. Depression was negatively correlated with overall physical activity and positively with sedentary behaviour, while BIP-I showed associations in the opposite direction. Depression and BIP-II had negative correlations with relative amplitude. All mood disorders were positively correlated with daytime sleepiness. Overall, we observed both genetic commonalities and differences across mood disorders in their relationships with biological rhythms: depression and BIP-I differed the most, while BIP-II was in an intermediate position. Gene-based analysis suggested potential targets for further investigation. The present results suggest shared genetic underpinnings for the clinically observed associations between mood disorders and biological rhythms. Research considering possible joint mechanisms may offer avenues for improving disease detection and treatment.

Schizophrenia is a devastating, highly heritable brain disorder of unknown etiology. Recently, the first common genetic variant associated on a genome-wide level with schizophrenia and possibly bipolar disorder was discovered in ZNF804A (rs1344706). We show, by using an imaging genetics approach, that healthy carriers of rs1344706 risk genotypes exhibit no changes in regional activity but pronounced gene dosage-dependent alterations in functional coupling (correlated activity) of dorsolateral prefrontal cortex (DLPFC) across hemispheres and with hippocampus, mirroring findings in patients, and abnormal coupling of amygdala. Our findings establish disturbed connectivity as a neurogenetic risk mechanism for psychosis supported by genome-wide association, show that rs1344706 or variation in linkage disequilibrium is functional in human brain, and validate the intermediate phenotype strategy in psychiatry.

Patients with ulcerative colitis (UC) are at increased risk for developing colorectal cancer (CRC). In contrast to sporadic colorectal tumorigenesis, TP53 mutations occur early in the progression from inflamed colonic epithelium to dysplasia to CRC, and are sometimes readily detectable in inflamed, (yet) non-dysplastic mucosa. Here, we analyzed formalin-fixed paraffin-embedded tissue samples from 19 patients with long-standing UC (median 18 years, range 3 to 34) who had developed CRC as a consequence of chronic inflammation of the large bowel. We performed microsatellite instability testing, copy number analysis by array-based comparative genomic hybridization, mutation analysis by targeted next generation sequencing (48-gene panel) and TP53 immunostaining. The results were compared to The Cancer Genome Atlas (TCGA) data on sporadic CRC. All UC-CRC lesions in our cohort were microsatellite stable. Overall, genomic imbalances of UC-CRCs showed patterns of chromosomal aneuploidies characteristic for sporadic CRC with the exception of gains of chromosome arm 5p (12 of 23 UC-CRC, 52%), which are rare in sporadic CRCs from TCGA (21 of 144, 15%; FDR adjusted P = 0.006). UC-CRCs showed a predilection for TP53 alterations, which was the most frequently mutated gene in our cohort (20 of 23, 87%). Interestingly, spatially separated tumor lesions from individual patients tended to harbor distinct TP53 mutations. Similar to CRCs arising in a background of Crohn's colitis, the genetic landscape of UC-CRCs was characterized by TP53 mutations and chromosomal aneuploidies including gains of chromosome arm 5p. Both alterations harbor the potential for early detection in precursor lesions, thus complementing morphologic diagnosis.

Social integration is a major resilience factor for staying healthy. However, the COVID-19-pandemic led to unprecedented restrictions in social life. The consequences of these social lockdowns on momentary well-being are yet not fully understood. We investigated the affective benefit from social interactions in a longitudinal birth cohort. We used two real-time, real-life ecological momentary assessments once before and once during the initial lockdown of the pandemic ( N  = 70 participants; n ~6800 observations) capturing the protective role of social interactions on well-being. Moreover, we used a multimethod approach to analyze ecological assessment data with individual risk and resilience factors, which are promising moderators in the relationship of social behavior, stress reactivity, and affective states (i.e., amygdala volume, neuroticism, polygenic risk for schizophrenia). Social contacts were linked to higher positive affect both during normal times and during the COVID-19-pandemic (beta coefficient = 0.1035), highlighting the beneficial role of social embedding. Interestingly, this relationship was differentially moderated by individual risk and resilience factors. In detail, participants with a larger left amygdala volume (beta coefficient = −0.0793) and higher neuroticism (beta coefficient = −0.0958) exhibited an affective benefit from more social interactions prior to the pandemic. This pattern changed during the pandemic with participants with smaller amygdala volumes and lower neurotic traits showing an affective gain during the pandemic. Moreover, participants with low genetic risk for schizophrenia showed an affective benefit (beta coefficient = −0.0528) from social interactions irrespective of the time point. Our results highlight the protective role of social integration on momentary well-being. Thereby, we offer new insights into how this relationship is differently affected by a person’s neurobiology, personality, and genes under adverse circumstances.

LIS1-lissencephaly is a neurodevelopmental disorder marked by reduced cortical folding and severe neurological impairment. Although all cases result from heterozygous mutations in the LIS1 gene, patients present a broad spectrum of severity. Here, we use patient-derived forebrain organoids representing mild, moderate, and severe LIS1-lissencephaly to uncover mechanisms underlying this variability. We show that LIS1 protein levels vary across patient lines and partly correlate with clinical severity, indicating mutation-specific effects on protein function. Integrated morphological, transcriptomic, and proteomic analyses reveal progressive changes in neural progenitor homeostasis and neurogenesis that scale with severity. Mechanistically, microtubule destabilization disrupts cell–cell junctions and impairs WNT signaling, and defects in protein homeostasis, causing stress from misfolded proteins, emerge as key severity-linked pathways. Pharmacological inhibition of mTORC1 partially rescues these defects. Our findings demonstrate that patient-derived organoids can model disease severity, enabling mechanistic dissection and guiding targeted strategies in neurodevelopmental disorders. Here authors used patient-derived forebrain organoids to reveal how LIS1 mutations cause varying severity in a neurodevelopmental disorder, uncovering links between cytoskeletal defects, protein stress, and potential therapeutic strategies.

Traumatic events may lead to post-traumatic stress disorder (PTSD), with higher prevalence in women. Adverse childhood experiences (ACE) increase PTSD risk in adulthood. Epigenetic mechanisms play important roles in PTSD pathogenesis and a mutation in the methyl-CpG binding protein 2 (MECP2) in mice provide susceptibility to PTSD-like alterations, with sex-dependent biological signatures. The present study examined whether the increased risk of PTSD associated with ACE exposure is accompanied by reduced MECP2 blood levels in humans, with an influence of sex. MECP2 mRNA levels were analyzed in the blood of 132 subjects (58 women). Participants were interviewed to assess PTSD symptomatology, and asked to retrospectively report ACE. Among trauma-exposed women, MECP2 downregulation was associated with the intensification of PTSD symptoms linked to ACE exposure. MECP2 expression emerges as a potential contributor to post-trauma pathophysiology fostering novel studies on the molecular mechanisms underlying its potential sex-dependent role in PTSD onset and progression.

Numerous mental illnesses arise following stressful events in vulnerable individuals, with females being generally more affected than males. Adverse childhood experiences are known to increase the risk of developing psychopathologies and DNA methylation was demonstrated to drive the long-lasting effects of early life stress and promote stress susceptibility. Methyl-CpG binding protein 2 (MECP2), an X-linked reader of the DNA methylome, is altered in many mental disorders of stress origin, suggesting MECP2 as a marker of stress susceptibility; previous works also suggest a link between MECP2 and early stress experiences. The present work explored whether a reduced expression of MECP2 is paralleled by an increased vulnerability to the negative outcomes of stress exposure during childhood. To this aim, blood MECP2 mRNA levels were analyzed in 63 people without history of mental disorders and traits pertaining to depressive and anxiety symptom clusters were assessed as proxies of the vulnerability to develop stress-related disorders; stress exposure during childhood was also evaluated. Using structural equation modeling, we demonstrate that reduced MECP2 expression is accompanied by symptoms of anxiety/depression in association with exposure to stress in early life, selectively in healthy women. These results suggest a gender-specific involvement of MECP2 in the maladaptive outcomes of childhood adversities, and shed new light on the complex biology underlying gender bias in stress susceptibility.

The cross-disorder risk gene CACNA1C is strongly implicated in multiple neuropsychiatric disorders, including autism spectrum disorder (ASD), bipolar disorder (BPD), and schizophrenia (SCZ), with deficits in social functioning being common for all major neuropsychiatric disorders. In the present study, we explored the role of Cacna1c in regulating disorder-relevant behavioral phenotypes, focusing on socio-affective communication after weaning during the critical developmental period of adolescence in rats. To this aim, we used a newly developed genetic Cacna1c rat model and applied a truly reciprocal approach for studying communication through ultrasonic vocalizations, including both sender and receiver. Our results show that a deletion of Cacna1c leads to deficits in social behavior and pro-social 50-kHz ultrasonic communication in rats. Reduced levels of 50-kHz ultrasonic vocalizations emitted during rough-and-tumble play may suggest that Cacna1c haploinsufficient rats derive less reward from playful social interactions. Besides the emission of fewer 50-kHz ultrasonic vocalizations in the sender, Cacna1c deletion reduced social approach behavior elicited by playback of 50-kHz ultrasonic vocalizations. This indicates that Cacna1c haploinsufficiency has detrimental effects on 50-kHz ultrasonic communication in both, sender and receiver. Together, these data suggest that Cacna1c plays a prominent role in regulating socio-affective communication in rats with relevance for ASD, BPD, and SCZ.