Biomedical subjects

Mirko Manchia

Publications and source records attributed to Mirko Manchia.

3 recordsLinked to original sources

PubMed2026

Genomic dimensions deconstruct the clinical heterogeneity of bipolar disorder.

Bipolar disorder's (BD) clinical heterogeneity has an unresolved genetic basis. We meta-analyzed genome-wide association studies (GWAS) of 16 BD subphenotypes in 226,032 individuals from 57 cohorts (38,022 cases); 10 advanced to multivariate and multi-trait analyses. Four factors (compulsive, psychotic, dysregulated, internalizing) explained 82.8% of shared genetic variance. BD1 and BD2 loaded on distinct factors despite a high genetic correlation; 87.0% of common-factor loci were significant in neither subtype. Unipolar mania aligned with psychosis over internalizing, and was distinguishable from BD1, and rapid cycling showed heritable cross-domain liability. We identified 356 risk loci, 158 novel, including the first univariate-GWAS associations for psychosis, unipolar mania, rapid cycling and schizoaffective disorder-and 249 credible genes (89 high-confidence), 12 with approved-drug or clinical-phase annotations. Cell-type association showed a midbrain dopaminergic-GABAergic gradient along the psychotic factor. BD's genetic architecture appears hierarchical-a general liability resolving into dimensions of course and comorbidity, beyond subtypes.

Journal Article↗

PubMed2026

Comparing trajectories of cognitive functioning in treatment-resistant and non-resistant depression: a multicentre linear mixed-effects analysis.

BACKGROUND: Impaired cognitive functioning is a severe symptom in major depressive disorder (MDD). Recent evidence suggests it may be a central characteristic in its treatment resistant form (TRD), potentially constituting a clinical marker for treatment resistance and a target amenable to intervention. To date, cognitive functioning in TRD remains poorly understood and longitudinal investigations are scarce. METHODS: This observational prospective cohort study, including 320 patients diagnosed with MDD from the multicentre PROMPT study, examined differences in cognitive functioning between 118 TRD and 202 non-TRD patients over a period of twelve weeks in a real-world setting, using linear mixed modelling. Patients that failed to respond to at least two prior antidepressants trials at baseline were classified as TRD. RESULTS: TRD patients showed significantly poorer baseline performances than non-TRD patients in attention/processing speed (β = -0.45; 95%CI[-0.70, -0.19]; FDR-p = 0.003) and verbal memory (β = -0.45; 95%CI[-0.72, -0.18]; FDR-p = 0.003). Significant time × group interactions were observed in motor speed and verbal fluency tasks. Post-hoc-analyses revealed stagnation in TRD patients and significant improvement in non-TRD patients. Across all other tasks improvement was observed in both groups, and random effects showed large heterogeneity between patients, indicating notable individual differences in cognitive performances. CONCLUSIONS: The results suggest distinct recovery patters between non-TRD and TRD patients, and diminished functioning in TRD patients at the domain level. However, intact and diminished performances likely occur in both groups, warranting further investigation of cognitive heterogeneity. These short-term findings highlight the need for more comprehensive longitudinal research on cognition in TRD.

Humans↗

PubMed2025

Genome-wide methylation biomarkers and biological aging in patients with bipolar disorder characterized for lithium response.

BACKGROUND: Epigenetic mechanisms might play a role in modulating susceptibility to bipolar disorder (BD) and response to lithium, the mainstay treatment for BD. Additionally, individuals with BD experience accelerated biological aging. METHODS: We compared blood DNA methylation profiles measured with EPIC v.2.0 arrays between patients with BD (33 lithium responders and 31 nonresponders) and nonpsychiatric controls (n = 32), as well as based on long-term lithium response. In addition, we compared cellular aging between these groups using epigenetic age, pace of aging, and, for the first time, transcriptional age acceleration based on bulk RNA sequencing in 93 patients and 56 controls. RESULTS: We identified 191 differentially methylated positions (DMPs) and 8 differentially methylated regions between patients with BD and controls, located in genes enriched for "Postsynaptic Density" (odds ratio = 6.81, p = 0.001). No DMP was significantly associated with lithium response after multiple testing correction. Patients showed a significantly higher biological age acceleration than controls based on two epigenetic clocks (GrimAge, Mann-Whitney U = 551, p = 0.0009; GrimAge2: U = 477, p = 9.0E-05) and pace of aging (DunedinPACE, t = 3.01, p = 0.003), but not on transcriptional age. While we observed no significant difference in epigenetic aging based on lithium response, lithium responders showed lower epigenetic acceleration using all clocks, with a trend observed using the PhenoAge clock (t = 1.97, p = 0.053). CONCLUSIONS: Our findings point to methylation patterns characterizing BD and support the hypothesis of accelerated cellular aging in BD.

Humans↗