Early-childhood temperament is associated with later mental health. Temperament continues to develop throughout the first years of life, and a single assessment cannot capture its trajectory. Whether departures from an individual's developmental trajectory carry psychiatric risk remains unknown. Using data from more than 50,000 children in the Norwegian Mother, Father and Child Cohort Study, we modeled longitudinal temperament at 1.5, 3, and 5 years of age with the FEMA-Long mixed-effects framework. We then quantified each child's departures from their predicted trajectories. Multivariate analysis revealed two transdiagnostic dimensions linking trajectory departures to psychiatric diagnoses across childhood and adolescence. Higher scores on the first dimension were associated with an increased hazard of subsequent ADHD diagnosis (hazard ratio = 1.54), and higher scores on the second with an increased hazard of Asperger syndrome (hazard ratio = 1.64). To examine the genetic basis of these associations, we performed longitudinal GWAS of temperament and conjunctional FDR analysis to detect loci shared with the associated diagnoses. The effects of these loci changed across early childhood, with some strengthening and others attenuating with age. These findings show that departures from predicted temperament trajectories reflect transdiagnostic psychiatric risk with a shared genetic basis. Longitudinal, trajectory-based monitoring could help identify children at elevated psychiatric risk.
J. Kopal, N. Bakken, P. Parekh et al.· Molecular Psychiatry· 0 citations
BACKGROUND
Bipolar disorder (BIP) frequently co-occurs with heightened substance use (SU) and substance use disorders (SUDs). Although the strong co-occurrence of these heritable traits points to shared genetic susceptibility, the extent to which there are differences in how SU and SUD overlap with BIP genetic architecture remains unclear.
METHODS
We quantified the polygenic overlap between BIP and SUDs (alcohol, cannabis, opioid, and tobacco), and BIP and SU traits (drinks per week, lifetime cannabis use, prescription opioid use, and smoking initiation) using GWAS summary statistics and trivariate MiXeR. We then isolated the general and unique genetic contributions of SUD and SU using GWAS-by-subtraction via Genomic SEM. Next, we tested associations between polygenic risk scores derived from these latent factors and diagnostic and behavioral outcomes in the Norwegian Mother, Father and Child Cohort Study. Finally, we applied GSA-MiXeR to explore pleiotropic pathway enrichment shared between the latent factors and BIP.
RESULTS
We found extensive polygenic overlap between traits, with SUDs being more genetically correlated with BIP than SU traits. The unique SUD factor correlated positively with psychiatric disorders, whereas unique SU correlated negatively. PRS for BIP, shared SUD/SU, and unique SUD were significantly associated with BIP, SUD, and comorbid SUD-BIP; PRS for unique SU was only associated with self-reported lifetime SU. GSA-MiXeR revealed richer gene-set enrichment for SUD/BIP than SU/BIP implicating dopamine signaling and interneuron function.
CONCLUSION
By dissecting the genetic liability to SUD and SU and investigating their relationship with BIP we find a genetic signature correlated with substance dependence but not substance use more broadly.
L. Ystaas, P. Parekh, N. Parker et al.· Biological Psychiatry· 0 citations
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.
Tracey van der Veen, M. Tesfaye, J. M. K. Yang et al.· Research Square· 0 citations
Clozapine (CLZ) is the only available pharmacological option for treatment resistant schizophrenia (TRS), but its use is limited due to adverse drug reactions and potential cytotoxicity. Despite decades of research, the precise mechanisms of action of CLZ in the human brain remain poorly understood. To address this, we derived cortical brain organoids from a large cohort of schizophrenia (SCZ) patients and healthy controls and employed a comprehensive multiomics strategy to dissect the cellular mechanisms of long-term CLZ exposure of up to 24 weeks. We uncovered a SCZ-specific and metabolism-independent alternative splicing program that was amenable to non-toxic CLZ treatment. In-depth analysis revealed a key role of exon skipping and intron retention in glutamatergic neurons. This program was further found to recapitulate disease mechanisms in primary human brain tissue and capture splicing-mediated genetic signals of SCZ risk. These findings highlight alternative splicing as a promising avenue for therapeutic developments in TRS.
I. Akkouh, Jordi Requena Osete, A. Szabo et al.· bioRxiv· 0 citations
It is found that schizophrenia and ADHD show distinct genetic patterns: schizophrenia shares more genetic factors with brain structure and diabetes, while ADHD is more strongly linked to metabolic pathways.
J. Kopal, A. Shadrin, D. van der Meer et al.· Communications Medicine· 0 citations
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