Human Brain Proteome-wide Association Study Provides Insights into the Genetic Components of Protein Abundance in Obesity

Backgrounds: Genome-wide association studies have identified multiple genetic variants associated with obesity. However, most obesity-associated loci were waiting to be translated into new biological insights. Given the critical role of brain in obesity development, we sought to explore whether obesity-associated genetic variants could be mapped to brain protein abundances. Methods: We performed proteome-wide association studies (PWAS) and colocalization analyses to identify genes whose cis-regulated brain protein abundances were associated with obesity-related traits, including body fat percentage, trunk fat percentage, body mass index, visceral adipose tissue, waist circumference, and waist-to-hip ratio. We then assessed the druggability of the identified genes and conducted pathway enrichment analysis to explore their functional relevance. Finally, we evaluated the effects of the significant PWAS genes at the brain transcriptional level. Results: By integrating human brain proteomes from discovery (ROSMAP, N = 376) and validation datasets (BANNER, N = 198) with genome-wide summary statistics of obesity-related phenotypes ( N ranged from 325 153 to 806 834), we identified 52 genes whose cis-regulated brain protein abundance was associated with obesity. These 52 genes were enriched in metabolic processes, e.g., small molecule metabolic process and metabolic pathways. Fourteen of the 52 genes had high drug repurposing value. Nine of the 52 genes were also associated with obesity at the transcriptome level, suggesting that genetic variants likely confer risk of obesity by regulating mRNA expression and protein abundance of these genes. Conclusions: Our study provides new insights into the genetic component of human brain protein abundance in obesity. The identified proteins represent promising therapeutic targets for future drug development.