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
