Association of Predicted Expression and Multimodel Association Analysis of Substance Abuse Traits

Complex Psychiatry. 2022 Sep;8(1-2):35-46. doi: 10.1159/000523748. Epub 2022 Feb 28.


Introduction: Genome-wide association studies (GWAS) have played a critical role in identifying many thousands of loci associated with complex phenotypes and diseases. This has led to several translations of novel disease susceptibility genes into drug targets and care. This however has not been the case for analyses where sample sizes are small, which suffer from multiple comparisons testing. The present study examined the statistical impact of combining a burden test methodology, PrediXcan, with a multimodel meta-analysis, cross phenotype association (CPASSOC).

Methods: The analysis was conducted on 5 addiction traits: family alcoholism, cannabis craving, alcohol, nicotine, and cannabis dependence and 10 brain tissues: anterior cingulate cortex BA24, cerebellar hemisphere, cortex, hippocampus, nucleus accumbens basal ganglia, caudate basal ganglia, cerebellum, frontal cortex BA9, hypothalamus, and putamen basal ganglia. Our sample consisted of 1,640 participants from the University of California, San Francisco (UCSF) Family Alcoholism Study. Genotypes were obtained through low pass whole genome sequencing and the use of Thunder, a linkage disequilibrium variant caller.

Results: The post-PrediXcan, gene-phenotype association without aggregation resulted in 2 significant results, HCG27 and SPPL2B. Aggregating across phenotypes resulted no significant findings. Aggregating across tissues resulted in 15 significant and 5 suggestive associations: PPIE, RPL36AL, FOXN2, MTERF4, SEPTIN2, CIAO3, RPL36AL, ZNF304, CCDC66, SSPOP, SLC7A9, LY75, MTRF1L, COA5, and RRP7A; RPS23, GNMT, ERV3-1, APIP, and HLA-B, respectively.

Discussion: Given the relatively small size of the cohort, this multimodel approach was able to find over a dozen significant associations between predicted gene expression and addiction traits. Of our findings, 8 had prior associations with similar phenotypes through investigation of the GWAS Atlas. With the onset of improved transcriptome data, this approach should increase in efficacy.

Keywords: Addiction; Burden test; Meta-analysis; Predictive genomics.

Grants and funding

This research was supported by the National Institute on Drug Abuse Grant R01 DA030976. Additional funding was provided by the State of California and the Ernest Gallo Clinic and the Research Center for Medical Research on Alcohol and Substance Abuse through the University of California at San Francisco.