Genes identified in rodent studies of alcohol intake are enriched for heritability of human substance use

Abstract

BackgroundRodent paradigms and human genome-wide association studies (GWASs) on drug use have the potential to provide biological insight into the pathophysiology of addiction.MethodsUsing GeneWeaver, we created rodent alcohol and nicotine gene-sets derived from 19 gene expression studies on alcohol and nicotine outcomes. We partitioned the SNP-heritability of these gene-sets using four large human GWASs: 1) alcoholic drinks per week, 2) problematic alcohol use, 3) cigarettes per day and 4) smoking cessation. We benchmarked our findings with curated human alcoholism and nicotine addiction gene-sets and performed specificity analyses using other rodent gene-sets (e.g., locomotor behavior) and other human GWASs (e.g., height).ResultsThe rodent alcohol gene-set was enriched for heritability of drinks per week, cigarettes per day, and smoking cessation, but not problematic alcohol use. However, the rodent nicotine gene-set was not significantly associated with any of these traits. Both rodent gene-sets showed enrichment for several non-substance use GWASs, and the extent of this relationship tended to increase as a function of trait heritability. In general, larger gene-sets demonstrated more significant enrichment. Finally, when evaluating human traits with similar heritabilities, both rodent gene-sets showed greater enrichment for substance use traits.ConclusionOur results suggest that rodent gene expression studies can help to identify genes that capture heritability of substance use traits in humans, yet the specificity to human substance use was less than expected due to various factors such as the genetic architecture of a trait. We outline various limitations, interpretations and considerations for future research.

Multi-omics analyses cannot identify true-positive novel associations from underpowered genome-wide association studies of four brain-related traits

“…Analyses focused on trait associations at the gene level, rather than individual SNPs (14). This enabled the additional integration of multi-omics data that did not use GWAS information, including results from post mortem studies of gene expression in patients and rodent models, and a gene-set for AUD/PAU that integrates information from a variety of rodent data sources (12). These methods were uniformly the least informative across all analyses.…”

“…We note that we did not systematically query the literature to derive comprehensive gene-sets for all traits. Indeed, the AUD/PAU rodent gene set, which was derived from a systematic review of the literature (12), achieved a higher PPV and sensitivity for AUD/PAU than data from individual studies of rodent models did for their respective traits. The gene-level focus reflects an additional weakness of the omics-integration approach, in that it could lead to improved knowledge of biology without narrowing down the identity of causal loci in human populations.…”

“…Results from 7 tissues were integrated using an aggregated Cauchy association test (39), which is also used by the FUSION TWAS method to integrate across tissues (25). An additional list of genes from rodent studies enriched for the heritability of alcohol use disorder was included as an additional method (12). MDD-associated genes came from a study examining differentially expressed genes in two brain tissues across three mouse chronic stress models (40).…”

“…In parallel to GWAS, there has been an explosion in the multiomics data (e.g., gene expression, Hi-C) which are now available to interrogate GWAS findings. For some traits, expression data can also be drawn from model organisms in experimentally controlled exposure and behavioral paradigms (12). As greater evidence arises for genome-wide significant signals to be enriched in regulatory regions, these multi-omics data have proved to be valuable in gene prioritization.…”

Testing Human Anxiety Associations of Genes Previously Implicated by Mouse Anxiety Models

“…For example, Palmer et al (2021) 16 found that sets of genes identified from nicotine-related behaviors in model organisms were enriched for associations with human tobacco consumption. Work by Huggett et al (2021) 17 found that rodent alcohol gene sets were enriched for heritability of various human substance use phenotypes, including drinks per week and cigarettes per day. Here, we apply a similar strategy to investigate whether human orthologs of genes previously implicated in mouse anxiety-like behaviors contribute to a range of human anxiety phenotypes, including different diagnoses and symptoms, and whether this relationship differs according to the human phenotype considered or the mouse behavioral test or brain region used.…”