Investigating the relationship between DNA methylation, genetic variation, and suicide attempt in bipolar disorder.

Individuals with bipolar disorder are at increased risk for suicide, and this can be influenced by a range of biological, clinical, and environmental risk factors. Biological components associated with suicide include DNA modifications that lead to changes in gene expression. Common genetic variation and DNA methylation changes are some of the most frequent types of DNA findings associated with an increased risk for suicidal behavior. Importantly, the interplay between genetic predisposition and DNA methylation patterns is becoming more prevalent in genetic studies. We hypothesized that DNA methylation patterns in specific loci already genetically associated with suicide would be altered in individuals with bipolar disorder and a history of suicide attempt. To test this hypothesis, we searched the literature to identify common genetic variants (N=34) previously associated with suicidal thoughts and behaviors in individuals with bipolar disorder. We then created a customized sequencing panel that covered our chosen genomic loci. We profiled DNA methylation patterns from blood samples collected from bipolar disorder participants with suicidal behavior (N=55) and without suicidal behavior (N=51). We identified seven differentially methylated CpG sites and five differentially methylated regions between the two groups. Additionally, we found that DNA methylation changes in MIF and CACNA1C were associated with lethality or number of suicide attempts. Finally, we identified three meQTLs in SIRT1 , IMPA2 , and INPP1 . This study illustrates that DNA methylation is altered in individuals with bipolar disorder and a history of suicide attempts in regions known to harbor suicide-related variants.

Blood epigenome-wide association studies of suicide attempt in adults with bipolar disorder.

Suicide attempt (SA) risk is elevated in individuals with bipolar disorder (BD), and DNA methylation patterns may serve as possible biomarkers of SA. We conducted epigenome-wide association studies (EWAS) of blood DNA methylation associated with BD and SA. DNA methylation was measured at >700,000 positions in a discovery cohort of n = 84 adults with BD with a history of SA (BD/SA), n = 79 adults with BD without history of SA (BD/non-SA), and n = 76 non-psychiatric controls (CON). EWAS revealed six differentially methylated positions (DMPs) and seven differentially methylated regions (DMRs) between BD/SA and BD/non-SA, with multiple immune-related genes implicated. There were no epigenome-wide significant differences when BD/SA and BD/non-SA were each compared to CON, and patterns suggested that epigenetics differentiating BD/SA from BD/non-SA do not differentiate BD/non-SA from CON. Weighted gene co-methylation network analysis and trait enrichment analysis of the BD/SA vs. BD/non-SA contrast further corroborated immune system involvement, while gene ontology analysis implicated calcium signalling. In an independent replication cohort of n = 48 BD/SA and n = 47 BD/non-SA, fold changes at the discovery cohort's significant sites showed moderate correlation across cohorts and agreement on direction. In both cohorts, classification accuracy for SA history among individuals with BD was highest when methylation at the significant CpG sites as well as information from clinical interviews were combined, with an AUC of 88.8% (CI = 83.8-93.8%) and 82.1% (CI = 73.6-90.5%) for the combined epigenetic-clinical classifier in the discovery and replication cohorts, respectively. Our results provide novel insight to the role of immune system functioning in SA and BD and also suggest that integrating information from multiple levels of analysis holds promise to improve risk assessment for SA in adults with BD.

Cerebellar morphological differences and associations with extrinsic factors in bipolar disorder type I.

BACKGROUND: The neural underpinnings of bipolar disorder (BD) remain poorly understood. The cerebellum is ideally positioned to modulate emotional regulation circuitry yet has been understudied in BD. Literature suggests differences in cerebellar activity and metabolism in BD, however findings on structural differences remain contradictory. Potential reasons include combining BD subtypes, small sample sizes, and potential moderators such as genetics, adverse childhood experiences (ACEs), and pharmacotherapy. METHODS: We collected 3 T MRI scans from participants with (N = 131) and without (N = 81) BD type I, as well as blood and questionnaires. We assessed differences in cerebellar volumes and explored potentially influential factors. RESULTS: The cerebellar cortex was smaller bilaterally in participants with BD. Polygenic propensity score did not predict any cerebellar volumes, suggesting that non-genetic factors may have greater influence on the cerebellar volume difference we observed in BD. Proportionate cerebellar white matter volumes appeared larger with more ACEs, but this may result from reduced ICV. Time from onset and symptom burden were not associated with cerebellar volumes. Finally, taking sedatives was associated with larger cerebellar white matter and non-significantly larger cortical volume. LIMITATIONS: This study was cross-sectional, limiting interpretation of possible mechanisms. Most of our participants were White, which could limit the generalizability. Additionally, we did not account for potential polypharmacy interactions. CONCLUSIONS: These findings suggest that external factors, such as sedatives and childhood experiences, may influence cerebellum structure in BD and may mask underlying differences. Accounting for such variables may be critical for consistent findings in future studies.

Blood epigenome-wide association studies of suicide attempt in adults with bipolar disorder.

Suicide attempt (SA) risk is elevated in individuals with bipolar disorder (BD), and DNA methylation patterns may serve as possible biomarkers of SA. We conducted epigenome-wide association studies (EWAS) of blood DNA methylation associated with BD and SA. DNA methylation was measured at > 700,000 positions in a discovery cohort of n = 84 adults with BD with a history of SA (BD/SA), n = 79 adults with BD without history of SA (BD/non-SA), and n = 76 non-psychiatric controls (CON). EWAS revealed six differentially methylated positions (DMPs) and seven differentially methylated regions (DMRs) between BD/SA and BD/non-SA, with multiple immune-related genes implicated. There were no epigenome-wide significant differences when BD/SA and BD/non-SA were each compared to CON, and patterns suggested that epigenetics differentiating BD/SA from BD/non-SA do not differentiate BD/non-SA from CON. Weighted gene co-methylation network analysis and trait enrichment analysis of the BD/SA vs. BD/non-SA contrast further corroborated immune system involvement, while gene ontology analysis implicated calcium signalling. In an independent replication cohort of n = 48 BD/SA and n = 47 BD/non-SA, fold-changes at the discovery cohort's significant sites showed moderate correlation across cohorts and agreement on direction. In both cohorts, classification accuracy for SA history among individuals with BD was highest when methylation at the significant CpG sites as well as information from clinical interviews were combined, with an AUC of 88.8% (CI = 83.8-93.8%) and 82.1% (CI = 73.6-90.5%) for the combined epigenetic-clinical predictor in the discovery and replication cohorts, respectively. Our results provide novel insight to the role of immune system functioning in SA and BD and also suggest that integrating information from multiple levels of analysis holds promise to improve risk assessment for SA in adults with BD.

Functional connectivity of the cerebellar vermis in bipolar disorder and associations with mood.

Purpose: Studies of the neural underpinnings of bipolar type I disorder have focused on the emotional control network. However, there is also growing evidence for cerebellar involvement, including abnormal structure, function, and metabolism. Here, we sought to assess functional connectivity of the cerebellar vermis with the cerebrum in bipolar disorder and to assess whether connectivity might depend on mood. Methods: This cross-sectional study enrolled 128 participants with bipolar type I disorder and 83 control comparison participants who completed a 3 T magnetic resonance imaging (MRI) study, which included anatomical as well as resting state Blood Oxygenation Level Dependent (BOLD) imaging. Functional connectivity of the cerebellar vermis to all other brain regions was assessed. Based on quality control metrics of the fMRI data, 109 participants with bipolar disorder and 79 controls were included in the statistical analysis comparing connectivity of the vermis. In addition, the data was explored for the potential impacts of mood, symptom burden, and medication in those with bipolar disorder. Results: Functional connectivity between the cerebellar vermis and the cerebrum was found to be aberrant in bipolar disorder. The connectivity of the vermis was found to be greater in bipolar disorder to regions involved in motor control and emotion (trending), while reduced connectivity was observed to a region associated with language production. In the participants with bipolar disorder, past depression symptom burden affected connectivity; however, no effects of medication were observed. Functional connectivity between the cerebellar vermis and all other regions revealed an inverse association with current mood ratings. Conclusion: Together the findings may suggest that the cerebellum plays a compensatory role in bipolar disorder. The proximity of the cerebellar vermis to the skull may make this region a potential target for treatment with transcranial magnetic stimulation.

Association between the epigenetic lifespan predictor GrimAge and history of suicide attempt in bipolar disorder.

Bipolar disorder (BD) has been previously associated with premature mortality and aging, including acceleration of epigenetic aging. Suicide attempts (SA) are greatly elevated in BD and are associated with decreased lifespan, biological aging, and poorer clinical outcomes. We investigated the relationship between GrimAge, an epigenetic clock trained on time-to-death and associated with mortality and lifespan, and SA in two independent cohorts of BD individuals (discovery cohort - controls (n = 50), BD individuals with (n = 77, BD/SA) and without (n = 67, BD/non-SA) lifetime history of SA; replication cohort - BD/SA (n = 48) and BD/non-SA (n = 47)). An acceleration index for the GrimAge clock (GrimAgeAccel) was computed from blood DNA methylation (DNAm) and compared between groups with multiple general linear models. Differences in epigenetic aging from the discovery cohort were validated in the independent replication cohort. In the discovery cohort, controls, BD/non-SA, and BD/SA significantly differed on GrimAgeAccel (F = 5.424, p = 0.005), with the highest GrimAgeAccel in BD/SA (p = 0.004, BD/SA vs. controls). Within the BD individuals, BD/non-SA and BD/SA differed on GrimAgeAccel in both cohorts (p = 0.008) after covariate adjustment. Finally, DNAm-based surrogates revealed possible involvement of plasminogen activator inhibitor 1, leptin, and smoking pack-years in driving accelerated epigenetic aging. These findings pair with existing evidence that not only BD, but also SA, may be associated with an accelerated biological aging and provide putative biological mechanisms for morbidity and premature mortality in this population.

Functional Connectivity of the Cerebellar Vermis in Bipolar Disorder and Associations with Mood.

Purpose: Studies of the neural underpinnings of bipolar type I disorder have focused on the emotional control network. However, there is also growing evidence for cerebellar involvement, including abnormal structure, function, and metabolism. Here, we sought to assess functional connectivity of the cerebellum with the cerebrum in bipolar disorder and to assess whether any effects might depend on mood. Methods: This cross-sectional study enrolled 128 participants with bipolar type I disorder and 83 control comparison participants who completed a 3T MRI scan, which included anatomical imaging as well as resting state BOLD imaging. Functional connectivity of the cerebellar vermis to all other brain regions was assessed. Based on quality control metrics of the fMRI data, 109 participants with bipolar disorder and 79 controls were used to in the statistical analysis comparing connectivity of the vermis as well as associations with mood. Potential impacts of medications were also explored. Results: Functional connectivity of the cerebellar vermis in bipolar disorder was found to differ significantly between brain regions known to be involved in the control of emotion, motor function, and language. While connections with emotion and motor control areas were significantly stronger in bipolar disorder, connection to a region associated language production was significantly weaker. In the participants with bipolar disorder, ratings of depression and mania were inversely associated with vermis functional connectivity. No effect of medications on these connections were observed. Conclusion: Together the findings suggest cerebellum may play a compensatory role in bipolar disorder and when it can no longer fulfill this role, depression and mania develop. The proximity of the cerebellar vermis to the skull may make this region a potential target for treatment with transcranial magnetic stimulation.

Metabolic abnormalities in the basal ganglia and cerebellum in bipolar disorder: A multi-modal MR study.

AIMS: Bipolar type I disorder (BD) is characterized by severe mood swings and occurs in about 1% of the population. The mechanisms underlying the disorder remain unknown. Prior studies have suggested abnormalities in brain metabolism using 1H and 31P magnetic resonance spectroscopy (MRS). Supporting altered metabolism, in previous studies we found T1ρ relaxation times in the cerebellum were elevated in participants with BD. In addition, T1ρ relaxation times in the basal ganglia were lower in participants with BD experiencing depressed mood. Based on these findings, this study sought to probe brain metabolism with a focus of extending these assessments to the cerebellum. METHODS: This study collected data from 64 participants with Bipolar type I disorder (BD) and 42 controls. Subjects were scanned at both 3T (anatomical, functional, and T1ρ imaging data) and 7T (31P and 1H spectroscopy). Regions of interest defined by the 1H MRS data were used to explore metabolic and functional changes in the cerebellar vermis and putamen. RESULTS: Elevated concentrations of n-Acetyl-l-aspartate (NAA), glutamate, glutathione, taurine, and creatine were found in the cerebellar vermis along with decreased intra-cellular pH. Similar trends were observed in the right putamen for glutamate, creatine, and pH. We also observed a relationship between T1ρ relaxation times and mood in the putamen. We did not observe a significant effect of medications on these measures. LIMITATIONS: The study was cross sectional in design and employed a naturalistic approach for assessing the impact of medications on the results. CONCLUSION: This study supports prior findings of reduced pH in mitochondrial dysfunction in BD while also showing that these differences extend to the cerebellum.

Depression and anxiety among postpartum and adoptive mothers.

Similar to biological mothers during the postpartum period, women who adopt children experience increased stress and life changes that may put them at risk for developing depression and anxiety. The purpose of the current study was to compare levels of depression and anxiety symptoms between postpartum and adoptive women and, among adoptive women, to examine associations between specific stressors and depressive symptoms. Data from adoptive mothers (n = 147), recruited from Holt International, were compared to existing data from postpartum women (n = 147). Differences in the level of depression and anxiety symptoms as measured by the Inventory of Depression and Anxiety Symptoms among postpartum and adoptive women were examined. Associations between specific stressors and depressive symptoms were examined among adoptive mothers. Postpartum and adoptive women had comparable levels of depressive symptoms, but adoptive women reported greater well-being and less anxiety than postpartum women. Stressors (e.g., sleep deprivation, history of infertility, past psychological disorder, and less marital satisfaction) were all significantly associated with depressive symptoms among adoptive women. The level of depressive symptoms was not significantly different between the two groups. In contrast, adoptive women experienced significantly fewer symptoms of anxiety and experienced greater well-being. Additionally, adoptive mothers experienced more depressive symptoms during the year following adoption when the stressors were present. Thus, women with these characteristics should be routinely screened for depression and anxiety.