Shared genetic variants across substance use disorders implicate common neurobiological pathways, a genome-wide mixed...

Area of Science:

• Genetics
• Psychiatry
• Neuroscience

Background:

• Substance use disorders (SUDs) are highly heritable, yet the shared and distinct genetic factors remain unclear.
• Understanding the genetic overlap and differences between alcohol use disorder (AUD), cannabis use disorder (CUD), and opioid use disorder (OUD) is crucial.

Purpose of the Study:

• To compare the genetic architectures of AUD, CUD, and OUD.
• To identify shared and unique genetic loci contributing to these substance use disorders.

Main Methods:

• Genome-wide association study (GWAS) summary statistics from European ancestry individuals were analyzed.
• Mixture models (MiXeR) estimated polygenicity, SNP-heritability, and discoverability for each SUD.
• Pairwise conditional/conjunctional false discovery rate (cond/conjFDR) analyses identified shared genetic loci.

Main Results:

• AUD exhibited the highest polygenicity, followed by CUD and OUD. SNP-heritability was 0.10 for AUD and OUD, and 0.01 for CUD.
• Genome-wide significant SNPs explained 2.0% of AUD variance, 0.3% of CUD, and 0.2% of OUD.
• Cond/conjFDR analysis revealed 39 novel loci for AUD, 10 for CUD, and 1 for OUD, with implicated genes primarily expressed in the brain.

Conclusions:

• SUDs share polygenic architectures and loci, but polygenicity levels differ significantly across disorders.
• Novel genetic loci implicate brain-expressed genes involved in neurotransmission, myelination, and cellular processes.
• Findings support a shared set of pleiotropic genes contributing to the etiology of SUDs and expand understanding of their genetic basis.