Human brain proteome-wide association study provides insights into the genetic components of protein abundance in obesity

Human brain proteome-wide association study provides insights into the genetic components of protein abundance in obesity

Synopsis

Backgrounds

Numerous genetic variations have been linked to obesity by genome-wide association studies. But the majority of loci linked to obesity were still awaiting fresh scientific understanding. We looked into the possibility of mapping obesity-associated genetic variations to brain protein abundances, given the essential role the brain plays in the development of obesity.

Methods

In order to identify genes whose cis-regulated brain protein abundances were associated with obesity-related traits, such as body fat percentage, trunk fat percentage, body mass index, visceral adipose tissue, waist circumference, and waist-to-hip ratio, we conducted proteome-wide association studies (PWAS) and colocalization analyses. Subsequently, we evaluated the genes’ druggability and carried out pathway enrichment analysis to investigate their potential functional significance. Lastly, we assessed the impact of the important PWAS genes on brain transcription.

Results

Through the integration of human brain proteomes from validation datasets (BANNER, N = 198) and discovery datasets (ROSMAP, N = 376), along with genome-wide summary statistics of phenotypes related to obesity (N = 325,153–806,834), we discovered 51 genes whose abundance of cis-regulated brain proteins was linked to obesity. These 51 genes showed enrichment in 11 metabolic activities, including metabolic pathways and small molecule metabolism. Of the 51 genes, 14 indicated a high potential for medication repurposing. A transcriptome analysis revealed that ten of the 51 genes were also linked to obesity, indicating that genetic variations most likely increase the risk of obesity via controlling the mRNA expression and protein abundance of these genes.

Conclusions

Our research sheds fresh light on the genetic basis of the abundance of human brain proteins in obesity. Future drug development may find the discovered proteins to be attractive therapeutic targets.