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.
Lars A. R. Ystaas, P. Parekh, Nadine Parker et al.· Biological Psychiatry· 0 citations
Increasing prevalence of neurodevelopmental disorders (NDDs) is a growing public health concern. Identifying early risk markers may facilitate earlier intervention and reduce long-term burden. Although birth weight has been widely studied in relation to NDDs, evidence from clinically ascertained samples with single and overlapping diagnoses remains limited. In this case-control study, we compared birth weight between clinically referred individuals with intellectual disability (ID), autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD) from the Norwegian BUPgen registry (n = 720) and a population-based sample from the Norwegian Mother, Father and Child Cohort Study (MoBa) (n = 98,716). Perinatal data were obtained through linkage to the Medical Birth Registry of Norway. Associations were examined using logistic regression adjusted for gestational age, sex, and parental age. Additional analyses assessed interactions by sex and parental age, and birth weight categories. For each 100 g decrease in birth weight, odds significantly increased for the groups any NDD (one or more NDD diagnoses; OR = 1.04) and multiple diagnoses (two or more co-occurring NDDs; OR = 1.07). In diagnosis specific analyses, odds significantly increased for ID (OR = 1.15) and ASD (OR = 1.03). No interactions were observed. In categorical analyses, low birth weight was associated with higher odds of ID (OR = 8.27, p < 0.001), multiple diagnoses (OR = 4.96, p < 0.001), and any NDD (OR = 2.11, p = 0.002). No associations were observed for high birth weight. These findings support low birth weight as an early marker of neurodevelopmental vulnerability across NDD outcomes.
Eden Nordvold Barak, Knut K. Kolskår, Christine Dahl et al.· Child Psychiatry and Human D...· 0 citations
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